Clinical Focus


  • Cancer > Hematology
  • Hematology

Academic Appointments


Honors & Awards


  • Charles Dorsey Armstrong Award for Excellence in Patient Care, Stanford Internal Medicine Residency Program (1998)
  • Hematology Division Faculty Teaching Award, Stanford Division of Hematology/Department of Medicine (2005, 2007, 2009)
  • NIH K23 Mentored Patient-Oriented Research Career Development Award (#HL04409), National Institutes of Health (2001-2006)

Professional Education


  • Medical Education: Stanford University School of Medicine (1995) CA
  • Fellowship: Stanford University Hematology and Oncology Fellowship (2003) CA
  • Residency: Stanford University Internal Medicine Residency (1998) CA
  • Internship: Stanford University Internal Medicine Residency (1996) CA
  • Board Certification: American Board of Internal Medicine, Hematology (2001)
  • B.A., Franklin & Marshall College, Biology; HAPOS (1990)
  • M.D., Stanford, Medicine (1995)
  • M.S., Stanford, Clinical Epidemiology (2003)

Current Research and Scholarly Interests


My research interests include phase I/II clinical trial evaluation of novel therapies for the following diseases:
--Myelodysplastic syndromes (MDS)
--Chronic myelogenous leukemia (CML)
--Acute myelogenous leukemia (AML)
--Myeloproliferative disorders (MPDs) including:
Hypereosinophilic syndrome
Systemic mastocytosis
BCR-ABL-negative MPDs

Clinical Trials


  • A Dose Escalation Study of Lenalidomide in Relapsed or Refractory B-cell Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of this study is to evaluate the safety of lenalidomide and to define the maximum tolerated escalation dose level (MTEDL) when administered by a stepwise dose-escalation schedule in subjects with relapsed or refractory B-cell CLL.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • A Dose-escalation Study of the Safety and Tolerability of Orally Administered TG101348 in Patients With Myelofibrosis Not Recruiting

    The purpose of this study is to evaluate the safety and tolerability of orally administered TG101348 in patients with myelofibrosis.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • A Long-Term Study of the Effects of Orally Administered SAR302503 in Patients With Myelofibrosis Not Recruiting

    The purpose of this study is to evaluate the long-term effects of orally administered SAR302503 (TG101348) in patients with myelofibrosis who have completed the MF-TG101348-001 study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • A Phase 2 Study With IPI-926 in Patients With Myelofibrosis Not Recruiting

    The purpose of this study is to determine the safety and efficacy of IPI-926 in patients with myelofibrosis (MF) (primary myelofibrosis [PMF], post-polycythemia vera myelofibrosis [post-PV MF], or post-essential thrombocythemia myelofibrosis [post-ET MF]).

    Stanford is currently not accepting patients for this trial. For more information, please contact Harshdeep Kaur, (650) 723 - 3589.

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  • A Randomized, Double-Blind, Placebo-Controlled Study of Idelalisib in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL) Not Recruiting

    This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of idelalisib in combination with rituximab on the onset, magnitude, and duration of tumor control in participants previously treated for chronic lymphocytic leukemia (CLL). Eligible patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either idelalisib plus rituximab or placebo plus rituximab. Participants who are tolerating primary study therapy but experience definitive CLL progression are eligible to receive active idelalisib therapy in the extension study, GS-US-312-0117.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • A Study of Darbepoetin Alfa in Patients With Myelodysplastic Syndrome (MDS) Not Recruiting

    The primary objectives of the trial are to assess erythroid response to darbepoetin alfa, as determined by changes in hemoglobin and/or red blood cell (RBC) transfusion-dependence and to describe the safety profile of darbepoetin alfa in patients with MDS. The secondary objective is to assess bone marrow progenitor BFU-E growth before and after treatment with darbepoetin alfa.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL Not Recruiting

    This study is to evaluate the safety and clinical activity of idelalisib alone and in combination with rituximab in patients with CLL or SLL. This Phase 2 study will be the first time that idelalisib is administered to previously untreated patients with hematologic malignancies. Idelalisib has demonstrated clinical activity as a single agent in relapsed or refractory CLL and SLL with acceptable toxicity, which supports its evaluation in previously untreated patients. The study population is limited to patients over 65 years of age because younger patients are generally appropriate for standard immunochemotherapy regimens that are highly active. Since the mechanism of action of idelalisib is distinct from rituximab, it is hypothesized that the combination will be more active than either agent alone. This study will establish initial safety and clinical activity of idelalisib in combination with rituximab in patients with CLL or SLL. Cohort 2 of this study will establish safety and clinical activity of idelalisib alone in subjects with untreated CLL or SLL.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML Not Recruiting

    Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.

    Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, 650-725-1647.

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  • An Extension Study for Subjects Who Are Deriving Benefit With Idelalisib (GS-1101; CAL-101) Following Completion of a Prior Idelalisib Study Not Recruiting

    This is a long-term safety extension study of idelalisib (GS-1101; CAL-101) in patients with hematologic malignancies who complete other idelalisib studies. It provides the opportunity for patients to continue treatment as long as the patient is deriving clinical benefit. Patients will be followed according to the standard of care as appropriate for their type of cancer. The dose of idelalisib will generally be the same as the dose that was administered at the end of the prior study, but may be titrated up to improve clinical response or down for toxicity. Patients will be withdrawn from the study if they develop progressive disease, unacceptable toxicity related to idelalisib, or if they no longer derive clinical benefit in the opinion of the investigator.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, 650-725-4041.

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  • Azacitidine and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia Not Recruiting

    This phase II trial is studying the side effects of giving azacitidine together with gemtuzumab ozogamicin to see how well it works in treating older patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Azacitidine may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as gemtuzumab ozogamicin, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving azacitidine together with gemtuzumab ozogamicin may kill more cancer cells.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

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  • Azacitidine With or Without Entinostat in Treating Patients With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia Not Recruiting

    This randomized phase II trial studies azacitidine with or without entinostat to see how well they work compared to azacitidine alone in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Entinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving azacitidine together with entinostat may work better in treating patients with myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Biomarker To Evaluate Protein Profiles of Neutropenic Fever/Infection With Acute or Chronic Leukemias Not Recruiting

    The purpose of this study is to measure, in pilot/observational study, panels of circulating proteins in real time at the onset of neutropenic fever/infection in patients with acute or chronic leukemias undergoing chemotherapy or other biologic treatment. And to generate preliminary trend results in panels of circulating proteins longitudinally during the period of neutropenia and to correlate those values to clinical/laboratory data and patient outcomes.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Bortezomib and Dexamethasone With or Without Lenalidomide in Treating Patients With Multiple Myeloma Previously Treated With Dexamethasone Not Recruiting

    This randomized phase III trial compares bortezomib, dexamethasone, and lenalidomide with bortezomib and dexamethasone to see how well they work in treating patients with multiple myeloma previously treated with dexamethasone. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bortezomib and dexamethasone is more effective with or without lenalidomide in treating multiple myeloma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nancy Mori, (650) 724 - 0201.

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  • Clofarabine, Cytarabine, and Filgrastim in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome, and/or Advanced Myeloproliferative Neoplasm Not Recruiting

    This phase II trial is studying how well giving clofarabine and cytarabine together with filgrastim works in treating patients with newly diagnosed acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS), and/or advanced myeloproliferative neoplasm. Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving the drugs in different doses may kill more cancer cells. Colony stimulating factors, such as filgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating young patients with newly diagnosed acute lymphoblastic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

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  • Compare Bosutinib To Imatinib In Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive CML Not Recruiting

    Two-arm, randomized, open-label trial designed to evaluate the efficacy and safety of bosutinib alone compared to imatinib alone in subjects newly diagnosed with chronic phase Chronic Myelogenous Leukemia (CML). The primary endpoint is cytogenetic response rate at one year.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment: The COMFORT-I Trial Not Recruiting

    This was a randomized, double-blind study comparing the efficacy and safety of ruxolitinib (INCB018424) tablets to matching placebo tablets in patients diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia Not Recruiting

    The purpose of this study is to compare the effects, good and/or bad, of a standard chemotherapy regimen for AML that includes the drugs daunorubicin and cytarabine combined with or without midostaurin (also known as PKC412), to find out which is better. This research is being done because it is unknown whether the addition of midostaurin to chemotherapy treatment is better than chemotherapy treatment alone. Midostaurin has been tested in over 400 patients and is being studied in a number of illnesses, including AML, colon cancer, and lung cancer. Midostaurin blocks an enzyme, produced by a gene known as FLT3, that may have a role in the survival and growth of AML cells. Not all leukemia cells will have the abnormal FLT3 gene. This study will focus only on patients with leukemia cells with the abnormal FLT3 gene.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Determination of Safe and Effective Dose of Romiplostim (AMG 531) in Subjects With Myelodysplastic Syndrome (MDS)Receiving Hypomethylating Agents Not Recruiting

    The purpose of this study is to evaluate the effect of Romiplostim (AMG 531) on the incidence of clinically significant thrombocytopenic events (grade 3 or 4 and/or receipt of platelet transfusions) in subjects with low or intermediate risk Myelodysplastic Syndrome (MDS) receiving hypomethylating agents. It is hypothesized that Romiplostim administration, at the appropriate dose and schedule, will result in reduction in the incidence of clinically significant thrombocytopenic events in low or intermediate risk MDS subjects receiving hypomethylating agents.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Dose Escalation Study of CAL-101 in Select Relapsed or Refractory Hematologic Malignancies Not Recruiting

    The purpose of this study is to determine the dose that can be safely given to see what effect it may have on your cancer and to determine how the drug is distributed in the body.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia Not Recruiting

    The purpose of this study was to determine the efficacy and safety of twice daily (bid) oral midostaurin in patients with Aggressive Systemic Mastocytosis (ASM) or Mast Cell Leukemia (MCL) with or without an Associated Hematological clonal Non-Mast cell lineage Disease (AHNMD).

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Efficacy and Safety of ON 01910.Na in Myelodysplastic Syndrome (MDS) Patients With Trisomy 8 or Classified as Intermediate-1, -2 or High Risk Not Recruiting

    This study will explore the efficacy and safety of a regimen of ON 01910.Na as a 48-hour continuous intravenous infusion once a week for 3 weeks of a 4-week cycle in MDS patients with Trisomy 8 or classified as Intermediate-1, -2 or High Risk who are not responding to current therapeutic options. The rationale for this trial is based upon data from laboratory studies with ON 01910.Na and upon activity that has been observed in other clinical trials with ON 01910.Na in patients with MDS.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis Not Recruiting

    This study is to evaluate the efficacy and safety of simtuzumab (GS-6624) on bone marrow fibrosis either alone or in combination with ruxolitinib in participants with primary myelofibrosis (PMF) and post polycythemia vera or post essential thrombocythemia myelofibrosis (ET/PV MF). The study is designed as a two-stage trial. In the stage 1, participants will be randomized into two cohorts to receive either 200 or 700 mg of study drug. In the stage 2, participants on ruxolitinib will be randomized to receive either 200 or 700 mg of study drug.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Efficacy Study of Oral Sapacitabine to Treat Acute Myeloid Leukemia in Elderly Patients Not Recruiting

    The main objective of this study is to learn which sapacitabine treatment is more likely to keep the cancer in check for at least one year in AML patients who are at least 70 years of age or older and in MDS patients who are at least 60 years of age.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Evaluating the Safety of Long Term Dosing of Romiplostim (Formerly AMG 531) in Thrombocytopenic Subjects With Myelodysplastic Syndromes (MDS) Not Recruiting

    This is an open label extension study of romiplostim for treatment of thrombocytopenia (platelet count ≤ 50 x 10^9/L) in MDS subjects. The study is designed to assess the long-term safety of treatment with romiplostim, as measured by incidence of overall adverse events, the incidence of bleeding events, the utilization of platelet transfusions, and the duration of platelet response. The study will further describe the time to disease progression to acute myeloid leukemia (AML) and survival.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Extension Study Evaluating the Long Term Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET) Not Recruiting

    This extension protocol to the core study CCL09101 allows patients who have tolerated the drug and derived a clinical benefit, to continue to receive treatment beyond the 9 cycles of the core protocol. Long term safety and efficacy of CYT387 (momelotinib) will be evaluated.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4027.

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  • Extension Study of Idelalisib in Participants With Chronic Lymphocytic Leukemia (CLL) Who Participated in GS-US-312-0116 (NCT01539512) Not Recruiting

    The primary objective of this extension study (GS-US-312-0117) that is a companion study to Study GS-US-312-0116 (NCT01539512), is to evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control. Randomization was done in study GS-US-312-0116, and carried forward to study GS-US-312-117.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Integrated Whole-Genome Analysis of Hematologic Disorders Not Recruiting

    We will use new technologies to look at the DNA, RNA, proteins, and metabolites in the disease-containing blood, bone marrow, or tissue and normal cells from the skin. Our goal is to analyze all of the genes in the diseased and normal skin sample. By comparing the results of the diseased sample and normal skin cells and the results of the two types of genetic information (DNA and RNA), we should be able to identify genetic changes that are important for the initiation, progression, or treatment response of that particular disorder.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jason D Merker, 650-922-1885.

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  • Investigation of Dysregulated Signaling in MPD Via Multiparameter Phospho-specific Flow Cytometry Not Recruiting

    The objective of this study is to better understand the underlying pathogenetic mechanisms of myeloproliferative disorders (MPDs). We will collect peripheral blood samples from MPD patients and utilize multiparameter phospho-specific flow cytometry to investigate dysregulated signaling in blood cells from these patients. This will provide deeper insights into the pathogenesis of MPDs and may lead to the identification of novel targets for therapeutic intervention.

    Stanford is currently not accepting patients for this trial. For more information, please contact Stephen Oh, 650-723-7875.

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  • Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia Not Recruiting

    This randomized phase III trial studies lenalidomide to see how well it works with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia. Lenalidomide may stop the growth of myelodysplastic syndrome by blocking blood flow to the cells. Colony stimulating factors, such as epoetin alfa, may increase the number of immune cells found in bone marrow or peripheral blood. It is not yet known whether lenalidomide is more effective with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia Not Recruiting

    An open-label, multicenter, phase 1, dose escalation study of MLN4924 in adult patients with acute myelogenous leukemia (AML), high-grade myelodysplastic syndrome (MDS). The patient population will consist of adults previously diagnosed with AML including high-grade MDS for which standard curative, life-prolonging treatment does not exist or is no longer effective.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Myelodysplastic Syndromes (MDS) Event Free Survival With Iron Chelation Therapy Study Not Recruiting

    This was a randomized, double-blind trial to evaluate deferasirox vs placebo in patients with myelodysplastic syndromes (low/int-1 risk) and transfusional iron overload .The trial was conducted in 17 countries, started in 2010 and ended in 2018.

    Stanford is currently not accepting patients for this trial. For more information, please contact Savita Kamble, (650) 723 - 8594.

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  • Phase 1-2 of Azacitidine + Lenalidomide for Previously Untreated Elderly Patients With Acute Myeloid Leukemia (AML) Not Recruiting

    This study has a phase 1 and a phase 2 component. In phase 1, the objective is to determine the maximum tolerated dose (MTD) of lenalidomide when after azacitidine. In phase 2, the objective is to determine the efficacy of the combination treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Phase 2 Midostaurin in Aggressive Systemic Mastocytosis and Mast Cell Leukemia Not Recruiting

    The safety and efficacy of midostaurin (PKC412), a novel investigational drug, will be evaluated on the basis of response rate, when administered to patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL)

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Phase 2 Study of Temozolomide to Treat Poor Risk / Refractory Acute Myeloid Leukemia Not Recruiting

    Open-label, non-randomized, parallel assignment, phase 2 trial assessing the safety and efficacy of distinct temozolomide treatment regimens for patients with AML and poor prognosis

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma Not Recruiting

    The primary objective was to compare progression-free survival in adults with relapsed multiple myeloma who are receiving CRd vs participants receiving Rd in a randomized multicenter setting.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Phase I Bortezomib (VELCADE) in Combo With Pralatrexate in Relapsed/Refractory MM Not Recruiting

    The purpose of this trial is to find out the maximum tolerated dose (MTD) of bortezomib (VELCADE) in combination with pralatrexate in patients with previously treated multiple myeloma, AL amyloid and Waldenstroem's macroglobulinemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ying Hao, 650-723-0646.

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  • Phase II Study of VELCADE for Relapsed or Refractory T-cell Prolymphocytic Leukemia Not Recruiting

    We hope to learn more about the clinical efficacy of bortezomib in T-cell prolymphocytic leukemia. Patients will be selected as a possible participant in this study because they have a bone marrow disorder known as T-cell prolymphocytic leukemia (T-cell PLL) which does not tend to respond well to conventional treatment with chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • Phase III Study of SAR302503 in Intermediate-2 and High Risk Patients With Myelofibrosis Not Recruiting

    Primary Objective: - To evaluate the efficacy of daily oral doses of 400 mg or 500 mg of SAR302503 (Investigational Medicinal Product, IMP) compared to placebo in the reduction of spleen volume as determined by magnetic resonance imaging (MRI) (or computed tomography scan in patients with contraindications for MRI). Secondary Objectives: - To evaluate the effect on Myelofibrosis (MF)-associated symptoms (key MF symptoms) as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) diary. - To evaluate the Overall Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo. - To evaluate the Progression Free Survival of patients treated with either 400 mg/day or 500 mg/day of IMP as compared to placebo. - To evaluate the durability of splenic response. - To evaluate the safety of IMP.

    Stanford is currently not accepting patients for this trial. For more information, please contact Harshdeep Kaur, (650) 723 - 3589.

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  • Pilot Lenalidomide in Adult Diamond-Blackfan Anemia Patients w/ RBC Transfusion-Dependent Anemia Not Recruiting

    This is a single-center, single arm, open-label study of oral lenalidomide monotherapy administered to red blood cell (RBC) transfusion dependent adult subjects with Diamond-Blackfan Anemia (DBA). Primary Objective: To evaluate the erythroid response rate as measured by rate of red blood cell transfusion independence [MDS International Working Group (IWG) 2000 Criteria will be applied]. Secondary Objective: 1)To evaluate the tolerability and safety profile of lenalidomide in patients with DBA and other inherited marrow failure syndromes 2) To correlate response to lenalidomide with biologic surrogates of DBA including ribosomal protein mutation status, ex vivo erythroid colony growth, and microarray gene expression

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, 650-725-4047.

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  • S0535, Gemtuzumab and Combination Chemotherapy in Treating Patients With Previously Untreated Acute Promyelocytic Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Gemtuzumab may also stop the growth of promyelocytic leukemia by blocking blood flow to the cancer. Giving gemtuzumab together with combination chemotherapy may be more effective in treating promyelocytic leukemia. PURPOSE: This phase II trial is studying how well giving gemtuzumab together with combination chemotherapy works in treating patients with previously untreated promyelocytic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • S0910 Epratuzumab, Cytarabine, and Clofarabine in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia Not Recruiting

    RATIONALE: Monoclonal antibodies, such as epratuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cytarabine and clofarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving epratuzumab together with cytarabine and clofarabine may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects and how well giving epratuzumab together with cytarabine and clofarabine works in treating patients with relapsed or refractory acute lymphoblastic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Safety & Efficacy Study of Oral Panobinostat (LBH589) With Chemotherapy in Patients < 65 Years Old With Acute Myeloid Leukemia (AML) Not Recruiting

    This study will be conducted to assess the maximum tolerated dose (MTD) of panobinostat given 3 times a week (administered on weeks 2 and 3 of a 4 week cycle) in combination with induction chemotherapy (idarubicin and cytarabine) in newly diagnosed patients with a cytopathologically confirmed diagnosis of high-risk AML, and to investigate the safety of the combination in this regimen.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jack Taw, (650) 723 - 2781.

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  • Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET) Not Recruiting

    This study seeks to (i) determine a safe and tolerated dose of CYT387 (momelotinib) given to patients with PMF, post-PV or post-ET and, (ii) assess the effectiveness of orally-administered CYT387 as a treatment for PMF, post-PV or post-ET.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Safety Study of CAT-8015 Immunooxin in Patients With HCL With Advance Disease Not Recruiting

    RATIONALE: The CAT-8015 immunotoxin can bind tumor cells and kill them without harming normal cells. This may be an effective treatment for hairy cell leukemia(HCL) that has not responded to chemotherapy, surgery or radiation therapy. PURPOSE: Phase I dose escalation study to determine the maximum tolerated dose of CAT-8015 immunotoxin in treating patients who have hairy cell leukemia (HCL) that has not responded to treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Safety Study of Human Myeloid Progenitor Cells (CLT-008) After Chemotherapy for Leukemia Not Recruiting

    Ex vivo expanded human myeloid progenitor cells (hMPCs; CLT-008) have the potential to accelerate neutrophil recovery and decrease the risk of febrile neutropenia and infection in patients receiving chemotherapy for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or high-risk myelodysplasia (MDS). In this study, the safety, tolerability and activity of CLT-008 administered after "standard of care" cytarabine-based consolidation or induction/re-induction chemotherapy will be determined by monitoring for adverse reactions, infusion reactions, graft-versus host disease (GVHD), neutrophil and platelet recovery, hMPC persistence, infections and complications.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL Not Recruiting

    This is a Phase II, open-label, non-randomized study to evaluate the safety, efficacy, and pharmacokinetics of tamibarotene in adult patients with relapsed or refractory acute promyelocytic leukemia (APL) following treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Patients must have received and failed therapy with ATRA and ATO. Treatment may have been administered either as combination therapy or sequentially as single agents. Patients who are intolerant to either drug are eligible for this study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Study of Lenalidomide to Evaluate Safety and Efficacy in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of this study is to determine the safety and effectiveness of different dose regimens of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Study to Determine Efficacy and Safety of Lenalidomide Plus Low-dose Dexamethasone Versus Melphalan, Prednisone, Thalidomide in Patients With Previously Untreated Multiple Myeloma Not Recruiting

    The purpose of this study is to compare the safety and efficacy of Lenalidomide plus low dose dexamethasone to that of the combination of melphalan, prednisone and thalidomide.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Study to Determine the Maximum Tolerated Dose and Evaluate the Efficacy and Safety of CEP-18770 (Delanzomib) in Patients With Relapsed Multiple Myeloma Refractory to the Most Recent Therapy Not Recruiting

    The primary objective for part 1 of the study is to determine the maximum tolerated dose (MTD) of CEP-18770 in patients with relapsed and refractory multiple myeloma. The primary objective for part 2 is to evaluate the antitumor activity of CEP-18770 in patients treated at the MTD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Study to Investigate Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 Monoclonal Antibody (mAb) in Participants With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia Not Recruiting

    The primary objective of the study is to evaluate the safety of idelalisib in combination with an anti-CD20 monoclonal antibody (mAb), a chemotherapeutic agent, a mammalian target of rapamycin (mTOR) inhibitor, a protease inhibitor, an antiangiogenic agent, and/or an immunomodulatory agent in participants with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, 650725-4041.

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  • Temozolomide Plus Vorinostat in Relapse/Refractory Acute Myeloid Leukemia (AML) Not Recruiting

    The purpose of the study is to first determine if temozolomide plus vorinostat in combination can control relapsed or refractory acute myeloid leukemia (AML) and determine if this combination can be safely taken. The study will look at the side effects of the Temozolomide plus Vorinostat in combination and whether the treatment schedule is tolerated.

    Stanford is currently not accepting patients for this trial. For more information, please contact Diana Dobbs, 650-736-6295.

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  • To Demonstrate Superiority of Decitabine Over Azacitidine in Subjects With Intermediate- or High-risk MDS. Not Recruiting

    The purpose of this study is to compare the response of patients with Intermediate or High Risk myelodysplastic syndromes (MDS) following treatment with decitabine or azacitidine.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Vorinostat and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia Not Recruiting

    RATIONALE: Vorinostat may stop the growth of cancer cells by interfering with various proteins needed for cell growth. Monoclonal antibodies, such as gemtuzumab ozogamicin (GO), can block cancer growth in different ways. GO finds cancer cells and helps kill them by carrying a cancer-killing substance to them. Giving vorinostat together with gemtuzumab ozogamicin may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving vorinostat together with gemtuzumab ozogamicin works in treating older patients with previously untreated acute myeloid leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin for Older Patients With Relapsed or Refractory AML Not Recruiting

    The purpose of this study is to test the safety of vorinostat (Zolinza) and azacitidine (Vidaza) when combined with gemtuzumab ozogamicin (GO) at different dose levels. These drugs increase the effect of GO against leukemia cells in the test tube, but we don't know yet whether they also increase the anti-leukemia effect of GO in people.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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2021-22 Courses


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  • What your HalphaT says about you. Blood Gotlib, J. 2021; 137 (2): 151–53

    View details for DOI 10.1182/blood.2020008466

    View details for PubMedID 33443557

  • Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis. Theranostics Kluin-Nelemans, H. C., Jawhar, M. n., Reiter, A. n., van Anrooij, B. n., Gotlib, J. n., Hartmann, K. n., Illerhaus, A. n., Oude Elberink, H. N., Gorska, A. n., Niedoszytko, M. n., Lange, M. n., Scaffidi, L. n., Zanotti, R. n., Bonadonna, P. n., Perkins, C. n., Elena, C. n., Malcovati, L. n., Shoumariyeh, K. n., von Bubnoff, N. n., Müller, S. n., Triggiani, M. n., Parente, R. n., Schwaab, J. n., Kundi, M. n., Fortina, A. B., Caroppo, F. n., Brockow, K. n., Zink, A. n., Fuchs, D. n., Angelova-Fischer, I. n., Yavuz, A. S., Doubek, M. n., Mattsson, M. n., Hagglund, H. n., Panse, J. n., Simonowski, A. n., Sabato, V. n., Schug, T. n., Jentzsch, M. n., Breynaert, C. n., Várkonyi, J. n., Kennedy, V. n., Hermine, O. n., Rossignol, J. n., Arock, M. n., Valent, P. n., Sperr, W. R. 2021; 11 (1): 292–303

    Abstract

    In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. Methods: We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Results: Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; p < 0.001). Correspondingly, organomegaly (male: 23% vs. female: 13%, p = 0.007) was more, whereas skin involvement (male: 71% vs. female: 86%, p = 0.001) was less frequent in males. In all patients together, OS (p < 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly (p = 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% vs. 5%, p = 0.006) or molecular aberrations (SRSF2/ASXL1/RUNX1 profile; 63% vs. 40%, p = 0.003) were more frequently present in males. Conclusions: Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.

    View details for DOI 10.7150/thno.51872

    View details for PubMedID 33391475

    View details for PubMedCentralID PMC7681091

  • Proposed global prognostic score for systemic mastocytosis: a retrospective prognostic modelling study. The Lancet. Haematology Muñoz-González, J. I., Álvarez-Twose, I. n., Jara-Acevedo, M. n., Zanotti, R. n., Perkins, C. n., Jawhar, M. n., Sperr, W. R., Shoumariyeh, K. n., Schwaab, J. n., Greiner, G. n., Henriques, A. n., Caldas, C. n., Fernández-Giménez, C. n., Sánchez-Muñoz, L. n., Mayado, A. n., Pérez-Pons, A. n., Schmitt-Graeff, A. n., Duyster, J. n., Tanasi, I. n., Olivieri, F. n., Mora-Casterá, E. n., Luna, I. n., Senent, L. n., Bañas, M. H., Nuñez-García, A. n., Jurado-Chacón, M. n., Martín-Sánchez, G. n., Colado, E. n., Xicoy, B. n., Gener-Ricós, G. n., Gotlib, J. n., Bonadonna, P. n., Reiter, A. n., Valent, P. n., García-Montero, A. C., Orfao, A. n. 2021

    Abstract

    Several risk stratification models have been proposed in recent years for systemic mastocytosis but have not been directly compared. Here we designed and validated a risk stratification model for progression-free survival (PFS) and overall survival (OS) in systemic mastocytosis on the basis of all currently available prognostic factors, and compared its predictive capacity for patient outcome with that of other risk scores.We did a retrospective prognostic modelling study based on patients diagnosed with systemic mastocytosis between March 1, 1983, and Oct 11, 2019. In a discovery cohort of 422 patients from centres of the Spanish Network on Mastocytosis (REMA), we evaluated previously identified, independent prognostic features for prognostic effect on PFS and OS by multivariable analysis, and designed a global prognostic score for mastocytosis (GPSM) aimed at predicting PFS (GPSM-PFS) and OS (GPSM-OS) by including only those variables that showed independent prognostic value (p<0·05). The GPSM scores were validated in an independent cohort of 853 patients from centres in Europe and the USA, and compared with pre-existing risk models in the total patient series (n=1275), with use of Harrells' concordance index (C-index) as a readout of the ability of each model to risk-stratify patients according to survival outcomes.Our GPSM-PFS and GPSM-OS models were based on unique combinations of independent prognostic factors for PFS (platelet count ≤100 × 109 cells per L, serum β2-microglobulin ≥2·5 μg/mL, and serum baseline tryptase ≥125 μg/L) and OS (haemoglobin ≤110 g/L, serum alkaline phosphatase ≥140 IU/L, and at least one mutation in SRSF2, ASXL1, RUNX1, or DNMT3A). The models showed clear discrimination between low-risk and high-risk patients in terms of worse PFS and OS prognoses in the discovery and validation cohorts, and further discrimination of intermediate-risk patients. The GPSM-PFS score was an accurate predictor of PFS in systemic mastocytosis (C-index 0·90 [95% CI 0·87-0·93], vs values ranging from 0·85 to 0·88 for pre-existing models), particularly in non-advanced systemic mastocytosis (C-index 0·85 [0·76-0·92], within the range for pre-existing models of 0·80 to 0·93). Additionally, the GPSM-OS score was able to accurately predict OS in the entire cohort (C-index 0·92 [0·89-0·94], vs 0·67 to 0·90 for pre-existing models), and showed some capacity to predict OS in advanced systemic mastocytosis (C-index 0·72 [0·66-0·78], vs 0·64 to 0·73 for pre-existing models).All evaluated risk classifications predicted survival outcomes in systemic mastocytosis. The REMA-PFS and GPSM-PFS models for PFS, and the International Prognostic Scoring System for advanced systemic mastocytosis and GPSM-OS model for OS emerged as the most accurate models, indicating that robust prognostication might be prospectively achieved on the basis of biomarkers that are accessible in diagnostic laboratories worldwide.Carlos III Health Institute, European Regional Development Fund, Spanish Association of Mastocytosis and Related Diseases, Rare Diseases Strategy of the Spanish National Health System, Junta of Castile and León, Charles and Ann Johnson Foundation, Stanford Cancer Institute Innovation Fund, Austrian Science Fund.

    View details for DOI 10.1016/S2352-3026(20)30400-2

    View details for PubMedID 33508247

  • Routine use of gemtuzumab ozogamicin in 7 + 3-based inductions for all 'non-adverse' risk AML. Leukemia & lymphoma Ladha, A. n., Hui, G. n., Cheung, E. n., Berube, C. n., Coutre, S. E., Gotlib, J. n., Liedtke, M. n., Zhang, T. Y., Muffly, L. n., Mannis, G. N. 2021: 1–6

    View details for DOI 10.1080/10428194.2021.1876869

    View details for PubMedID 33491527

  • Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors Proceedings of the National Academy of Sciences Wernig, G. 2021; 118 (2) (Jan 2021)

    View details for DOI 10.1073/pnas.2017849118

  • Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis THERANOSTICS Kluin-Nelemans, H. C., Jawhar, M., Reiter, A., van Anrooij, B., Gotlib, J., Hartmann, K., Illerhaus, A., Elberink, H., Gorska, A., Niedoszytko, M., Lange, M., Scaffidi, L., Zanotti, R., Bonadonna, P., Perkins, C., Elena, C., Malcovati, L., Shoumariyeh, K., von Bubnoff, N., Mueller, S., Triggiani, M., Parente, R., Schwaab, J., Kundi, M., Fortina, A., Caroppo, F., Brockow, K., Zink, A., Fuchs, D., Angelova-Fischer, I., Yavuz, A., Doubek, M., Mattsson, M., Hagglund, H., Panse, J., Simonowski, A., Sabato, V., Schug, T., Jentzsch, M., Breynaert, C., Varkonyi, J., Kennedy, V., Hermine, O., Rossignol, J., Arock, M., Valent, P., Sperr, W. R. 2021; 11 (1): 292–303

    View details for DOI 10.7150/thno.51872

    View details for Web of Science ID 000582957500019

  • Tuning MPL signaling to influence hematopoietic stem cell differentiation and inhibit essential thrombocythemia progenitors. Proceedings of the National Academy of Sciences of the United States of America Cui, L. n., Moraga, I. n., Lerbs, T. n., Van Neste, C. n., Wilmes, S. n., Tsutsumi, N. n., Trotman-Grant, A. C., Gakovic, M. n., Andrews, S. n., Gotlib, J. n., Darmanis, S. n., Enge, M. n., Quake, S. n., Hitchcock, I. S., Piehler, J. n., Garcia, K. C., Wernig, G. n. 2021; 118 (2)

    Abstract

    Thrombopoietin (TPO) and the TPO-receptor (TPO-R, or c-MPL) are essential for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Agents that can modulate TPO-R signaling are highly desirable for both basic research and clinical utility. We developed a series of surrogate protein ligands for TPO-R, in the form of diabodies (DBs), that homodimerize TPO-R on the cell surface in geometries that are dictated by the DB receptor binding epitope, in effect "tuning" downstream signaling responses. These surrogate ligands exhibit diverse pharmacological properties, inducing graded signaling outputs, from full to partial TPO agonism, thus decoupling the dual functions of TPO/TPO-R. Using single-cell RNA sequencing and HSC self-renewal assays we find that partial agonistic diabodies preserved the stem-like properties of cultured HSCs, but also blocked oncogenic colony formation in essential thrombocythemia (ET) through inverse agonism. Our data suggest that dampening downstream TPO signaling is a powerful approach not only for HSC preservation in culture, but also for inhibiting oncogenic signaling through the TPO-R.

    View details for DOI 10.1073/pnas.2017849118

    View details for PubMedID 33384332

  • Scoring the risk of having systemic mastocytosis in adult patients with mastocytosis in the skin. The journal of allergy and clinical immunology. In practice Fuchs, D., Kilbertus, A., Kofler, K., von Bubnoff, N., Shoumariyeh, K., Zanotti, R., Bonadonna, P., Scaffidi, L., Doubek, M., Elberink, H. O., Span, L. F., Hermine, O., Elena, C., Benvenuti, P., Yavuz, A. S., Brockow, K., Zink, A., Aberer, E., Gorska, A., Romantowski, J., Hadzijusufovic, E., Fortina, A. B., Caroppo, F., Perkins, C., Illerhaus, A., Panse, J., Vucinic, V., Jawhar, M., Sabato, V., Triggiani, M., Parente, R., Bergstrom, A., Breynaert, C., Gotlib, J., Reiter, A., Hartmann, K., Niedoszytko, M., Arock, M., Kluin-Nelemans, H. C., Sperr, W. R., Greul, R., Valent, P. 2020

    Abstract

    BACKGROUND: Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy (BMB) is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a BMB is not performed the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients.OBJECTIVE: To develop a risk score to predict SM in adults with MIS.METHODS: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis (ECNM) registry who underwent a BMB. 944 patients had SM and 201 patients had cutaneous mastocytosis (CM); 63.7% were female, 36.3% were male. Median age was 44±13.3 years. The median serum tryptase level amounted to 29.3±81.9 ng/ml. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver operating curves.RESULTS: In the multivariate model, the tryptase level (p<0.001), constitutional/cardiovascular symptoms (p=0.014) and bone symptoms/osteoporosis (p<0.001) were independent predictors of SM (p<0.001, sensitivity 90.7%, specificity 69.1%). A 6-point risk score was established (risk, 10.7-98.0%) and validated.CONCLUSIONS: Using a large dataset of the ECNM registry we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure CM.

    View details for DOI 10.1016/j.jaip.2020.12.022

    View details for PubMedID 33346151

  • Sustained Complete Molecular Remission With Imatinib Monotherapy in a Child Presenting With Blast Phase FIP1L1-PDGFRA-Associated Myeloid Neoplasm With Eosinophilia. HemaSphere Jain, J., Weinzierl, E. P., Saxe, D., Bergsagel, J., Gotlib, J., Reiter, A., Raikar, S. S. 2020; 4 (6): e486

    View details for DOI 10.1097/HS9.0000000000000486

    View details for PubMedID 33196011

  • Practical Management of Adverse Events in Patients With Advanced Systemic Mastocytosis Receiving Midostaurin. Expert opinion on biological therapy Gotlib, J., Kluin-Nelemans, H. C., Akin, C., Hartmann, K., Valent, P., Reiter, A. 2020

    Abstract

    INTRODUCTION: Systemic mastocytosis (SM) is characterized by the over-production and accumulation of neoplastic mast cells (MCs) in the bone marrow, skin, and visceral organs. The KIT D816V mutation is found in approximately 90% of cases. In advanced SM (advSM), inferior survival often relates to MC-induced organ damage that may impact multiple organ systems. In addition, mediator symptoms related to MC activation can severely impact quality of life. The oral multikinase/KIT inhibitor midostaurin was approved by the US Food and Drug Administration and the European Medicines Agency as monotherapy for advSM based on data from phase 2 clinical studies.AREAS COVERED: This review discusses the management of common adverse events (AEs) in patients with advSM who participated in phase 2 clinical studies that led to the approval of midostaurin.EXPERT OPINION: In the advSM population undergoing treatment with midostaurin, treatment-related AEs are often difficult to distinguish from disease-related symptoms, which can lead to premature discontinuation and improper dose reduction of midostaurin therapy in patients who might have benefitted from continued therapy. Here we present strategies to help optimize AE management and maximize the potential benefits of midostaurin in advSM.

    View details for DOI 10.1080/14712598.2021.1837109

    View details for PubMedID 33063554

  • Core-binding factor acute myeloid leukemia with inv(16): Older age and high white blood cell count are risk factors for treatment failure. International journal of laboratory hematology Ustun, C., Morgan, E. A., Ritz, E. M., Vestergaard, H., Pullarkat, S., Kluin, P. M., Ohgami, R., Baughn, L. B., Kim, Y., Ku, N. K., Czuchlewski, D., Boe Moller, M., Schiefer, A., Mrozek, K., Horny, H., George, T. I., Kielsgaard Kristensen, T., Beck, T., Nathan, S., Arana Yi, C., Yeung, C., Pullarkat, V., Gotlib, J., Akin, C., Kohlschmidt, J., Salhotra, A., Soma, L., Chen, D., Han, S. Y., Cho, C., Sperr, W., Broesby-Olsen, S., Linden, M. A., Dolan, M., Hoermann, G., Hornick, J. L., Bloomfield, C., Nakamura, R., Joachim Deeg, H., Litzow, M. R., Borthakur, G., Weisdorf, D., Huls, G., Perales, M., Valent, P., Marcucci, G. 2020

    View details for DOI 10.1111/ijlh.13338

    View details for PubMedID 32926565

  • Dynamic and Time-To-Event Analyses Demonstrate Marked Reduction in Transfusion Requirements for Janus Kinase Inhibitor-Naive Myelofibrosis Patients Treated with Momelotinib Compared Head to Head with Ruxolitinib McLornan, D., Mesa, R., Catalano, J., Cervantes, F., Devos, T., Egyed, M., Gotlib, J., Kiladjian, J., Oh, S., Shimoda, K., Coart, E., D'Hollander, K., Donahue, R., Kowalski, M. CIG MEDIA GROUP, LP. 2020: S329–S330
  • Real-World Outcomes of Ruxolitinib Treatment for Polycythemia Vera. Clinical lymphoma, myeloma & leukemia Coltoff, A., Mesa, R., Gotlib, J., Shulman, J., Rampal, R. K., Siwoski, O., Yacoub, A., Moliterno, A., Yang, A., Braunstein, E., Gerds, A. T., Hobbs, G. S., Winton, E. F., Goel, S., Wadleigh, M., Tremblay, D., Moshier, E., Mascarenhas, J. 2020

    Abstract

    INTRODUCTION: Ruxolitinib is approved for the treatment of polycythemia vera (PV) with hydroxyurea resistance or intolerance. Approval was based on the phase III RESPONSE trial, which demonstrated efficacy in a highly selected patient population.MATERIALS AND METHODS: To characterize the tolerability and outcomes of ruxolitinib outside of a clinical trial, we performed a multi-center retrospective analysis of patients with PV treated with ruxolitinib at 11 participating sites across the United States. Outcomes of interest included change in phlebotomy requirements after starting ruxolitinib and spleen response, as these were included in the primary composite outcome in the RESPONSE trial.RESULTS: One hundred twenty-six patients met eligibility criteria, and the median duration of follow-up was 22.4 months (range, 0-63.0 months). At 32 weeks after starting ruxolitinib, the percentage of patients who received at least 1 phlebotomy was significantly decreased compared with before ruxolitinib (37% vs. 56%; relative risk [RR], 0.66; 95% confidence interval [CI], 0.52-0.84; P< .001). Phlebotomy requirements were similarly decreased in patients who had received at least 3 phlebotomies prior to ruxolitinib initiation (28% vs. 17%; RR, 1.65; 95% CI, 1.13-2.40; P< .01). Resolution of palpable splenomegaly was also documented (48% vs. 20%; RR, 2.45; 95% CI, 1.70-3.53; P< .0001). A total of 9.5% of patients discontinued ruxolitinib owing to treatment-emergent adverse events, and 81.7% of patients were receiving ruxolitinib at last known follow-up.CONCLUSION: These real-world results are similar to those reported from the RESPONSE trial, although additional follow-up is necessary to assess long-term outcomes and potential for late-onset toxicity.

    View details for DOI 10.1016/j.clml.2020.05.019

    View details for PubMedID 32624445

  • Non-hematologic diagnosis of systemic mastocytosis: Collaboration of radiology and pathology. Blood reviews Ozturk, K., Cayci, Z., Gotlib, J., Akin, C., George, T. I., Ustun, C. 2020: 100693

    Abstract

    Systemic mastocytosis (SM) is a hematologic disease with a wide range of clinical courses ranging from an indolent condition with normal life expectancy to exceedingly aggressive disorder with a poor prognosis. The symptoms and signs of SM result from the release of mast cell mediators with heterogeneous functions, and/or organ damage from neoplastic mast cell infiltration, or both. Diagnostic criteria for SM are well-defined by the World Health Organization (WHO). However, the diagnosis of SM can be difficult when especially it is not in the differential diagnosis. Routinely used radiologic techniques (e.g., X-ray, ultrasound, CT scans can show findings such as lytic-, sclerotic- or mixed-bone lesions, splenomegaly, hepatomegaly, retroperitoneal or periportal mesenteric lymphadenopathy, and omental thickening). It is essential to emphasize that the constellation of these radiologic findings should strongly concern of SM, especially in patients who also have a skin rash, allergic reactions, gastrointestinal tract symptoms (lasting, intermittent nausea, diarrhea), paroxysmal tachycardias, unexplained weight loss, persistent bone pain, cytopenias, liver dysfunction, eosinophilia. These findings, even coincidentally noted, will likely lead to a tissue biopsy, which reveals diagnosis (as we discussed and illustrated some tissue biopsies here). Moreover, the role of MRI and new techniques such as [18-fluorodeoxyglucose positron emission computed tomography, fibroscan] in the diagnosis of SM have been discussed. Furthermore, we reviewed the use of radiologic methods to evaluate treatment response and prognostication of SM..

    View details for DOI 10.1016/j.blre.2020.100693

    View details for PubMedID 32334853

  • Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis. Blood Ronner, L., Podoltsev, N., Gotlib, J., Heaney, M. L., Kuykendall, A. T., O'Connell, C., Shammo, J., Fleischman, A. G., Scherber, R. M., Mesa, R., Yacoub, A., Perkins, C., Meckstroth, S., Behlman, L., Chiaramonte, M., Salehi, M., Ziadkhanpour, K., Nguyen, H., Siwoski, O., Hung, A. K., Janania Martinez, M., Nguyen, J., Patel, S., Kollipara, R., Dave, A., Randall, M., Grant, M., Harrison, M., Fernandez Soto, P., Tremblay, D., Hoffman, R., Moshier, E. L., Mascarenhas, J. 2020

    Abstract

    There are unresolved questions regarding the association between persistent leukocytosis and risk of thrombosis and disease evolution in polycythemia vera (PV), as much of the published literature on the topic does not appropriately utilize repeated measures data or time-dependent modeling to answer these questions. To address this knowledge gap, we analyzed a retrospective database of 520 PV patients seen at 10 academic institutions across the United States. Taking hematologic lab data at approximate 3-month intervals (or as available) for all patients for duration of follow-up, we used group-based trajectory modeling (GBTM) to identify latent clusters of patients who follow distinct trajectories with regards to their leukocyte, hematocrit, and platelet counts over time. We then tested the association between trajectory membership and hazard of two major outcomes: thrombosis and disease evolution to myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia. Controlling for relevant covariates, we found that persistently elevated leukocyte trajectories were not associated with hazard of thrombotic event (p = 0.4163), but were significantly associated with increased hazard of disease evolution in an ascending stepwise manner (overall p = 0.0002). Additionally, we found that neither hematocrit nor platelet count were significantly associated with hazard of thrombosis or disease evolution.

    View details for DOI 10.1182/blood.2019003347

    View details for PubMedID 32107559

  • MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis Jawhar, M., Schwaab, J., Alvarez-Twose, I., Shoumariyeh, K., Naumann, N., Luebke, J., Perkins, C., Munoz-Gonzalez, J. I., Meggendorfer, M., Kennedy, V., Metzgeroth, G., Fabarius, A., Pfeifer, D., Sotlar, K., Horny, H., von Bubnoff, N., Haferlach, T., Cross, N. P., Hofmann, W., Sperr, W. R., Garcia-Montero, A. C., Valent, P., Gotlib, J., Orfao, A., Reiter, A. KARGER. 2020: 107–8
  • Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Deininger, M. W., Shah, N. P., Altman, J. K., Berman, E., Bhatia, R., Bhatnagar, B., DeAngelo, D. J., Gotlib, J., Hobbs, G., Maness, L., Mead, M., Metheny, L., Mohan, S., Moore, J. O., Naqvi, K., Oehler, V., Pallera, A. M., Patnaik, M., Pratz, K., Pusic, I., Rose, M. G., Smith, B. D., Snyder, D. S., Sweet, K. L., Talpaz, M., Thompson, J., Yang, D. T., Gregory, K. M., Sundar, H. 2020; 18 (10): 1385–1415

    Abstract

    Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

    View details for DOI 10.6004/jnccn.2020.0047

    View details for PubMedID 33022644

  • Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis. The Journal of allergy and clinical immunology Hartmann, K. n., Gotlib, J. n., Akin, C. n., Hermine, O. n., Awan, F. T., Hexner, E. n., Mauro, M. J., Menssen, H. D., Redhu, S. n., Knoll, S. n., Sotlar, K. n., George, T. I., Horny, H. P., Valent, P. n., Reiter, A. n., Kluin-Nelemans, H. C. 2020

    Abstract

    Advanced systemic mastocytosis (advSM) is characterized by the presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage, eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss. Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level.We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM.In 116 patients with SM (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study, NCT00782067), QOL and symptom burden were assessed during treatment with midostaurin using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale (MSAS) patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated using a specific physician-reported questionnaire.Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and MSAS scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms.QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM. (ClinicalTrials.gov number, NCT00782067).

    View details for DOI 10.1016/j.jaci.2020.03.044

    View details for PubMedID 32437738

  • Venetoclax and hypomethylating agent therapy in high risk myelodysplastic syndromes: a retrospective evaluation of a real-world experience. Leukemia & lymphoma Azizi, A. n., Ediriwickrema, A. n., Dutta, R. n., Patel, S. A., Shomali, W. n., Medeiros, B. n., Iberri, D. n., Gotlib, J. n., Mannis, G. n., Greenberg, P. n., Majeti, R. n., Zhang, T. n. 2020: 1–8

    Abstract

    Treatment with hypomethylating agents (HMAs) azacitidine or decitabine is the current standard of care for high risk myelodysplastic syndromes (MDSs) but is associated with low rates of response. The limited number of treatment options for patients with high risk MDS highlights a need for new therapeutic options. Venetoclax is an inhibitor of the BCL-2 protein which, when combined with an HMA, has shown high response rates in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of high risk MDS patients receiving combination HMA plus venetoclax in order to determine their effectiveness in this context. We show that in our cohort, the combination results in high response rates but is associated with a high frequency of myelosuppression. These data highlight the efficacy of combination HMA plus venetoclax in high risk MDS, warranting further prospective evaluation in clinical trials.

    View details for DOI 10.1080/10428194.2020.1775214

    View details for PubMedID 32543932

  • Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network : JNCCN Gerds, A. T., Gotlib, J., Bose, P., Deininger, M. W., Dunbar, A., Elshoury, A., George, T. I., Gojo, I., Gundabolu, K., Hexner, E., Hobbs, G., Jain, T., Jamieson, C., Kuykendall, A. T., McMahon, B., Mohan, S. R., Oehler, V., Oh, S., Pardanani, A., Podoltsev, N., Ranheim, E., Rein, L., Salit, R., Snyder, D. S., Stein, B. L., Talpaz, M., Thota, S., Vachhani, P., Wadleigh, M., Walsh, K., Ward, D. C., Bergman, M. A., Sundar, H. 2020; 18 (9): 1248–69

    Abstract

    Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

    View details for DOI 10.6004/jnccn.2020.0042

    View details for PubMedID 32886902

  • Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts. Theranostics Valent, P., Akin, C., Hartmann, K., Nilsson, G., Reiter, A., Hermine, O., Sotlar, K., Sperr, W. R., Escribano, L., George, T. I., Kluin-Nelemans, H. C., Ustun, C., Triggiani, M., Brockow, K., Gotlib, J., Orfao, A., Kovanen, P. T., Hadzijusufovic, E., Sadovnik, I., Horny, H., Arock, M., Schwartz, L. B., Austen, K. F., Metcalfe, D. D., Galli, S. J. 2020; 10 (23): 10743–68

    Abstract

    The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.

    View details for DOI 10.7150/thno.46719

    View details for PubMedID 32929378

  • Risk and Management of Patients with Mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) Pandemic: Expert Opinions. The Journal of allergy and clinical immunology Valent, P. n., Akin, C. n., Bonadonna, P. n., Brockow, K. n., Niedoszytko, M. n., Nedoszytko, B. n., Butterfield, J. H., Alvarez-Twose, I. n., Sotlar, K. n., Schwaab, J. n., Jawhar, M. n., Reiter, A. n., Castells, M. n., Sperr, W. R., Kluin-Nelemans, H. C., Hermine, O. n., Gotlib, J. n., Zanotti, R. n., Broesby-Olsen, S. n., Horny, H. P., Triggiani, M. n., Siebenhaar, F. n., Orfao, A. n., Metcalfe, D. D., Arock, M. n., Hartmann, K. n. 2020

    Abstract

    The COVID-19 (SARS-CoV-2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase and patients at risk can only be protected to a degree, since the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here within, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. As no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Whereas the overall risk to acquire the SARS-CoV-2 virus may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain co-morbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. By contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.

    View details for DOI 10.1016/j.jaci.2020.06.009

    View details for PubMedID 32561389

  • Clinical Features and Survival of Patients with Indolent Systemic Mastocytosis defined by the Updated WHO Classification. Allergy Trizuljak, J. n., Sperr, W. R., Nekvindová, L. n., Oude Elberink, H. n., Gleixner, K. V., Gorska, A. n., Lange, M. n., Hartmann, K. n., Illerhaus, A. n., Bonifacio, M. n., Perkins, C. n., Elena, C. n., Malcovati, L. n., Belloni Fortina, A. n., Shoumariyeh, K. n., Jawhar, M. n., Zanotti, R. n., Bonadonna, P. n., Caroppo, F. n., Zink, A. n., Triggiani, M. n., Parente, R. n., von Bubnoff, N. n., Selim Yavuz, A. n., Hägglund, H. n., Mattsson, M. n., Panse, J. n., Jäkel, N. n., Kilbertus, A. n., Hermine, O. n., Arock, M. n., Fuchs, D. n., Sabato, V. n., Brockow, K. n., Bretterklieber, A. n., Niedoszytko, M. n., van Anrooij, B. n., Reiter, A. n., Gotlib, J. n., Kluin-Nelemans, H. C., Mayer, J. n., Doubek, M. n., Valent, P. n. 2020

    Abstract

    In indolent systemic mastocytosis (ISM) several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM.We employed a data set of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM.We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM) and smouldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status and organomegaly.Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.

    View details for DOI 10.1111/all.14248

    View details for PubMedID 32108361

  • New Developments in Diagnosis, Prognostication, and Treatment of Advanced Systemic Mastocytosis. Blood Reiter, A. n., George, T. I., Gotlib, J. R. 2020

    Abstract

    Systemic mastocytosis (SM) has greatly benefited from the broad application of precision medicine techniques to hematolymphoid neoplasms. Sensitive detection of the recurrent KIT D816V mutation and use of next generation sequencing (NGS) panels to profile the genetic landscape of SM variants have been critical adjuncts to the diagnosis of SM, subclassification of SM, and development of clinical-molecular prognostic scoring systems. Multilineage KIT involvement and multi-mutated clones are characteristic of advanced SM, especially SM with an associated hematologic neoplasm (SM-AHN). A major challenge is how to integrate conventional markers of mast cell disease burden (percent bone marrow mast cell infiltration, serum tryptase levels) with molecular data (e.g. serial monitoring of both KIT D816V variant allele frequency and NGS panels) to lend more diagnostic and prognostic clarity to the heterogeneous clinical presentations and natural histories of advanced SM. The approval of the multikinase / KIT inhibitor midostaurin has validated the paradigm of KIT inhibition in advanced SM, while the efficacy and safety of 2nd generation agents, such as the switch-control inhibitor ripretinib (DCC-2618) and the D816V-selective inhibitor avapritinib (BLU-285) are being further defined in ongoing clinical trials. Looking forward, perhaps the most fruitful marriage of the advances in molecular genetics and treatment will be the design of adaptive basket trials that combine histopathology and genetic profiling to individualize treatment approaches for patients with diverse AHNs and relapsed/refractory SM.

    View details for DOI 10.1182/blood.2019000932

    View details for PubMedID 32106312

  • New developments in the field of mastocytosis and mast cell activation syndromes: a summary of the Annual Meeting of the European Competence Network on Mastocytosis (ECNM) 2019. Leukemia & lymphoma Arock, M., Sotlar, K., Gotlib, J., Sperr, W. R., Hartmann, K., Schwartz, L. B., Akin, C., Horny, H., Valent, P. 2019: 1–9

    Abstract

    Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical mast cells in one or several organs/tissues, often accompanied by mast cell activation. Whereas in children the disease manifestations are mostly limited to the skin, in adults the disease is usually systemic (systemic mastocytosis; SM) and involves the bone marrow and/or other internal organs. Several variants of SM have been defined. Whereas most patients have indolent SM, some patients have advanced SM, which underlines the complexity of SM. In 2002, a European consortium of clinicians and scientists initiated a multidisciplinary, multi-national cooperative network, termed the 'European Competence Network on Mastocytosis' (ECNM), with the aim to improve diagnosis and therapy of patients with mastocytosis and other mast cell activation disorders. Since then, members of the ECNM have organized Annual Meetings in several European countries. The present article provides a summary of advances in the field presented during the 17th Annual ECNM meeting held in Salzburg in October 2019.

    View details for DOI 10.1080/10428194.2019.1703974

    View details for PubMedID 31876203

  • Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry. Leukemia Kluin-Nelemans, H. C., Reiter, A., Illerhaus, A., van Anrooij, B., Hartmann, K., Span, L. F., Gorska, A., Niedoszytko, M., Lange, M., Scaffidi, L., Zanotti, R., Bonadonna, P., Perkins, C., Elena, C., Malcovati, L., Shoumariyeh, K., von Bubnoff, N., Parente, R., Triggiani, M., Schwaab, J., Jawhar, M., Caroppo, F., Fortina, A. B., Brockow, K., Zink, A., Fuchs, D., Kilbertus, A., Yavuz, A. S., Doubek, M., Mattsson, M., Hagglund, H., Panse, J., Sabato, V., Aberer, E., Niederwieser, D., Breynaert, C., Varkonyi, J., Kennedy, V., Lortholary, O., Jakob, T., Hermine, O., Rossignol, J., Arock, M., Gotlib, J., Valent, P., Sperr, W. R. 2019

    Abstract

    Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5*109/l), and 3.1% hypereosinophilia (HE; >1.5*109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p<0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n=1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.

    View details for DOI 10.1038/s41375-019-0632-4

    View details for PubMedID 31740811

  • International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study. The Lancet. Haematology Sperr, W. R., Kundi, M., Alvarez-Twose, I., van Anrooij, B., Oude Elberink, J. N., Gorska, A., Niedoszytko, M., Gleixner, K. V., Hadzijusufovic, E., Zanotti, R., Bonadonna, P., Bonifacio, M., Perkins, C., Illerhaus, A., Elena, C., Merante, S., Shoumariyeh, K., von Bubnoff, N., Parente, R., Jawhar, M., Belloni Fortina, A., Caroppo, F., Brockow, K., Zink, A., Fuchs, D., Kilbertus, A. J., Yavuz, A. S., Doubek, M., Hagglund, H., Panse, J., Sabato, V., Bretterklieber, A., Niederwieser, D., Breynaert, C., Hartmann, K., Triggiani, M., Nedoszytko, B., Reiter, A., Orfao, A., Hermine, O., Gotlib, J., Arock, M., Kluin-Nelemans, H. C., Valent, P. 2019

    Abstract

    BACKGROUND: The WHO classification separates mastocytosis into distinct variants, but prognostication remains a clinical challenge. The aim of this study was to improve prognostication for patients with mastocytosis.METHODS: We analysed data of the registry of the European Competence Network on Mastocytosis including 1639 patients (age 17-90 years) diagnosed with mastocytosis according to WHO criteria between Jan 12, 1978, and March 16, 2017. Univariate and multivariate analyses with Cox regression were applied to identify prognostic variables predicting survival outcomes and to establish a prognostic score. We validated this International Prognostic Scoring System in Mastocytosis (IPSM) with data of 462 patients (age 17-79 years) from the Spanish network Red Espanola de Mastocitosis diagnosed between Jan 22, 1998, and Nov 2, 2017.FINDINGS: The prognostic value of the WHO classification was confirmed in our study (p<0·0001). For patients with non-advanced mastocytosis (n=1380), we identified age 60 years or older (HR 10·75, 95% CI 5·68-20·32) and a concentration of alkaline phosphatase 100 U/L or higher (2·91, 1·60-5·30) as additional independent prognostic variables for overall survival. The resulting scoring system divided patients with non-advanced mastocytosis into three groups: low (no risk factors), intermediate 1 (one risk factor), and intermediate 2 (two risk factors). Overall survival and progression-free survival differed significantly among these groups (p<0·0001). In patients with advanced mastocytosis (n=259), age 60 years or older (HR 2·14, 95% CI 1·42-3·22), a concentration of tryptase 125 ng/mL or higher (1·81, 1·20-2·75), a leukocyte count of 16 * 109 per L or higher (1·88, 1·27-2·79), haemoglobin of 11 g/dL or lower (1·71, 1·13-2·57), a platelet count of 100 * 109 per L or lower (1·63, 1·13-2·34), and skin involvement (0·46, 0·30-0·69) were prognostic variables. Based on these variables, a separate score for advanced mastocytosis with four risk categories was established, with significantly different outcomes for overall survival and progression-free survival (p<0·0001). The prognostic value of both scores was confirmed in 413 patients with non-advanced disease and 49 with advanced mastocytosis from the validation cohort.INTERPRETATION: The IPSM scores for patients with non-advanced and advanced mastocytosis can be used to predict survival outcomes and guide treatment decisions. However, the predictive value of the IPSM needs to be confirmed in forthcoming trials.FUNDING: Austrian Science Fund, Deutsche Forschungsgemeinschaft, Koeln Fortune Program, Charles and Ann Johnson Foundation, Instituto de Salud Carlos III, Fondos FEDER, Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek, Clinical Research-Fund of the University Hospitals Leuven, and Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek.

    View details for DOI 10.1016/S2352-3026(19)30166-8

    View details for PubMedID 31676322

  • Impact of bone marrow fibrosis grade in post-polycythemia vera and post-essential thrombocythemia myelofibrosis. A study of the MYSEC group. American journal of hematology Mora, B., Guglielmelli, P., Rumi, E., Maffioli, M., Barraco, D., Rambaldi, A., Caramella, M., Komrokji, R. S., Kiladjian, J., Gotlib, J., Iurlo, A., Cervantes, F., Devos, T., Palandri, F., De Stefano, V., Ruggeri, M., Silver, R. T., Albano, F., Benevolo, G., Cavalloni, C., Uccella, S., Accetta, R., Siracusa, C., Agnoli, S., Merli, M., Barbui, T., Berto, L., Cazzola, M., Vannucchi, A. M., Passamonti, F. 2019

    View details for DOI 10.1002/ajh.25644

    View details for PubMedID 31588594

  • A phase 2 study of brentuximab vedotin in patients with CD30-positive advanced systemic mastocytosis. Blood advances Gotlib, J., Baird, J. H., George, T. I., Langford, C., Reyes, I., Abuel, J., Perkins, C., Schroeder, K., Bose, P., Verstovsek, S. 2019; 3 (15): 2264–71

    Abstract

    There is an unmet need for effective therapies for advanced systemic mastocytosis (advSM). CD30 is expressed on the surface of neoplastic mast cells (MC) in more than 50% of patients with advSM. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate with preclinical evidence supporting both an antineoplastic effect and an attenuation of immunoglobulin E-associated mediator release. These observations are the basis for this phase 2 trial of BV monotherapy (1.8 mg/kg IV every 3 weeks up to 8 cycles) in patients with CD30-positive advSM. The primary objective was to determine the efficacy of BV according to International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) response criteria. Secondary objectives included evaluation of safety, changes in bone marrow (BM) MC burden, serum tryptase level, flow cytometric quantification of MC surface expression of CD30, and self-reported symptom burden. The trial enrolled 10 patients with a diagnosis of CD30+ advSM (aggressive SM, SM with an associated hematologic neoplasm [SM-AHN], or mast cell leukemia [MCL]) with 1 or more signs of SM-related organ damage. According to IWG-MRT-ECNM criteria, none of the patients demonstrated better than stable disease with BV. In addition, there were no significant reductions in BM MC burden, serum tryptase levels, or MC surface expression of CD30. Self-reported symptom scores showed no durable improvement with BV treatment. We conclude that BV is not active as a single agent in CD30+ advSM. This trial was registered at www.clinicaltrials.gov as #NCT01807598.

    View details for DOI 10.1182/bloodadvances.2019000152

    View details for PubMedID 31350306

  • Genomic landscape of Neutrophilic Leukemias of Ambiguous Diagnosis. Blood Zhang, H., Wilmot, B., Bottomly, D., Dao, K. T., Stevens, E., Eide, C. A., Khanna, V., Rofelty, A., Savage, S., Reister-Schultz, A., Long, N., White, L., Carlos, A., Henson, R. A., Lin, C., Searles, R., Collins, R. H., DeAngelo, D. J., Deininger, M. W., Dunn, T., Than, H., Luskin, M. R., Medeiros, B. C., Oh, S. T., Pollyea, D. A., Steensma, D. P., Stone, R. M., Druker, B. J., McWeeney, S. K., Maxson, J. E., Gotlib, J. R., Tyner, J. W. 2019

    Abstract

    Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare, heterogeneous myeloid disorders. There is strong morphologic resemblance amongst these distinct diagnostic entities as well as lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole exome and RNA-sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not co-segregation of clinical and genetic disease features with transcriptional clusters. In conclusion, these group of diseases represent a continuum of related diseases rather than discrete diagnostic entities.

    View details for DOI 10.1182/blood.2019000611

    View details for PubMedID 31366621

  • MYC regulates the HIF-2alpha stemness pathway via Nanog and Sox2 to maintain self-renewal in cancer stem cells versus non-stem cancer cells. Cancer research Das, B., Pal, B., Bhuyan, R., Li, H., Sarma, A., Gayan, S., Talukdar, J., Sandhya, S., Bhuyan, S., Gogoi, G., Gouw, A. M., Baishya, D., Gotlib, J. R., Kataki, A. C., Felsher, D. W. 2019

    Abstract

    Cancer stem cells (CSC) maintain both undifferentiated self-renewing CSCs and differentiated, non-self-renewing non-CSCs through cellular division. However, molecular mechanisms that maintain self-renewal in CSCs versus non-CSCs are not yet clear. Here, we report that in a transgenic mouse model of MYC-induced T cell leukemia, MYC maintains self-renewal in Sca1+ CSCs versus Sca-1- non-CSCs. MYC preferentially bound to the promoter and activated HIF-2alpha in Sca-1+ cells only. Further, the reprogramming factors Nanog and Sox2 facilitated MYC regulation of HIF-2alpha in Sca-1+ versus Sca-1- cells. Reduced expression of HIF-2alpha inhibited the self-renewal of Sca-1+ cells; this effect was blocked through suppression of reactive oxygen species (ROS) by N-acetyl cysteine (NAC) or the knock down of p53, Nanog or Sox2. Similar results were seen in ABCG2+ CSCs versus ABCG2- non-CSCs from primary human T cell lymphoma. Thus, MYC maintains self-renewal exclusively in CSCs by selectively binding to the promoter and activating the HIF-2alpha stemness pathway. Identification of this stemness pathway as a unique CSC determinant may have significant therapeutic implications.

    View details for DOI 10.1158/0008-5472.CAN-18-2847

    View details for PubMedID 31266772

  • Revisiting diagnostic criteria for myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis: Borderline cases without anemia exist INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Li, P., Shahmarvand, N., Lynch, D., Gotlib, J. R., Merker, J. D., Zehnder, J. L., George, T., Ohgami, R. S. 2019; 41 (3): 345–52

    View details for DOI 10.1111/ijlh.12981

    View details for Web of Science ID 000468370800013

  • Emerging translational science discoveries, clonal approaches and treatment trends in chronic myeloproliferative neoplasms. Hematological oncology Mughal, T. I., Pemmaraju, N., Radich, J. P., Deininger, M. W., Kucine, N., Kiladjian, J., Bose, P., Gotlib, J., Valent, P., Chen, C., Barbui, T., Rampal, R., Verstovsek, S., Koschmieder, S., Saglio, G., Van Etten, R. A. 2019

    Abstract

    The 60th American Society of Hematology (ASH) held in San Diego in December 2018 was followed by the 13th Post-ASH chronic myeloproliferative neoplasms (MPNs) workshop on the 4th -5th December 2018. This closed annual workshop, first introduced in 2006 by Goldman and Mughal, was organized in collaboration with Alpine Oncology Foundation and allowed experts in preclinical and clinical research in the chronic MPNs to discuss the current scenario, including relevant presentations at ASH, and address pivotal open questions that impact translational research and clinical management. This review is based on the presentations and deliberations at this workshop, and rather than provide a resume of the proceedings, we have selected some of the important translational science and treatment issues which require clarity. We discuss the experimental and observational evidence to support the intimate interaction between aging, inflammation, and clonal evolution of MPNs, the clinical impact of the unfolding mutational landscape on the emerging targets and treatment of MPNs, new methods to detect clonal heterogeneity, the challenges in managing childhood and adolescent MPN, and reflect on the treatment of systemic mastocytosis (SM) following the licensing of midostaurin.

    View details for DOI 10.1002/hon.2622

    View details for PubMedID 31013548

  • Predictive models for splenic response to JAK-inhibitor therapy in patients with myelofibrosis LEUKEMIA & LYMPHOMA Menghrajani, K., Boonstra, P. S., Mercer, J. A., Perkins, C., Gowin, K. L., Weber, A. A., Mesa, R., Gotlib, J. R., Wang, L., Singer, J. W., Talpaz, M. 2019; 60 (4): 1036–42

    Abstract

    JAK inhibitors for myelofibrosis (MF) reduce spleen size, control constitutional symptoms, and may improve survival. We studied the clinical characteristics of 548 MF patients treated with JAK inhibitors from 2008 to 2016 to better understand predictors of splenic response. Response was defined as a 50% decrease in spleen size at early (3-4 months on therapy) and late (5-12 months) timepoints after therapy initiation. Early response positively correlated with higher doses of JAK inhibitor, baseline spleen size 5-10 cm, and hemoglobin. Early response negatively correlated with baseline spleen size >20 cm and high WBC. The strongest predictor of late response was whether a patient had a response at the earlier timepoint (OR 8.88). Our response models suggest that clinical factors can be used to predict which patients are more likely to respond to JAK inhibitors, and those who do not achieve an early response, i.e. within 3-4 months, should consider alternative treatments.

    View details for DOI 10.1080/10428194.2018.1509315

    View details for Web of Science ID 000463807800023

    View details for PubMedID 30234400

    View details for PubMedCentralID PMC6426689

  • TIM3 and Galectin-9 are Novel Therapeutic Targets for Mastocytosis Williams, M., George, T., Tripp, S., Deininger, M., Gotlib, J., Hartmann, K. NATURE PUBLISHING GROUP. 2019
  • TIM3 and Galectin-9 are Novel Therapeutic Targets for Mastocytosis Williams, M., George, T., Tripp, S., Deininger, M., Gotlib, J., Hartmann, K. NATURE PUBLISHING GROUP. 2019
  • Revisiting diagnostic criteria for myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis: Borderline cases without anemia exist. International journal of laboratory hematology Li, P., Shahmarvand, N., Lynch, D., Gotlib, J. R., Merker, J. D., Zehnder, J. L., George, T. I., Ohgami, R. S. 2019

    Abstract

    INTRODUCTION: Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease in the 2016 revised World Health Organization (WHO) classification. Diagnostic criteria include the following: persistent thrombocytosis (>450*109 /L) with clustering of atypical megakaryocytes, refractory anemia, dyserythropoiesis with ring sideroblasts, and the presence of the spliceosome factor 3b subunit (SF3B1) mutation. It is unclear if anemia should be a required criterion for this diagnosis as cases which show all other features of MDS/MPN-RS-T but without anemia exist.METHODS: We searched for borderline cases of MDS/MPN-RS-T in which refractory anemia was absent at diagnosis in two major academic institutes.RESULTS: Three cases without anemia were identified. These cases all showed other classic morphologic and clinical features of MDS/MPN-RS-T, including thrombocytosis, atypical megakaryocytes with clustering, and characteristic SF3B1 and JAK2 V617F mutations.CONCLUSION: Given these findings, the requirement of refractory anemia as a diagnostic criterion for MDS/MPN-RS-T should be re-evaluated. Removal of refractory anemia as a diagnostic criterion would incorporate current borderline cases and extend the spectrum of this disorder.

    View details for PubMedID 30811101

  • Proposed Diagnostic Algorithm for Patients With Suspected Mast Cell Activation Syndrome. The journal of allergy and clinical immunology. In practice Valent, P., Akin, C., Bonadonna, P., Hartmann, K., Brockow, K., Niedoszytko, M., Nedoszytko, B., Siebenhaar, F., Sperr, W. R., Oude Elberink, J. N., Butterfield, J. H., Alvarez-Twose, I., Sotlar, K., Reiter, A., Kluin-Nelemans, H. C., Hermine, O., Gotlib, J., Broesby-Olsen, S., Orfao, A., Horny, H., Triggiani, M., Arock, M., Schwartz, L. B., Metcalfe, D. D. 2019

    Abstract

    Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, an MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, or infectious) unrelated to MCA or suffer from MCA-related (eg, allergic) disorders and/or comorbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed that they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. To avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the 2 principal diagnoses that may underlie MCAS, namely, severe allergy and systemic mastocytosis accompanied by severe MCA. Although validation is required, we anticipate that this algorithm will facilitate the management of patients with suspected MCAS.

    View details for PubMedID 30737190

  • Second primary malignancies in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 2233 patients. Cancer medicine Mora, B. n., Rumi, E. n., Guglielmelli, P. n., Barraco, D. n., Maffioli, M. n., Rambaldi, A. n., Caramella, M. n., Komrokji, R. n., Gotlib, J. n., Kiladjian, J. J., Cervantes, F. n., Devos, T. n., Palandri, F. n., De Stefano, V. n., Ruggeri, M. n., Silver, R. T., Benevolo, G. n., Albano, F. n., Cavalloni, C. n., Pietra, D. n., Barbui, T. n., Rotunno, G. n., Cazzola, M. n., Vannucchi, A. M., Giorgino, T. n., Passamonti, F. n. 2019

    Abstract

    Patients with myeloproliferative neoplasms (MPN) are known to have higher incidence of nonhematological second primary malignancies (SPM) compared to general population. In the MYSEC study on 781 secondary myelofibrosis (SMF) patients, the incidence of SPM after SMF diagnosis resulted 0.98/100 patient-years. When including non-melanoma skin cancers (NMSC), the incidence arose to 1.56/100 patient-years. In SMF, JAK inhibitor treatment was associated only with NMSC occurrence. Then, we merged the MYSEC cohort with a large dataset of PV and ET not evolving into SMF. In this subanalysis, we did not find any correlation between SPM and SMF occurrence. These findings highlight the need of studies aimed at identifying MPN patients at higher risk of SPM.

    View details for DOI 10.1002/cam4.2107

    View details for PubMedID 31173472

  • MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Jawhar, M. n., Schwaab, J. n., Álvarez-Twose, I. n., Shoumariyeh, K. n., Naumann, N. n., Lübke, J. n., Perkins, C. n., Muñoz-González, J. I., Meggendorfer, M. n., Kennedy, V. n., Metzgeroth, G. n., Fabarius, A. n., Pfeifer, D. n., Sotlar, K. n., Horny, H. P., von Bubnoff, N. n., Haferlach, T. n., Cross, N. C., Hofmann, W. K., Sperr, W. R., García-Montero, A. C., Valent, P. n., Gotlib, J. n., Orfao, A. n., Reiter, A. n. 2019: JCO1900640

    Abstract

    To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics.The study included 383 patients with AdvSM from the German Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe, all within the European Competence Network on Mastocytosis (validation set; n = 152). A Cox multivariable model was used to select variables that were predictive of overall survival (OS).In multivariable analysis, the following risk factors were identified as being associated with OS: age greater than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 109/L), presence of one high molecular risk gene mutation (ie, in SRSF2, ASXL1, and/or RUNX1), and presence of two or more high molecular risk gene mutations. By assigning hazard ratio-weighted points to these variables, the following three risk categories were defined: low risk (median OS, not reached), intermediate risk (median OS, 3.9 years; 95% CI, 2.1 to 5.7 years), and high risk (median OS, 1.9 years; 95% CI, 1.3 to 2.6 years; P < .001). The mutation-adjusted risk score (MARS) was independent of the WHO classification and was confirmed in the independent validation set. During a median follow-up time of 2.2 years (range, 0 to 23 years), 63 (16%) of 383 patients experienced a leukemic transformation to secondary mast cell leukemia (32%) or secondary acute myeloid leukemia (68%). The MARS was also predictive for leukemia-free survival (P < .001).The MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with AdvSM and may improve up-front treatment stratification for these rare hematologic neoplasms.

    View details for DOI 10.1200/JCO.19.00640

    View details for PubMedID 31509472

  • Efficacy of Ruxolitinib in Patients With Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Dao, K. T., Gotlib, J. n., Deininger, M. M., Oh, S. T., Cortes, J. E., Collins, R. H., Winton, E. F., Parker, D. R., Lee, H. n., Reister, A. n., Schultz, n. n., Savage, S. n., Stevens, n. n., Brockett, C. n., Subbiah, N. n., Press, R. D., Raess, P. W., Cascio, M. n., Dunlap, J. n., Chen, Y. n., Degnin, C. n., Maxson, J. E., Tognon, C. E., Macey, T. n., Druker, B. J., Tyner, J. W. 2019: JCO1900895

    Abstract

    Colony-stimulating factor-3 receptor (CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status.We conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival.ORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed.Ruxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.

    View details for DOI 10.1200/JCO.19.00895

    View details for PubMedID 31880950

  • A Kindred with a β-Globin Base Substitution [β89(F5)Ser→Arg (AGT>AGG); HBB: c.270T>G] Resulting in Hemoglobin Vanderbilt. Hemoglobin Shomali, W. n., Brar, R. n., Arekapudi, S. R., Gotlib, J. R. 2019: 1–4

    Abstract

    High oxygen affinity hemoglobins (Hbs), characterized by a decreased ability to release oxygen to the tissues and a left-shifted oxygen dissociation curve, are a rare cause of secondary erythrocytosis. Here, we report a base substitution in the β-globin gene at codon 89 (AGT>AGG) in a kindred with familial erythrocytosis resulting in Hb Vanderbilt, a high oxygen affinity variant.

    View details for DOI 10.1080/03630269.2019.1680382

    View details for PubMedID 31657650

  • World Health Organization-defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management. American journal of hematology Shomali, W. n., Gotlib, J. n. 2019

    Abstract

    The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1.5 x 109 /L and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunophenotyping, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm.Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes which includes the major category 'myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2', and the MPN subtype, chronic eosinophilic leukemia, not otherwise specified' (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1.5 x 109 /L) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alfa have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. The use of antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), as well as other targets on eosinophils remains an active area of investigation. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/ajh.25617

    View details for PubMedID 31423623

  • Systemic Mastocytosis, Version 2.2019 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Gotlib, J., Gerds, A. T., Bose, P., Castells, M. C., Deininger, M. W., Gojo, I., Gundabolu, K., Hobbs, G., Jamieson, C., McMahon, B., Mohan, S. R., Oehler, V., Oh, S., Padron, E., Pancari, P., Papadantonakis, N., Pardanani, A., Podoltsev, N., Rampal, R., Ranheim, E., Rein, L., Snyder, D. S., Stein, B. L., Talpaz, M., Thota, S., Wadleigh, M., Walsh, K., Bergman, M., Sundar, H. 2018; 16 (12): 1500–1537

    Abstract

    Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

    View details for DOI 10.6004/jnccn.2018.0088

    View details for Web of Science ID 000453034100013

    View details for PubMedID 30545997

  • The new tool "KIT" in advanced systemic mastocytosis. Hematology. American Society of Hematology. Education Program Shomali, W., Gotlib, J. 2018; 2018 (1): 127–36

    Abstract

    Mastocytosis is a rare disease characterized by KIT-driven expansion and accumulation of neoplastic mast cells in various tissues. Although mediator symptoms related to mast cell activation can impose a symptom burden in cutaneous disease and across the spectrum of systemic mastocytosis subtypes, the presence of an associated hematologic neoplasm and/or organ damage denotes advanced disease and the potential for increased morbidity and mortality. In addition to the revised 2016 World Health Organization classification of mastocytosis, a new diagnostic and treatment toolkit, tethered to enhanced molecular characterization and monitoring, is poised to transform the management of patients with advanced systemic mastocytosis (advSM). Although the efficacy of midostaurin and novel selective KIT D816V inhibitors, such as avapritinib (BLU-285), have validated KIT as a therapeutic target, the clinical and biologic heterogeneity of advSM requires that we reimagine the blueprint for tackling these diseases and use tools that move beyond KIT-centric approaches.

    View details for PubMedID 30504301

  • Comparison of the Transcriptomic Signature of Pediatric Vs. Adult CML and Normal Bone Marrow Stem Cells Chae, H., Murphy, L. C., Donato, M., Lee, A. G., Sweet-Cordero, E., Abidi, P., Bittencourt, H., Lacayo, N. J., Dahl, G., Aftandilian, C., Davis, K. L., Huang, M., Sumarsono, N., Redell, M., Fu, C. H., Chen, I. L., Alonzo, T. A., Eklund, E. A., Gotlib, J. R., Khatri, P., Hijiya, N., Sakamoto, K. M. AMER SOC HEMATOLOGY. 2018
  • PRM-151 in Myelofibrosis: Efficacy and Safety in an Open Label Extension Study Verstovsek, S., Hasserjian, R. P., Pozdnyakova, O., Veletic, I., Mesa, R. A., Foltz, L., Mascarenhas, J., Ritchie, E. K., Palmer, J., Silver, R. T., Kremyanskaya, M., van den Blink, B., Gupta, R., Manshouri, T., Yin, C., Estrov, Z. E., Gotlib, J. R. AMER SOC HEMATOLOGY. 2018
  • Interim Results from Fight-203, a Phase 2, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Pemigatinib (INCB054828) in Patients with Myeloid/Lymphoid Neoplasms with Rearrangement of Fibroblast Growth Factor Receptor 1 (FGFR1) Verstovsek, S., Vannucchi, A. M., Rambaldi, A., Gotlib, J. R., Mead, A. J., Hochhaus, A., Kiladjian, J., Hernandez Boluda, J., Asatiani, E., Lihou, C., Zhen, H., Reiter, A. AMER SOC HEMATOLOGY. 2018
  • Avapritinib, a Potent and Selective Inhibitor of KIT D816V, Improves Symptoms of Advanced Systemic Mastocytosis (AdvSM): Analyses of Patient Reported Outcomes (PROs) from the Phase 1 (EXPLORER) Study Using the (AdvSM) Symptom Assessment Form (AdvSM-SAF), a New PRO Questionnaire for (AdvSM) Gotlib, J. R., Radia, D., DeAngelo, D. J., Bose, P., Drummond, M. W., Hexner, E. O., Robinson, W. A., Conlan, M. G., Oren, R. G., Shi, H., Deininger, M. W. AMER SOC HEMATOLOGY. 2018
  • Phase 2 Study of Ruxolitinib in Patients with Chronic Neutrophilic Leukemia or Atypical Chronic Myeloid Leukemia Dao, K., Collins, R. H., Cortes, J. E., Deininger, M. W., Druker, B. J., Gotlib, J. R., Macey, T., Oh, S. T., Tyner, J. W., Winton, E. F. AMER SOC HEMATOLOGY. 2018
  • Comprehensive Cytokine Profiling of Patients with Advanced Systemic Mastocytosis Treated with Midostaurin Ediriwickrema, A., DeAngelo, D. J., George, T. I., Rosenberg-Hasson, Y., Perkins, C., Langford, C., Gotlib, J. R. AMER SOC HEMATOLOGY. 2018
  • Solid Tumors in Post-Polycythemia Vera and Post-Essential Thrombocythemia Myelofibrosis: A Study on 2220 Patients Mora, B., Rumi, E., Guglielmelli, P., Barraco, D., Maffioli, M., Rambaldi, A., Caramella, M., Komrokji, R. S., Gotlib, J. R., Kiladjian, J., Cervantes, F., Devos, T., Palandri, F., De Stefano, V., Ruggeri, M., Silver, R. T., Benevolo, G., Albano, F., Cavalloni, C., Pietra, D., Barbui, T., Rotunno, G., Cazzola, M., Vannucchi, A. M., Giorgino, T., Passamonti, F. AMER SOC HEMATOLOGY. 2018
  • Impact of somatic and germline mutations on the outcome of systemic mastocytosis. Blood advances Munoz-Gonzalez, J. I., Jara-Acevedo, M., Alvarez-Twose, I., Merker, J. D., Teodosio, C., Hou, Y., Henriques, A., Roskin, K. M., Sanchez-Munoz, L., Tsai, A. G., Caldas, C., Matito, A., Sanchez-Gallego, J. I., Mayado, A., Dasilva-Freire, N., Gotlib, J. R., Escribano, L., Orfao, A., Garcia-Montero, A. C. 2018; 2 (21): 2814–28

    Abstract

    Systemic mastocytosis (SM) is a highly heterogeneous disease with indolent and aggressive forms, with the mechanisms leading to malignant transformation still remaining to be elucidated. Here, we investigated the presence and frequency of genetic variants in 34 SM patients with multilineal KIT D816V mutations. Initial screening was performed by targeted sequencing of 410 genes in DNA extracted from purified bone marrow cells and hair from 12 patients with nonadvanced SM and 8 patients with advanced SM, followed by whole-genome sequencing (WGS) in 4 cases. Somatic mutations were further investigated in another 14 patients with advanced SM. Despite the fact that no common mutation other than KIT D816V was found in WGS analyses, targeted next-generation sequencing identified 67 nonsynonymous genetic variants involving 39 genes. Half of the mutations were somatic (mostly multilineal), whereas the other half were germline variants. The presence of ≥1 multilineal somatic mutation involving genes other than KIT D816V, ≥3 germline variants, and ≥1 multilineal mutation in the SRSF2, ASXL1, RUNX1, and/or EZH2 genes (S/A/R/E genes), in addition to skin lesions, splenomegaly, thrombocytopenia, low hemoglobin levels, and increased alkaline phosphatase and beta2-microglobulin serum levels, were associated with a poorer patient outcome. However, the presence of ≥1 multilineal mutation, particularly involving S/A/R/E genes, was the only independent predictor for progression-free survival and overall survival in our cohort.

    View details for PubMedID 30373888

  • The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives. The journal of allergy and clinical immunology. In practice Valent, P., Oude Elberink, J. N., Gorska, A., Lange, M., Zanotti, R., van Anrooij, B., Bonifacio, M., Bonadonna, P., Gleixner, K. V., Hadzijusufovic, E., Perkins, C., Hartmann, K., Illerhaus, A., Merante, S., Elena, C., Shoumariyeh, K., von Bubnoff, N., Parente, R., Triggiani, M., Schwaab, J., Jawhar, M., Caroppo, F., Fortina, A. B., Brockow, K., David Fuchs, Greul, R., Yavuz, A. S., Doubek, M., Mattsson, M., Hagglund, H., Panse, J., Sabato, V., Aberer, E., Al-Ali, H. K., Morren, M., Varkonyi, J., Zink, A., Niedoszytko, M., Niederwieser, D., Malcovati, L., Reiter, A., Kennedy, V., Gotlib, J., Lortholary, O., Hermine, O., Arock, M., Kluin-Nelemans, H., Sperr, W. R., Study Group of the European Competence Network on Mastocytosis (ECNM) 2018

    Abstract

    Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.

    View details for PubMedID 30416055

  • A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis BLOOD Masarova, L., Verstovsek, S., Hidalgo-Lopez, J. E., Pemmaraju, N., Bose, P., Estrov, Z., Jabbour, E. J., Ravandi-Kashani, F., Takahashi, K., Cortes, J. E., Ning, J., Ohanian, M., Alvarado, Y., Zhou, L., Pierce, S., Gergis, R., Patel, K. P., Luthra, R., Kadia, T. M., DiNardo, C. D., Borthakur, G., Bhalla, K., Garcia-Manero, G., Bueso-Ramos, C. E., Kantarjian, H. M., Daver, N. 2018; 132 (16): 1664–74

    Abstract

    Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.

    View details for PubMedID 30185431

  • Gender effect on phenotype and genotype in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis: results from the MYSEC project BLOOD CANCER JOURNAL Barraco, D., Mora, B., Guglielmelli, P., Rumi, E., Maffioli, M., Rambaldi, A., Caramella, M., Komrokji, R., Gotlib, J., Kiladjian, J., Cervantes, F., Devos, T., Palandri, F., De Stefano, V., Ruggeri, M., Silver, R. T., Benevolo, G., Albano, F., Merli, M., Pietra, D., Barbui, T., Rotunno, G., Cazzola, M., Giorgino, T., Vannucchi, A., Passamonti, F. 2018; 8
  • Gender effect on phenotype and genotype in patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis: results from the MYSEC project. Blood cancer journal Barraco, D., Mora, B., Guglielmelli, P., Rumi, E., Maffioli, M., Rambaldi, A., Caramella, M., Komrokji, R., Gotlib, J., Kiladjian, J. J., Cervantes, F., Devos, T., Palandri, F., De Stefano, V., Ruggeri, M., Silver, R. T., Benevolo, G., Albano, F., Merli, M., Pietra, D., Barbui, T., Rotunno, G., Cazzola, M., Giorgino, T., Vannucchi, A. M., Passamonti, F. 2018; 8 (10): 89

    View details for PubMedID 30291232

  • Chronic Myeloid Leukemia, Version 1.2019 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Radich, J. P., Deininger, M., Abboud, C. N., Altman, J. K., Berman, E., Bhatia, R., Bhatnagar, B., Curtin, P., DeAngelo, D. J., Gotlib, J., Hobbs, G., Jagasia, M., Kantarjian, H. M., Maness, L., Metheny, L., Moore, J. O., Pallera, A., Pancari, P., Patnaik, M., Purev, E., Rose, M. G., Shah, N. P., Smith, B., Snyder, D. S., Sweet, K. L., Talpaz, M., Thompson, J., Yang, D. T., Gregory, K. M., Sundar, H. 2018; 16 (9): 1108–35

    Abstract

    Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.

    View details for DOI 10.6004/jnccn.2018.0071

    View details for Web of Science ID 000443581300010

    View details for PubMedID 30181422

  • PLATELET TRANSCRIPTOMIC SIGNATURES IN MYELOPROLIFERATIVE NEOPLASMS Krishnan, A., Perkins, C., Gotlib, J., Zehnder, J. WILEY. 2018: E34
  • THE NUMBER AND TYPE OF MUTATIONS IN CANCER-LINKED GENES IS ASSOCIATED WITH OUTCOME OF SYSTEMIC MASTOCYTOSIS. Munoz-Gonzalez, J. I., Jara-Acevedo, M., Alvarez-Twose, I., Merker, J. D., Teodosio, C., Henriques, A., Sanchez-Munoz, L., Matito, A., Caldas, C., Ignacio Sanchez-Gallego, J., Mayado, A., Dasilva-Freire, N., Gotlib, J. R., Escribano, L., Orfao, A., Garcia-Montero, A. C. WILEY. 2018: 102
  • Core-binding factor acute myeloid leukemia with t(8;21) Risk factors and a novel scoring system (I-CBFit) CANCER MEDICINE Ustun, C., Morgan, E., Moodie, E. M., Pullarkat, S., Yeung, C., Broesby-Olsen, S., Ohgami, R., Kim, Y., Sperr, W., Vestergaard, H., Chen, D., Kluin, P. M., Dolan, M., Mrozek, K., Czuchlewski, D., Horny, H., George, T. I., Kristensen, T., Ku, N. K., Yi, C., Moller, M., Marcucci, G., Baughn, L., Schiefer, A., Hilberink, J. R., Pullarkat, V., Shanley, R., Kohlschmidt, J., Coulombe, J., Salhotra, A., Soma, L., Cho, C., Linden, M. A., Akin, C., Gotlib, J., Hoermann, G., Hornick, J., Nakamura, R., Deeg, J., Bloomfield, C. D., Weisdorf, D., Litzow, M. R., Valent, P., Huls, G., Perales, M., Borthakur, G. 2018; 7 (9): 4447–55

    Abstract

    Although the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.Eleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).Complete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P < 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P < 0.0001).I-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).

    View details for PubMedID 30117318

  • Mast cell activation syndrome: Importance of consensus criteria and call for research JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Valent, P., Akin, C., Bonadonna, P., Hartmann, K., Broesby-Olsen, S., Brockow, K., Butterfield, J. H., Reiter, A., Gotlib, J., Castells, M., Milner, J. D., Carter, M. C., Komarow, H., Radia, D., Pardanani, A., Sotlar, K., Triggiani, M., Horny, H., Arock, M., Schwartz, L. B., Metcalfe, D. D. 2018; 142 (3): 1008-+

    View details for PubMedID 29928922

  • Value of cytogenetic abnormalities in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study of the MYSEC project HAEMATOLOGICA Mora, B., Giorgino, T., Guglielmelli, P., Rumi, E., Maffioli, M., Rambaldi, A., Caramella, M., Komrokji, R., Gotlib, J., Kiladjian, J., Cervantes, F., Devos, T., Palandri, F., De Stefano, V., Ruggeri, M., Silver, R. T., Benevolo, G., Albano, F., Cavalloni, C., Barraco, D., Merli, M., Pietra, D., Casalone, R., Barbui, T., Rotunno, G., Cazzola, M., Vannucchi, A., Passamonti, F. 2018; 103 (9): E392–E394

    View details for PubMedID 29622658

  • Clinical Validation of KIT Inhibition in Advanced Systemic Mastocytosis. Current hematologic malignancy reports Baird, J. H., Gotlib, J. 2018

    Abstract

    PURPOSE OF REVIEW: We discuss recent developments in the treatment of advanced systemic mastocytosis (advSM) with inhibitors of the KIT receptor tyrosine kinase.RECENT FINDINGS: advSM is a heterogeneous group of neoplasms of poor prognosis characterized by the accumulation of neoplastic mast cells. The canonical KIT D816V mutation is present in approximately 90% of SM patients, and its detection is critical for both diagnosis and therapeutic decision-making. The multikinase/KIT inhibitor midostaurin was recently approved for advSM. This agent can reverse SM-related organ damage and disease symptoms, and decrease the bone marrow mast cell burden and splenomegaly. However, complete remissions are rare and durability of responses is variable. Potent and selective KIT D816V inhibitors including avapritinib (BLU-285) and DCC-2618 have entered clinical trials, and rational combination strategies are under development. The clinical efficacy of KIT inhibitors validate KIT as a key oncogenic driver in mast cell neoplasms. An improved understanding of the genetic heterogeneity beyond KIT will help inform the dynamics of response and relapse.

    View details for PubMedID 30155614

  • Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells BLOOD ADVANCES Yun, H., Felices, M., Vallera, D. A., Hinderlie, P., Cooley, S., Arock, M., Gotlib, J., Ustun, C., Miller, J. S. 2018; 2 (13): 1580–84

    View details for PubMedID 29980573

    View details for PubMedCentralID PMC6039654

  • Phenotype variability of patients with post polycythemia vera and post essential thrombocythemia myelofibrosis is associated with the time to progression from polycythemia vera and essential thrombocythemia LEUKEMIA RESEARCH Mora, B., Giorgino, T., Guglielmelli, P., Rumi, E., Maffioli, M., Rambaldi, A., Caramella, M., Komrokji, R., Gotlib, J., Kiladjian, J., Cervantes, F., Devos, T., Palandri, F., De Stefano, V., Ruggeri, M., Silver, R. T., Benevolo, G., Albano, F., Cavalloni, C., Barraco, D., Pietra, D., Barbui, T., Rotunno, G., Vannucchi, A., Passamonti, F. 2018; 69: 100–102

    View details for PubMedID 29734070

  • Treatment With JAK Inhibitors in Myelofibrosis Patients Nullifies the Prognostic Impact of Unfavorable Cytogenetics CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Ma, V. T., Boonstra, P. S., Menghrajani, K., Perkins, C., Gowin, K. L., Mesa, R. A., Gotlib, J. R., Talpaz, M. 2018; 18 (5): E201–E210

    Abstract

    In the era before Janus kinase (JAK) inhibitors, cytogenetic information was used to predict survival in myelofibrosis patients. However, the prognostic value of cytogenetics in the setting of JAK inhibitor therapy remains unknown.We performed a retrospective analysis of 180 patients with bone marrow biopsy-proven myelofibrosis from 3 US academic medical centers. We fit Cox proportional hazards models for overall survival and transformation-free survival on the bases of 3 factors: JAK inhibitor therapy as a time-dependent covariate, dichotomized cytogenetic status (favorable vs. unfavorable), and statistical interaction between the two. The median follow-up time was 37.1 months.Among patients treated with best available therapy, unfavorable cytogenetic status was associated with decreased survival (hazard ratio = 2.31; P = .025). At initiation of JAK inhibitor therapy, unfavorable cytogenetics was (nonsignificantly) associated with increased survival compared to favorable cytogenetics (hazard ratio = 0.292; P = .172). The ratio of hazard ratios was 0.126 (P = .034). These findings were similar after adjusting for standard clinical prognostic factors as well as when measured against transformation-free survival.The initiation of JAK inhibitor therapy appears to change the association between cytogenetics and overall survival. There was little difference in survival between treatment types in patients with favorable cytogenetics. However, the use of JAK inhibitor therapy among patients with unfavorable cytogenetics was not associated with worse survival compared to favorable cytogenetics. Our analyses suggest that initiation of JAK inhibitor therapy nullifies the negative prognostic implication of unfavorable cytogenetics established in the pre-JAK inhibitor therapy era.

    View details for PubMedID 29574002

    View details for PubMedCentralID PMC5927833

  • Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis A Randomized Clinical Trial JAMA ONCOLOGY Mascarenhas, J., Hoffman, R., Talpaz, M., Gerds, A. T., Stein, B., Gupta, V., Szoke, A., Drummond, M., Pristupa, A., Granston, T., Daly, R., Al-Fayoumi, S., Callahan, J. A., Singer, J. W., Gotlib, J., Jamieson, C., Harrison, C., Mesa, R., Verstovsek, S. 2018; 4 (5): 652–59

    Abstract

    Myelofibrosis is a hematologic malignancy characterized by splenomegaly and debilitating symptoms. Thrombocytopenia is a poor prognostic feature and limits use of Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) inhibitor ruxolitinib.To compare the efficacy and safety of JAK2 inhibitor pacritinib with that of best available therapy (BAT), including ruxolitinib, in patients with myelofibrosis and thrombocytopenia.For this phase 3 randomized international multicenter study-the PERSIST-2 study-of pacritinib vs BAT, 311 patients with myelofibrosis and platelet count 100 × 109/L or less were recruited for analysis. Crossover from BAT was allowed after week 24 or for progression of splenomegaly.Patients were randomized 1:1:1 to pacritinib 400 mg once daily, pacritinib 200 mg twice daily, or BAT.Coprimary end points were rates of patients achieving 35% or more spleen volume reduction (SVR) and 50% or more reduction in total symptom score (TSS) at week 24. Efficacy analyses were performed on the intention-to-treat efficacy population, comprising all patients with a randomization date allowing for week 24 data.Overall, 311 patients (mean [SD] age, 63.70 [9.08] years; 171 men [55%] and 140 women [45%]) were included in the study; 149 patients (48%) had prior ruxolitinib. The most common BAT was ruxolitinib (44 patients [45%]); 19 patients (19%) received watchful-waiting only. The intention-to-treat efficacy population included 75 patients randomized to pacritinib once daily; 74, pacritinib twice daily, and 72, BAT. Pacritinib (arms combined) was more effective than BAT for 35% or more SVR (27 patients [18%] vs 2 patients [3%]; P = .001) and had a nonsignificantly greater rate of 50% or more reduction in TSS (37 patients [25%] vs 10 patients [14%]; P = .08). Pacritinib twice daily led to significant improvements in both end points over BAT (≥35% SVR: 16 patients [22%] vs 2 patients [3%]; P = .001; ≥50% reduction in TSS: 24 patients [32%] vs 10 patients [14%]; P = .01). Clinical improvement in hemoglobin and reduction in transfusion burden were greatest with pacritinib twice daily. For pacritinib once daily, pacritinib twice daily, and BAT, the most common (>10%) grade 3 or 4 adverse events were thrombocytopenia (32 patients [31%], 34 patients [32%], 18 patients [18%]), and anemia (28 patients [27%], 23 patients [22%], 14 patients [14%]). In the pacritinib once daily, twice daily, and BAT arms, discontinuation owing to adverse events occurred in 15 patients (14%), 10 patients (9%), and 4 patients (4%).In patients with myelofibrosis and thrombocytopenia, including those with prior anti-JAK therapy, pacritinib twice daily was more effective than BAT, including ruxolitinib, for reducing splenomegaly and symptoms.clinicaltrials.gov Identifier: NCT02055781.

    View details for PubMedID 29522138

    View details for PubMedCentralID PMC5885169

  • Recent advances in the genomics and therapy of BCR/ABL1-positive and -negative chronic myeloproliferative neoplasms LEUKEMIA RESEARCH Mughal, T. I., Gotlib, J., Mesa, R., Koschmieder, S., Khoury, H., Cortes, J. E., Barbui, T., Hehlmann, R., Mauro, M., Saussele, S., Radich, J. P., Van Etten, R. A., Saglio, G., Verstovek, S., Gale, R., Abdel-Wahab, O. 2018; 67: 67–74

    Abstract

    This review is based on the presentations and deliberations at the 7th John Goldman Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN) Colloquium which took place in Estoril, Portugal on the 15th October 2017, and the 11th post-ASH International Workshop on CML and MPN which took place on the 6th-7th December 2016, immediately after the 58th American Society of Hematology Annual Meeting. Rather than present a resume of the proceedings, we have elected to address some of the topical translational research and clinically relevant topics in greater detail. We address recent updates in the genetics and epigenetics of MPN, the mechanisms of transformation by mutant calreticulin, advances in the biology and therapy of systemic mastocytosis, clinical updates on JAK2 inhibitors and other therapeutic approaches for patients with MPNs, cardiovascular toxicity related to tyrosine kinase inhibitors and the concept of treatment-free remission for patients with CML.

    View details for DOI 10.1016/j.leukres.2018.02.008

    View details for Web of Science ID 000428145900012

    View details for PubMedID 29466766

  • Trispecific Killer Engager CD16xIL15xCD33 Enhances Alloreactivity of NK Cells Against Aberrant Mast Cells of Patients with Systemic Mastocytosis Yun, H., Felices, M., Vallera, D. A., Cooley, S., Gotlib, J. R., Ustun, C., Miller, J. S. ELSEVIER SCIENCE INC. 2018: S148–S149
  • The Significance of Dim Cytoplasmic CD3 Expression in Acute Myeloid Leukemia: A Long-Term Retrospective Study Identifies an Association with Acute Promyelocytic Leukemia with FLT3-ITD Mutations Kumar, J., Nagy, A., Lacayo, N., Gotlib, J., Zehnder, J. L., Ohgami, R. NATURE PUBLISHING GROUP. 2018: 529
  • Myelophthisic marrow involved by breast cancer and acute myeloid leukemia BLOOD Shomali, W., Gotlib, J. 2018; 131 (9): 1036

    View details for PubMedID 29496704

  • Variability of PD-L1 expression in mastocytosis BLOOD ADVANCES Hatch, E. W., Geeze, M., Martin, C., Salama, M. E., Hartmann, K., Eisenwort, G., Blatt, K., Valent, P., Gotlib, J., Lee, J., Chen, L., Ward, H. H., Lidke, D. S., George, T. I. 2018; 2 (3): 189–99

    Abstract

    Mastocytosis is a rare disease with heterogeneous clinical manifestations and few effective therapies. Programmed death-1 (PD-1) and its ligands (PD-L1 and PD-L2) protect tissues from immune-mediated damage and permit tumors to evade immune destruction. Therapeutic antibodies against PD-1 and PD-L1 are effective in the treatment of a variety of neoplasms. In the present study, we sought to systematically analyze expression of PD-1 and PD-L1 in a large number of patients with mastocytosis using immunohistochemistry and multiplex fluorescence staining. PD-L1 showed membrane staining of neoplastic mast cells (MCs) in 77% of systemic mastocytosis (SM) cases including 3 of 3 patients with MC leukemia, 2 of 2 with aggressive SM, 1 of 2 with smoldering SM, 3 of 4 with indolent SM, and 9 of 12 with SM with an associated hematologic neoplasm (SM component only). Ninety-two percent (23 of 25) of cutaneous mastocytosis (CM) cases and 1 of 2 with myelomastocytic leukemia expressed PD-L1, with no expression found in 15 healthy/reactive marrows, 18 myelodysplastic syndromes (MDSs), 16 myeloproliferative neoplasms (MPNs), 5 MDS/MPNs, and 3 monoclonal MC activation syndromes. Variable PD-L1 expression was observed between and within samples, with PD-L1 staining of MCs ranging from 10% to 100% (mean, 50%). PD-1 dimly stained 4 of 27 CM cases (15%), with no expression in SM or other neoplasms tested; PD-1 staining of MCs ranged from 20% to 50% (mean, 27%). These results provide support for the expression of PD-L1 in SM and CM, and PD-1 expression in CM. These data support the exploration of agents with anti-PD-L1 activity in patients with advanced mastocytosis.

    View details for PubMedID 29378725

    View details for PubMedCentralID PMC5812326

  • SOHO State-of-the-Art Update and Next Questions: MPN CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Bose, P., Gotlib, J., Harrison, C. N., Verstovsek, S. 2018; 18 (1): 1–12

    Abstract

    The discovery of the activating Janus kinase (JAK)2V617F mutation in 2005 in most patients with the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) spurred intense interest in research into these disorders, culminating in the identification of activating mutations in MPL in 2006 and indels in the gene encoding calreticulin (CALR) in 2013, thus providing additional mechanistic explanations for the universal activation of JAK-signal transducer and activator of transcription (JAK-STAT) observed in these conditions, and the success of the JAK1/2 inhibitor ruxolitinib, which first received regulatory approval in 2011. The field has continued to advance rapidly since then, and the past 2 years have witnessed important changes to the classification of MPN and diagnostic criteria for polycythemia vera (PV), novel insights into the mechanisms of bone marrow fibrosis in primary myelofibrosis (PMF), increasing appreciation of the biologic differences between essential thrombocythemia (ET), prefibrotic and overt PMF, and between primary and post-PV/ET myelofibrosis (MF). Additionally, the mechanisms through which mutant CALR drives JAK-STAT pathway activation and oncogenic transformation are now better understood. Although mastocytosis is no longer included under the broad heading of MPN in the 2016 revision to the World Health Organization classification, an important milestone in mastocytosis research was reached in 2017 with the regulatory approval of midostaurin for patients with advanced systemic mastocytosis (AdvSM). In this article, we review the major recent developments in the areas of PV, ET, and MF, and also briefly summarize the literature on midostaurin and other KIT inhibitors for patients with AdvSM.

    View details for PubMedID 29277359

    View details for PubMedCentralID PMC5915302

  • A phase I, open-label, dose-escalation study of amrubicin in combination with lenalidomide and weekly dexamethasone in previously treated adults with relapsed or refractory multiple myeloma. International journal of hematology Dinner, S. n., Dunn, T. J., Price, E. n., Coutré, S. E., Gotlib, J. n., Berube, C. n., Kaufman, G. P., Medeiros, B. C., Liedtke, M. n. 2018

    Abstract

    This phase 1 study investigated the safety of the anthracycline amrubicin combined with lenalidomide and dexamethasone in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous amrubicin 40-80 mg/m2 on day one, lenalidomide 15 mg orally on days 1-14, and dexamethasone 40 mg orally weekly on 21 day cycles. 14 patients were enrolled, and completed a median of three cycles. The maximum tolerated dose was not reached. One patient experienced dose limiting toxicity of dizziness and diarrhea. The most frequent non-hematologic toxicity was infection (79%). Serious adverse events included cord compression and sepsis. Three patients (21%) had a partial response or better, and seven (50%) had stable disease. The median duration of response was 4.4 months, and the median progression-free survival was 3 months. Amrubicin combined with lenalidomide and dexamethasone, was safe and demonstrated clinical activity in relapsed or refractory multiple myeloma.Clinicaltrials.gov identifier: NCT01355705.

    View details for PubMedID 29802551

  • Proposed Terminology and Classification of Pre-Malignant Neoplastic Conditions: A Consensus Proposal EBIOMEDICINE Valent, P., Akin, C., Arock, M., Bock, C., George, T. I., Galli, S. J., Gotlib, J., Haferlach, T., Hoermann, G., Hermine, O., Jaeger, U., Kenner, L., Kreipe, H., Majeti, R., Metcalfe, D. D., Orfao, A., Reiter, A., Sperr, W. R., Staber, P. B., Sotlar, K., Schiffer, C., Superti-Furga, G., Horny, H. 2017; 26: 17–24
  • World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2017; 92 (11): 1243–59

    Abstract

    The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1500/mm3 and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder.Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes which includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2," and the "MPN subtype, chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant hypereosinophilia is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., < 1500/mm3 ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. The use of antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), and CD52 (alemtuzumab), as well as other targets on eosinophils remains an active area of investigation.

    View details for DOI 10.1002/ajh.24880

    View details for Web of Science ID 000413166800026

    View details for PubMedID 29044676

  • A novel TRIP11-FLT3 fusion in a patient with a myeloid/lymphoid neoplasm with eosinophilia CANCER GENETICS Chung, A., Hou, Y., Ohgami, R. S., Von Gehr, A., Fisk, D. G., Roskin, K. M., Li, X., Gojenola, L., Bangs, C. D., Arber, D. A., Fire, A. Z., Cherry, A. M., Zehnder, J. L., Gotlib, J., Merker, J. D. 2017; 216: 10–15

    Abstract

    FLT3 fusions are associated with myeloid and lymphoid neoplasms with eosinophilia. We describe a patient presenting with clinicopathologic features of both chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) and systemic mastocytosis (SM). The bone marrow demonstrated a myeloproliferative neoplasm with eosinophilia and aggregates of atypical mast cells. Cytogenetic analysis revealed a t(13;14)(q12;q32), which was subsequently molecularly characterized as a novel TRIP11-FLT3 rearrangement. A KIT D816V mutation was also identified. The patient rapidly transformed to T-lymphoblastic leukemia/lymphoma and expired shortly after diagnosis. This is the fifth FLT3 fusion gene described in the literature; the presence of both myeloid and lymphoid neoplasms implicates involvement of an early hematopoietic progenitor by rearranged FLT3. We suggest that leukemias and lymphomas with FLT3 fusion genes exhibit similar clinicopathologic features to, and should be included in, the WHO category of "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2."

    View details for PubMedID 29025582

  • NCCN Guidelines (R) Insights Myeloproliferative Neoplasms, Version 2.2018 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Mesa, R. A., Jamieson, C., Bhatia, R., Deininger, M. W., Fletcher, C. D., Gerds, A. T., Gojo, I., Gotlib, J., Gundabolu, K., Hobbs, G., McMahon, B., Mohan, S. R., Oh, S., Padron, E., Papadantonakis, N., Pancari, P., Podoltsev, N., Rampal, R., Ranheim, E., Reddy, V., Rein, L. M., Scott, B., Snyder, D. S., Stein, B. L., Talpaz, M., Verstovsek, S., Wadleigh, M., Wang, E. S., Bergman, M., Gregory, K. M., Sundar, H. 2017; 15 (10): 1193–1207

    Abstract

    Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.

    View details for DOI 10.6004/jnccn.2017.0157

    View details for Web of Science ID 000412320900005

    View details for PubMedID 28982745

  • Recent Progress in Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia CURRENT HEMATOLOGIC MALIGNANCY REPORTS Dao, K. T., Tyner, J. W., Gotlib, J. 2017; 12 (5): 432–41

    Abstract

    We reviewed recent diagnostic and therapeutic progress in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We summarized recent genetic data that may guide future efforts towards implementing risk-adapted therapy based on mutational profile and improving disease control and survival of affected patients.Recent genetic data in CNL and aCML prompted modifications to the World Health Organization (WHO) diagnostic criteria, which have improved our understanding of how CNL and aCML are different diseases despite sharing common findings of peripheral granulocytosis and marrow myeloid hyperplasia. The overlap of recurrently mutated genes between aCML and CMML support considering CSF3R-T618I mutated cases as a distinct entity, either as CNL or CNL with dysplasia. Ongoing preclinical and clinical studies will help to further inform the therapeutic approach to these diseases. Our understanding of CNL and aCML has greatly advanced over the last few years. This will improve clarity for the diagnosis of these diseases, provide a strategy for risk stratification, and guide risk-adapted therapy.

    View details for PubMedID 28983816

  • Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses JOURNAL OF HEMATOLOGY & ONCOLOGY Verstovsek, S., Gotlib, J., Mesa, R. A., Vannucchi, A. M., Kiladjian, J., Cervantes, F., Harrison, C. N., Paquette, R., Sun, W., Naim, A., Langmuir, P., Dong, T., Gopalakrishna, P., Gupta, V. 2017; 10: 156

    Abstract

    Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF.This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24.A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24.These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF.ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .

    View details for PubMedID 28962635

  • SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor-Naive Patients With Myelofibrosis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Mesa, R. A., Kiladjian, J., Catalano, J. V., Devos, T., Egyed, M., Hellmann, A., McLornan, D., Shimoda, K., Winton, E. F., Deng, W., Dubowy, R. L., Maltzman, J. D., Cervantes, F., Gotlib, J. 2017: JCO2017734418

    Abstract

    Purpose We evaluated the efficacy and safety of momelotinib, a potent and selective Janus kinase 1 and 2 inhibitor (JAKi), compared with ruxolitinib, in JAKi-naive patients with myelofibrosis. Patients and Methods Patients (N = 432) with high risk or intermediate-2 risk or symptomatic intermediate-1 risk myelofibrosis were randomly assigned to receive 24 weeks of treatment with momelotinib 200 mg once daily or ruxolitinib 20 mg twice a day (or per label), after which all patients could receive open-label momelotinib. The primary end point was a ≥ 35% reduction in spleen volume at 24 weeks of therapy. Secondary end points were rates of symptom response and effects on RBC transfusion requirements. Results A ≥ 35% reduction in spleen volume at week 24 was achieved by a similar proportion of patients in both treatment arms: 26.5% of the momelotinib group and 29% of the ruxolitinib group (noninferior; P = .011). A ≥ 50% reduction in the total symptom score was observed in 28.4% and 42.2% of patients who received momelotinib and ruxolitinib, respectively, indicating that noninferiority was not met ( P = .98). Transfusion rate, transfusion independence, and transfusion dependence were improved with momelotinib (all with nominal P ≤ .019). The most common grade ≥ 3 hematologic abnormalities in either group were thrombocytopenia and anemia. Grade ≥ 3 infections occurred in 7% of patients who received momelotinib and 3% of patients who received ruxolitinib. Treatment-emergent peripheral neuropathy occurred in 10% of patients who received momelotinib (all grade ≤ 2) and 5% of patients who received ruxolitinib (all grade ≤ 3). Conclusion In JAKi-naive patients with myelofibrosis, 24 weeks of momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response. Momelotinib treatment was associated with a reduced transfusion requirement.

    View details for DOI 10.1200/JCO.2017.73.4418

    View details for PubMedID 28930494

  • Tyrosine Kinase Inhibitors in the Treatment of Eosinophilic Neoplasms and Systemic Mastocytosis HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Gotlib, J. 2017; 31 (4): 643-+

    Abstract

    The World Health Organization's semimolecular classification of eosinophilias emphasizes neoplasms driven by fusion tyrosine kinases. More than 80% of patients with systemic mastocytosis carry the KIT D816V mutation, the primary driver of disease pathogenesis. Genetic annotation of these diseases is critical and affords opportunities for targeted therapy. This article discusses our understanding of the mutated tyrosine kinome of eosinophilic neoplasms and systemic mast cell disease, and the successes and limitations of available therapies. Use of tyrosine kinase inhibitors as a bridge to hematopoietic stem cell transplantation, and development of more selective and potent tyrosine kinase inhibitors is also highlighted.

    View details for PubMedID 28673393

  • A molecular roadmap for midostaurin in mastocytosis BLOOD Gotlib, J. 2017; 130 (2): 98–100

    View details for DOI 10.1182/blood-2017-05-781237

    View details for Web of Science ID 000405397400002

    View details for PubMedID 28705853

  • Allogeneic NK cells eradicate myeloblasts but not neoplastic mast cells in systemic mastocytosis associated with acute myeloid leukemia AMERICAN JOURNAL OF HEMATOLOGY Ustun, C., Williams, S., Skendzel, S., Kodal, B., Arock, M., Gotlib, J., Vallera, D. A., Cooley, S., Felices, M., Weisdorf, D., Miller, J. 2017; 92 (5): E66–E68

    View details for DOI 10.1002/ajh.24673

    View details for Web of Science ID 000399359300003

    View details for PubMedID 28187525

  • Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future. Cancer research Valent, P., Akin, C., Hartmann, K., Nilsson, G., Reiter, A., Hermine, O., Sotlar, K., Sperr, W. R., Escribano, L., George, T. I., Kluin-Nelemans, H. C., Ustun, C., Triggiani, M., Brockow, K., Gotlib, J., Orfao, A., Schwartz, L. B., Broesby-Olsen, S., Bindslev-Jensen, C., Kovanen, P. T., Galli, S. J., Austen, K. F., Arber, D. A., Horny, H., Arock, M., Metcalfe, D. D. 2017

    Abstract

    Mastocytosis is a term used to denote a heterogeneous group of conditions defined by the expansion and accumulation of clonal (neoplastic) tissue mast cells in various organs. The classification of the World Health Organization (WHO) divides the disease into cutaneous mastocytosis, systemic mastocytosis, and localized mast cell tumors. On the basis of histomorphologic criteria, clinical parameters, and organ involvement, systemic mastocytosis is further divided into indolent systemic mastocytosis and advanced systemic mastocytosis variants, including aggressive systemic mastocytosis and mast cell leukemia. The clinical impact and prognostic value of this classification has been confirmed in numerous studies, and its basic concept remains valid. However, refinements have recently been proposed by the consensus group, the WHO, and the European Competence Network on Mastocytosis. In addition, new treatment options are available for patients with advanced systemic mastocytosis, including allogeneic hematopoietic stem cell transplantation and multikinase inhibitors directed against KIT D816V and other key signaling molecules. Our current article provides an overview of recent advances in the field of mastocytosis, with emphasis on classification, prognostication, and emerging new treatment options in advanced systemic mastocytosis. Cancer Res; 77(6); 1261-70. ©2017 AACR.

    View details for DOI 10.1158/0008-5472.CAN-16-2234

    View details for PubMedID 28254862

  • Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. Journal of hematology & oncology Verstovsek, S., Mesa, R. A., Gotlib, J., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Paquette, R., Raza, A., Jones, M., Kornacki, D., Sun, K., Kantarjian, H. 2017; 10 (1): 55-?

    Abstract

    The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib-the first myelofibrosis-approved therapy-reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results.Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment.Patients were randomized (September 2009-April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50-0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%).The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF.ClinicalTrials.gov, NCT00952289.

    View details for DOI 10.1186/s13045-017-0417-z

    View details for PubMedID 28228106

  • A phase 2 study of simtuzumab in patients with primary, post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. British journal of haematology Verstovsek, S., Savona, M. R., Mesa, R. A., Dong, H., Maltzman, J. D., Sharma, S., Silverman, J., Oh, S. T., Gotlib, J. 2017

    Abstract

    Simtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase-like-2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open-label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post-polycythaemia vera MF and post-essential thrombocythaemia MF. Fifty-four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose-proportionally between the 200-mg and 700-mg treatment groups. Therapy-related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700-mg group, 1 (6·7%) in the simtuzumab 200-mg + ruxolitinib group, and 2 (13·3%) in the simtuzumab 700-mg + ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.

    View details for DOI 10.1111/bjh.14501

    View details for PubMedID 28220932

  • How I treat atypical chronic myeloid leukemia BLOOD Gotlib, J. 2017; 129 (7): 838-845

    Abstract

    Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML) is a rare myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. The challenges of aCML relate to its heterogeneous clinical and genetic features, high rate of transformation to acute myeloid leukemia, and historically poor survival. Therefore, allogeneic hematopoietic stem cell transplantation should always be an initial consideration for eligible patients with a suitable donor. Nontransplant approaches for treating aCML have otherwise largely relied on adopting treatment strategies used for MDS and MPN. However, such therapies, including hypomethylating agents, are based on a paucity of data. With an eye toward making a more meaningful impact on response rates and modification of the natural history of the disease, progress will rely on enrollment of patients into clinical trials and molecular profiling of individuals so that opportunities for targeted therapy can be exploited.

    View details for DOI 10.1182/blood-2016-08693630

    View details for Web of Science ID 000397019000008

    View details for PubMedID 27899359

  • Proposed diagnostic criteria and classification of basophilic leukemias and related disorders. Leukemia Valent, P., Sotlar, K., Blatt, K., Hartmann, K., Reiter, A., Sadovnik, I., Sperr, W. R., Bettelheim, P., Akin, C., Bauer, K., George, T. I., Hadzijusufovic, E., Wolf, D., Gotlib, J., Mahon, F., Metcalfe, D. D., Horny, H., Arock, M. 2017

    Abstract

    Basophils form a distinct cell lineage within the hematopoietic cell family. In various myeloid neoplasms, including chronic myeloid leukemia, basophilia is frequently seen. Acute and chronic basophilic leukemias, albeit rare, have also been described. However, no generally accepted criteria and classification of basophilic leukemias have been presented to date. To address this unmet need, a series of Working Conferences and other meetings were organized between March 2015 and March 2016. The current article provides a summary of consensus statements from these meetings, together with proposed criteria to delineate acute basophilic leukemia (ABL) from chronic basophilic leukemia (CBL) and primary forms of the disease where no preceding myeloid malignancy is detected, from the more common 'secondary' variants. Moreover, the term hyperbasophilia (HB) is proposed for cases with a persistent peripheral basophil count ⩾1000 per μl of blood. This condition, HB, is highly indicative of the presence of an underlying myeloid neoplasm. Therefore, HB is an important checkpoint in the diagnostic algorithm and requires a detailed hematologic investigation. In these patients, an underlying myeloid malignancy is often found and is then labeled with the appendix -baso, whereas primary cases of ABL or CBL are very rare. The criteria and classification proposed in this article should facilitate the diagnosis and management of patients with unexplained basophilia and basophil neoplasms in routine practice, and in clinical studies.

    View details for DOI 10.1038/leu.2017.15

    View details for PubMedID 28090091

  • Myeloid neoplasms with eosinophilia BLOOD Reiter, A., Gotlib, J. 2017; 129 (6): 704-714

    Abstract

    Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases generated by dysregulated fusion tyrosine kinase (TK) genes is recognized by the World Health Organization (WHO) category, "Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2" In addition to myeloproliferative neoplasms (MPN), these patients can present with myelodysplastic syndrome/MPN, as well as de novo or secondary mixed-phenotype leukemias or lymphomas. Eosinophilia is a common, but not invariable, feature of these diseases. The natural history of PDGFRA- and PDGFRB-rearranged neoplasms has been dramatically altered by imatinib. In contrast, patients with FGFR1 and JAK2 fusion TK genes exhibit a more aggressive course and variable sensitivity to current TK inhibitors, and in most cases, long-term disease-free survival may only be achievable with allogeneic hematopoietic stem cell transplantation. Similar poor prognosis outcomes may be observed with rearrangements of FLT3 or ABL1 (eg, both of which commonly partner with ETV6), and further investigation is needed to validate their inclusion in the current WHO-defined group of eosinophilia-associated TK fusion-driven neoplasms. The diagnosis chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is assigned to patients with MPN with eosinophilia and nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts. Myeloid mutation panels have identified somatic variants in patients with a provisional diagnosis of hypereosinophilia of undetermined significance, reclassifying some of these cases as eosinophilia-associated neoplasms. Looking forward, one of the many challenges will be how to use the results of molecular profiling to guide prognosis and selection of actionable therapeutic targets.

    View details for DOI 10.1182/blood-2016-10-695973

    View details for Web of Science ID 000397017100009

    View details for PubMedID 28028030

  • The Significance of CD56 Expression and the RAM Immunophenotype, a Recurrent Immunophenotype Seen in Children, in Adult Acute Myeloid Leukemia Lazzareschi, D., Cherry, A., Zehnder, J., Gotlib, J., Arber, D. A., Lacayo, N., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 358A–359A
  • Mast Cell Leukemia (MCL); Clinicopathologic Features of a Rare Disease Davion, S., Wang, S., Silva, O., Sadigh, S., Arber, D. A., Bagg, A., Gotlib, J., George, T. NATURE PUBLISHING GROUP. 2017: 345A
  • Quantitative Analysis of Ki67 in Mastocytosis Distinguishes Mast Cell Leukemia from Other Subtypes Sojitra, P., Hatch, E. W., Martin, C., Gotlib, J. R., Ward, H., Lidke, D. S., George, T. NATURE PUBLISHING GROUP. 2017: 378A
  • Mast Cell Leukemia (MCL); Clinicopathologic Features of a Rare Disease Davion, S., Wang, S., Silva, O., Sadigh, S., Arber, D. A., Bagg, A., Gotlib, J., George, T. NATURE PUBLISHING GROUP. 2017: 345A
  • Quantitative Analysis of Ki67 in Mastocytosis Distinguishes Mast Cell Leukemia from Other Subtypes Sojitra, P., Hatch, E. W., Martin, C., Gotlib, J. R., Ward, H., Lidke, D. S., Geoige, T. NATURE PUBLISHING GROUP. 2017: 378A
  • The Significance of Morphologic Dysplasia in 432 Cases of Acute Lymphoblastic Leukemia and Acute Leukemia of Ambiguous Lineage: Correlation with Cytogenetic, Immunophenotypic, and Molecular Findings Segal, J., Dahl, G., Lacayo, N., Gotlib, J., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 376A
  • A Detailed Multi parameter Flow Cytometry Study of 365 Cases of B-Lymphoblastic Leukemia with Subtyping According to the 2016 WHO: A Single Institutional Study Segal, J., Lacayo, N., Gotlib, J., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 376A
  • Detailed Multiparameter Flow Cytometry Study of 365 Cases of B-Lymphoblastic Leukemia with Subtyping According to the 2016 WHO: A Single Institutional Study Segal, J., Lacayo, N., Gotlib, J., Ohgamt, R. NATURE PUBLISHING GROUP. 2017: 376A
  • The Significance of Morphologic Dysplasia in 432 Cases of Acute Lymphoblastic Leukemia and Acute Leukemia of Ambiguous Lineage: Correlation with Cytogenetic, Immunophenotypic, and Molecular Findings Segal, J., Dahl, G., Lacayo, N., Gotlib, J., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 376A
  • The Significance of CD56 Expression and the RAM Immunophenotype, a Recurrent Immunophenotype Seen in Children, in Adult Acute Myeloid Leukemia Lazzareschi, D., Cherry, A., Zehnder, J., Gotlib, J., Arber, D. A., Lacayo, N., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 358A–359A
  • The clinicopathologic significance of lymphocyte subsets in acute myeloid leukemia. International journal of laboratory hematology Alcasid, M., Ma, L., Gotlib, J. R., Arber, D. A., Ohgami, R. S. 2017

    Abstract

    While the role of the immune system in altering and modulating the progression of solid tumors is well studied, the impact of the immune system on the outcome and progression of hematolymphoid neoplasms is still poorly understood.Here, we report a retrospective study detailing our analysis of 130 patients with acute myeloid leukemia (AML), with flow cytometry immunophenotypic evaluation of major lymphocyte subsets including B cells, T cells, and NK cells.Our study identifies differential signatures of lymphocyte subsets pertaining to distinct subcategories of AML, and prognostic correlations in patients. In multivariate analysis, NK cells (specifically CD56+/CD16+ NK cells at a cutoff of ≥5%) were found to be an independent indicator of improved overall and disease-free survival; cytogenetic risk was also shown to be critical in stratifying patients with AML.In total, we demonstrate that in AML, the subset distribution of immune system lymphocytes is nonrandom, and suggest an important role for distinct lymphocyte subsets, particularly NK cells, in this disease.

    View details for DOI 10.1111/ijlh.12594

    View details for PubMedID 28133918

  • Intricate and Cell Type-Specific Populations of Endogenous Circular DNA (eccDNA) in Caenorhabditis elegans and Homo sapiens G3: GENES, GENOMES, GENETICS Shoura, M., Gabdank, I., Merker, J., Gotlib, J., Levene, S., Fire, A. 2017; 7: 3295-3303

    Abstract

    Investigations aimed at defining the 3D configuration of eukaryotic chromosomes have consistently encountered an endogenous population of chromosome-derived circular genomic DNA, referred to as extrachromosomal circular DNA (eccDNA). While the production, distribution, and activities of eccDNAs remain understudied, eccDNA formation from specific regions of the linear genome has profound consequences on the regulatory and coding capabilities for these regions. Here, we define eccDNA distributions in Caenorhabditis elegans and in three human cell types, utilizing a set of DNA topology-dependent approaches for enrichment and characterization. The use of parallel biophysical, enzymatic, and informatic approaches provides a comprehensive profiling of eccDNA robust to isolation and analysis methodology. Results in human and nematode systems provide quantitative analysis of the eccDNA loci at both unique and repetitive regions. Our studies converge on and support a consistent picture, in which endogenous genomic DNA circles are present in normal physiological states, and in which the circles come from both coding and noncoding genomic regions. Prominent among the coding regions generating DNA circles are several genes known to produce a diversity of protein isoforms, with mucin proteins and titin as specific examples.

    View details for DOI 10.1534/g3.117.300141

    View details for PubMedCentralID PMC5633380

  • Proposed Terminology and Classification of Pre-Malignant Neoplastic Conditions: A Consensus Proposal. EBioMedicine Valent, P. n., Akin, C. n., Arock, M. n., Bock, C. n., George, T. I., Galli, S. J., Gotlib, J. n., Haferlach, T. n., Hoermann, G. n., Hermine, O. n., Jäger, U. n., Kenner, L. n., Kreipe, H. n., Majeti, R. n., Metcalfe, D. D., Orfao, A. n., Reiter, A. n., Sperr, W. R., Staber, P. B., Sotlar, K. n., Schiffer, C. n., Superti-Furga, G. n., Horny, H. P. 2017; 26: 17–24

    Abstract

    Cancer evolution is a step-wise non-linear process that may start early in life or later in adulthood, and includes pre-malignant (indolent) and malignant phases. Early somatic changes may not be detectable or are found by chance in apparently healthy individuals. The same lesions may be detected in pre-malignant clonal conditions. In some patients, these lesions may never become relevant clinically whereas in others, they act together with additional pro-oncogenic hits and thereby contribute to the formation of an overt malignancy. Although some pre-malignant stages of a malignancy have been characterized, no global system to define and to classify these conditions is available. To discuss open issues related to pre-malignant phases of neoplastic disorders, a working conference was organized in Vienna in August 2015. The outcomes of this conference are summarized herein and include a basic proposal for a nomenclature and classification of pre-malignant conditions. This proposal should assist in the communication among patients, physicians and scientists, which is critical as genome-sequencing will soon be offered widely for early cancer-detection.

    View details for PubMedID 29203377

  • Intricate and Cell Type-Specific Populations of Endogenous Circular DNA (eccDNA) in Caenorhabditis elegans and Homo sapiens. G3 (Bethesda, Md.) Shoura, M. J., Gabdank, I. n., Hansen, L. n., Merker, J. n., Gotlib, J. n., Levene, S. D., Fire, A. Z. 2017; 7 (10): 3295–3303

    Abstract

    Investigations aimed at defining the 3D configuration of eukaryotic chromosomes have consistently encountered an endogenous population of chromosome-derived circular genomic DNA, referred to as extrachromosomal circular DNA (eccDNA). While the production, distribution, and activities of eccDNAs remain understudied, eccDNA formation from specific regions of the linear genome has profound consequences on the regulatory and coding capabilities for these regions. Here, we define eccDNA distributions in Caenorhabditis elegans and in three human cell types, utilizing a set of DNA topology-dependent approaches for enrichment and characterization. The use of parallel biophysical, enzymatic, and informatic approaches provides a comprehensive profiling of eccDNA robust to isolation and analysis methodology. Results in human and nematode systems provide quantitative analysis of the eccDNA loci at both unique and repetitive regions. Our studies converge on and support a consistent picture, in which endogenous genomic DNA circles are present in normal physiological states, and in which the circles come from both coding and noncoding genomic regions. Prominent among the coding regions generating DNA circles are several genes known to produce a diversity of protein isoforms, with mucin proteins and titin as specific examples.

    View details for PubMedID 28801508

  • Prognostic Factors and Survival Prediction in 1,088 Patients with Mastocytosis Collected in the Registry of the European Competence Network on Mastocytosis (ECNM Registry) Sperr, W. R., Kundi, M., Elberink, H., van Anrooij, B., Gleixner, K. V., Hadzijusufovic, E., Gorska, A., Lange, M., Rabenhorst, A., Merante, S., Elena, C., Fortina, A., Fontana, E., Schwaab, J., Jawhar, M., Zanotti, R., Bonadonna, P., Triggiani, M., Perkins, C., Gotlib, J. R., Doubek, M., Shoumaryeh, K., Fuchs, D., Sabato, V., Brockow, K., Bretterklieber, A., Jaekel, N., Reiter, A., Hartmann, K., Niedoszytko, M., Kluin-Nelemans, H. C., Valent, P. AMER SOC HEMATOLOGY. 2016
  • NCCN Guidelines (R) Insights Chronic Myeloid Leukemia, Version 1.2017 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Pallera, A., Altman, J. K., Berman, E., Abboud, C. N., Bhatnagar, B., Curtin, P., DeAngelo, D. J., Gotlib, J., Hagelstrom, R. T., Hobbs, G., Jagasia, M., Kantarjian, H. M., Kropf, P., Metheny, L., Moore, J. O., Ontiveros, E., Purev, E., Quiery, A., Reddy, V. V., Rose, M. G., Shah, N. P., Smith, B. D., Snyder, D. S., Sweet, K. L., Tibes, R., Yang, D. T., Gregory, K., Sundar, H., Deininger, M., Radich, J. P. 2016; 14 (12): 1505-1512

    Abstract

    The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population.

    View details for Web of Science ID 000389962100004

  • Myeloproliferative Neoplasms, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network Mesa, R., Jamieson, C., Bhatia, R., Deininger, M. W., Gerds, A. T., Gojo, I., Gotlib, J., Gundabolu, K., Hobbs, G., Klisovic, R. B., Kropf, P., Mohan, S. R., Oh, S., Padron, E., Podoltsev, N., Pollyea, D. A., Rampal, R., Rein, L. A., Scott, B., Snyder, D. S., Stein, B. L., Verstovsek, S., Wadleigh, M., Wang, E. S., Bergman, M. A., Gregory, K. M., Sundar, H. 2016; 14 (12): 1572-1611

    Abstract

    Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.

    View details for PubMedID 27956542

  • Myeloproliferative Neoplasms, Version 2.2017 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Mesa, R., Jamieson, C., Bhatia, R., Deininger, M. W., Gerds, A. T., Gojo, I., Gotlib, J., Gundabolu, K., Hobbs, G., Klisovic, R. B., Kropf, P., Mohan, S. R., Oh, S., Padron, E., Podoltsev, N., Pollyea, D. A., Rampal, R., Rein, L. A., Scott, B., Snyder, D. S., Stein, B. L., Verstovsek, S., Wadleigh, M., Wang, E. S., Bergman, M. A., Gregory, K. M., Sundar, H. 2016; 14 (12): 1572-1611

    Abstract

    Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The diagnosis and the management of patients with MPNs have evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL mutations) and the development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnostic workup of MPN (MF, PV, and ET), risk stratification, treatment, and supportive care strategies for the management of MF.

    View details for Web of Science ID 000389962100011

  • Advanced systemic mastocytosis: from molecular and genetic progress to clinical practice. Haematologica Ustun, C., Arock, M., Kluin-Nelemans, H. C., Reiter, A., Sperr, W. R., George, T., Horny, H., Hartmann, K., Sotlar, K., Damaj, G., Hermine, O., Verstovsek, S., Metcalfe, D. D., Gotlib, J., Akin, C., Valent, P. 2016; 101 (10): 1133-1143

    Abstract

    Systemic mastocytosis is a heterogeneous disease characterized by the accumulation of neoplastic mast cells in the bone marrow and other organ organs/tissues. Mutations in KIT, most frequently KIT D816V, are detected in over 80% of all systemic mastocytosis patients. While most systemic mastocytosis patients suffer from an indolent disease variant, some present with more aggressive variants, collectively called "advanced systemic mastocytosis", which include aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic, clonal non mast cell-lineage disease, and mast cell leukemia. Whereas patients with indolent systemic mastocytosis have a near normal life expectancy, patients with advanced systemic mastocytosis have a reduced life expectancy. Although cladribine and interferon-alpha are of benefit in a group of patients with advanced systemic mastocytosis, no curative therapy is available for these patients except possible allogeneic hematopoietic stem cell transplantation. Recent studies have also revealed additional somatic defects (apart from mutations in KIT) in a majority of patients with advanced systemic mastocytosis. These include TET2, SRSF2, ASXL1, RUNX1, JAK2, and/or RAS mutations, which may adversely impact prognosis and survival in particular systemic mastocytosis with an associated hematological neoplasm. In addition, several additional signaling molecules involved in the abnormal proliferation of mast cells in systemic mastocytosis have been identified. These advances have led to a better understanding of the biology of advanced systemic mastocytosis and to the development of new targeted treatment concepts. Herein, we review the biology and pathogenesis of advanced systemic mastocytosis, with a special focus on novel molecular findings as well as current and evolving therapeutic options.

    View details for PubMedID 27694501

  • Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood Hinds, D. A., Barnholt, K. E., Mesa, R. A., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. Y., Nguyen, H. M., Zhang, H., Gojenola, L., Zehnder, J. L., Gotlib, J. 2016; 128 (8): 1121-1128

    Abstract

    We conducted a genome-wide association study (GWAS) to identify novel predisposition alleles associated with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and JAK2 V617F clonal hematopoiesis in the general population. We recruited a web-based cohort of 726 individuals with polycythemia vera, essential thrombocythemia, and myelofibrosis and 252 637 population controls unselected for hematologic phenotypes. Using a single-nucleotide polymorphism (SNP) array platform with custom probes for the JAK2 V617F mutation (V617F), we identified 497 individuals (0.2%) among the population controls who were V617F carriers. We performed a combined GWAS of the MPN cases plus V617F carriers in the control population (n = 1223) vs the remaining controls who were noncarriers for V617F (n = 252 140). For these MPN cases plus V617F carriers, we replicated the germ line JAK2 46/1 haplotype (rs59384377: odds ratio [OR] = 2.4, P = 6.6 × 10(-89)), previously associated with V617F-positive MPN. We also identified genome-wide significant associations in the TERT gene (rs7705526: OR = 1.8, P = 1.1 × 10(-32)), in SH2B3 (rs7310615: OR = 1.4, P = 3.1 × 10(-14)), and upstream of TET2 (rs1548483: OR = 2.0, P = 2.0 × 10(-9)). These associations were confirmed in a separate replication cohort of 446 V617F carriers vs 169 021 noncarriers. In a joint analysis of the combined GWAS and replication results, we identified additional genome-wide significant predisposition alleles associated with CHEK2, ATM, PINT, and GFI1B All SNP ORs were similar for MPN patients and controls who were V617F carriers. These data indicate that the same germ line variants endow individuals with a predisposition not only to MPN, but also to JAK2 V617F clonal hematopoiesis, a more common phenomenon that may foreshadow the development of an overt neoplasm.

    View details for DOI 10.1182/blood-2015-06-652941

    View details for PubMedID 27365426

  • Complete response to gemtuzumab ozogamicin in a patient with refractory mast cell leukemia. Leukemia Alvarez-Twose, I., Martínez-Barranco, P., Gotlib, J., García-Montero, A., Morgado, J. M., Jara-Acevedo, M., Merker, J. D., Peñalver, F. J., Matito, A., Hou, Y., Sánchez-Muñoz, L., Mayado, A., Mollejo, M., Escribano, L., Orfao, A. 2016; 30 (8): 1753-1756

    View details for DOI 10.1038/leu.2016.30

    View details for PubMedID 26876592

  • Consensus Opinion on Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Ustun, C., Gotlib, J., Popat, U., Artz, A., Litzow, M., Reiter, A., Nakamura, R., Kluin-Nelemans, H. C., Verstovsek, S., Gajewskil, J., Perales, M., George, T., Shore, T., Sperr, W., Saber, W., Kota, V., Yavuz, A., Pullarkat, V., Rogosheske, J., Hogan, W., Van Besien, K., Hagglund, H., Damaj, G., Arock, M., Horny, H., Metcalfe, D. D., Deeg, H., Devine, S., Weisdorfl, D., Akin, C., Valent, P. 2016; 22 (8): 1348–56

    View details for PubMedID 27131865

  • Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis NEW ENGLAND JOURNAL OF MEDICINE Gotlib, J., Kluin-Nelemans, H. C., George, T. I., Akin, C., Sotlar, K., Hermine, O., Awan, F. T., Hexner, E., Mauro, M. J., Sternberg, D. W., Villeneuve, M., Labed, A. H., Stanek, E. J., Hartmann, K., Horny, H., Valent, P., Reiter, A. 2016; 374 (26): 2530-2541

    Abstract

    Advanced systemic mastocytosis comprises rare hematologic neoplasms that are associated with a poor prognosis and lack effective treatment options. The multikinase inhibitor midostaurin inhibits KIT D816V, a primary driver of disease pathogenesis.We conducted an open-label study of oral midostaurin at a dose of 100 mg twice daily in 116 patients, of whom 89 with mastocytosis-related organ damage were eligible for inclusion in the primary efficacy population; 16 had aggressive systemic mastocytosis, 57 had systemic mastocytosis with an associated hematologic neoplasm, and 16 had mast-cell leukemia. The primary outcome was the best overall response.The overall response rate was 60% (95% confidence interval [CI], 49 to 70); 45% of the patients had a major response, which was defined as complete resolution of at least one type of mastocytosis-related organ damage. Response rates were similar regardless of the subtype of advanced systemic mastocytosis, KIT mutation status, or exposure to previous therapy. The median best percentage changes in bone marrow mast-cell burden and serum tryptase level were -59% and -58%, respectively. The median overall survival was 28.7 months, and the median progression-free survival was 14.1 months. Among the 16 patients with mast-cell leukemia, the median overall survival was 9.4 months (95% CI, 7.5 to not estimated). Dose reduction owing to toxic effects occurred in 56% of the patients; re-escalation to the starting dose was feasible in 32% of those patients. The most frequent adverse events were low-grade nausea, vomiting, and diarrhea. New or worsening grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 24%, 41%, and 29% of the patients, respectively, mostly in those with preexisting cytopenias.In this open-label study, midostaurin showed efficacy in patients with advanced systemic mastocytosis, including the highly fatal variant mast-cell leukemia. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT00782067.).

    View details for DOI 10.1056/NEJMoa1513098

    View details for PubMedID 27355533

  • A phase 1, open-label, dose-escalation study of pralatrexate in combination with bortezomib in patients with relapsed/refractory multiple myeloma. British journal of haematology Dunn, T. J., Dinner, S., Price, E., Coutré, S. E., Gotlib, J., Hao, Y., Berube, C., Medeiros, B. C., Liedtke, M. 2016; 173 (2): 253-259

    Abstract

    Pralatrexate inhibits folic acid metabolism, and preclinical studies have shown that it is cytotoxic to multiple myeloma cells. This phase 1 study investigated the safety and efficacy of pralatrexate in combination with bortezomib in adults with relapsed or refractory multiple myeloma. A standard 3 + 3 design was used. Patients received intravenous pralatrexate at doses ranging from 10 to 30 mg/m(2) and intravenous bortezomib at a dose of 1·3 mg/m(2) on days 1, 8 and 15 of each 4-week cycle. Eleven patients were enrolled and completed a median of two cycles. The maximum tolerated dose was 20 mg/m(2) . Two patients experienced dose-limiting toxicity of mucositis. The most frequent non-haematological toxicities were fatigue (55%) and mucositis (45%). There were three serious adverse events in three patients: rash, sepsis and hypotension. One patient (9%) had a very good partial response, 1 (9%) had a partial response, 1 (9%) had minimal response and two (18%) had progressive disease. The median duration of response was 4 months, the median time to next treatment was 3·4 months and the median time to progression was 4 months. Pralatrexate, in combination with bortezomib, was generally safe and demonstrated modest activity in relapsed or refractory multiple myeloma. Clinicaltrials.gov identifier: NCT01114282.

    View details for DOI 10.1111/bjh.13946

    View details for PubMedID 27040320

  • Age-related mutations and chronic myelomonocytic leukemia LEUKEMIA Mason, C. C., Khorashad, J. S., Tantravahi, S. K., Kelley, T. W., Zabriskie, M. S., Yan, D., Pomicter, A. D., Reynolds, K. R., Eiring, A. M., Kronenberg, Z., Sherman, R. L., Tyner, J. W., Dalley, B. K., Dao, K., Yandell, M., Druker, B. J., Gotlib, J., O'Hare, T., Deininger, M. W. 2016; 30 (4): 906-913

    Abstract

    Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

    View details for DOI 10.1038/leu.2015.337

    View details for PubMedID 26648538

  • Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia Khodadoust, M. S., Luo, B., Medeiros, B. C., Johnson, R. C., Ewalt, M. D., Schalkwyk, A. S., Bangs, C. D., Cherry, A. M., Arai, S., Arber, D. A., Zehnder, J. L., Gotlib, J. 2016; 30 (4): 947-950

    View details for DOI 10.1038/leu.2015.136

    View details for PubMedID 26055304

  • Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome LEUKEMIA & LYMPHOMA Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

    Abstract

    The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

    View details for DOI 10.3109/10428194.2015.1091930

    View details for Web of Science ID 000372499800017

  • Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leukemia & lymphoma Narayan, R., Garcia, J. S., Percival, M. M., Berube, C., Coutre, S., Gotlib, J., Greenberg, P., Liedtke, M., Hewitt, R., Regan, K., Williamson, C., Doykan, C., Cardone, M. H., McMillan, A., Medeiros, B. C. 2016; 57 (3): 609-615

    Abstract

    The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). We describe a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. Median number of treatment cycles on study was two (range, 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders versus non-responders was 9.8 versus 4.0 months, respectively (HR 0.36, p=0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

    View details for DOI 10.3109/10428194.2015.1091930

    View details for PubMedID 26374199

  • The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618I. Clinical cancer research Maxson, J. E., Luty, S. B., Macmaniman, J. D., Paik, J. C., Gotlib, J., Greenberg, P., Bahamadi, S., Savage, S. L., Abel, M. L., Eide, C. A., Loriaux, M. M., Stevens, E. A., Tyner, J. W. 2016; 22 (3): 757-764

    Abstract

    Colony-stimulating factor 3 receptor (CSF3R) mutations have been identified in the majority of chronic neutrophilic leukemia (CNL) and a smaller percentage of atypical chronic myeloid leukemia (aCML) cases. Although CSF3R point mutations (e.g., T618I) are emerging as key players in CNL/aCML, the significance of rarer CSF3R mutations is unknown. In this study, we assess the importance of the CSF3R T640N mutation as a marker of CNL/aCML and potential therapeutic target.Sanger sequencing of leukemia samples was performed to identify CSF3R mutations in CNL and aCML. The oncogenicity of the CSF3R T640N mutation relative to the T618I mutation was assessed by cytokine independent growth assays and by mouse bone marrow transplant. Receptor dimerization and O-glycosylation of the mutants was assessed by Western blot, and JAK inhibitor sensitivity was assessed by colony assay.Here, we identify a CSF3R T640N mutation in two patients with CNL/aCML, one of whom was originally diagnosed with MDS and acquired the T640N mutation upon evolution of disease to aCML. The T640N mutation is oncogenic in cellular transformation assays and an in vivo mouse bone marrow transplantation model. It exhibits many similar phenotypic features to T618I, including ligand independence and altered patterns of O-glycosylation-despite the transmembrane location of T640 preventing access by GalNAc transferase enzymes. Cells transformed by the T640N mutation are sensitive to JAK kinase inhibition to a similar degree as cells transformed by CSF3R T618I.Because of its similarities to CSF3R T618I, the T640N mutation likely has diagnostic and therapeutic relevance in CNL/aCML. Clin Cancer Res; 1-8. ©2015 AACR.

    View details for DOI 10.1158/1078-0432.CCR-14-3100

    View details for PubMedID 26475333

  • PD-1/PD-L1 Are Novel Therapeutic Targets for Mastocytosis Geeze, M., Hatch, E., Martin, C., Perkins, S. L., Hartmann, K., Valent, P., Gotlib, J., Lidke, D., George, T. I. NATURE PUBLISHING GROUP. 2016: 346A
  • PD-1/PD-L1 Are Novel Therapeutic Targets for Mastocytosis Geeze, M., Hatch, E., Martin, C., Perkins, S. L., Hartmann, K., Valent, P., Gotlib, J., Lidke, D., George, T. I. NATURE PUBLISHING GROUP. 2016: 346A
  • Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Hartmann, K., Escribano, L., Grattan, C., Brockow, K., Carter, M. C., Alvarez-Twose, I., Matito, A., Broesby-Olsen, S., Siebenhaar, F., Lange, M., Niedoszytko, M., Castells, M., Oude Elberink, J. N., Bonadonna, P., Zanotti, R., Hornick, J. L., Torrelo, A., Grabbe, J., Rabenhorst, A., Nedoszytko, B., Butterfield, J. H., Gotlib, J., Reiter, A., Radia, D., Hermine, O., Sotlar, K., George, T. I., Kristensen, T. K., Kluin-Nelemans, H. C., Yavuz, S., Hagglund, H., Sperr, W. R., Schwartz, L. B., Triggiani, M., Maurer, M., Nilsson, G., Horny, H., Arock, M., Orfao, A., Metcalfe, D. D., Akin, C., Valent, P. 2016; 137 (1): 35-45

    Abstract

    Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.

    View details for DOI 10.1016/j.jaci.2015.08.034

    View details for Web of Science ID 000367724300041

  • Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. The Journal of allergy and clinical immunology Hartmann, K. n., Escribano, L. n., Grattan, C. n., Brockow, K. n., Carter, M. C., Alvarez-Twose, I. n., Matito, A. n., Broesby-Olsen, S. n., Siebenhaar, F. n., Lange, M. n., Niedoszytko, M. n., Castells, M. n., Oude Elberink, J. N., Bonadonna, P. n., Zanotti, R. n., Hornick, J. L., Torrelo, A. n., Grabbe, J. n., Rabenhorst, A. n., Nedoszytko, B. n., Butterfield, J. H., Gotlib, J. n., Reiter, A. n., Radia, D. n., Hermine, O. n., Sotlar, K. n., George, T. I., Kristensen, T. K., Kluin-Nelemans, H. C., Yavuz, S. n., Hägglund, H. n., Sperr, W. R., Schwartz, L. B., Triggiani, M. n., Maurer, M. n., Nilsson, G. n., Horny, H. P., Arock, M. n., Orfao, A. n., Metcalfe, D. D., Akin, C. n., Valent, P. n. 2016; 137 (1): 35–45

    Abstract

    Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.

    View details for PubMedID 26476479

  • PRM-151 in Myelofibrosis: Durable Efficacy and Safety at 72 Weeks Verstovsek, S., Mesa, R. A., Foltz, L. M., Gupta, V., Mascarenhas, J. O., Ritchie, E. K., Hoffman, R., Silver, R. T., Kremyanskaya, M., Pozdnyakova, O., Hasserjian, R. P., Trehu, E., Salama, M. E., Kantarjian, H. M., Gotlib, J. AMER SOC HEMATOLOGY. 2015
  • A Phase 2 Study to Evaluate the Efficacy and Safety of Simtuzumab in Adult Subjects with Primary, Post Polycythemia Vera (PV) or Post Essential Thrombocythemia (ET) Myelofibrosis Verstovsek, S., Savona, M. R., Mesa, R. A., Oh, S., Dong, H., Thai, D., Gotlib, J. AMER SOC HEMATOLOGY. 2015
  • Tyrosine Kinase Inhibitors and Therapeutic Antibodies in Advanced Eosinophilic Disorders and Systemic Mastocytosis CURRENT HEMATOLOGIC MALIGNANCY REPORTS Gotlib, J. 2015; 10 (4): 351-361

    Abstract

    World Health Organization-defined myeloproliferative neoplasms share a common pathobiologic theme of constitutive activation of tyrosine kinases (TKs). While myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA or PDGFRB exhibit exquisite responsiveness to imatinib, other eosinophilic disorders such as chronic eosinophilic leukemia--not otherwise specified (CEL-NOS) and idiopathic hypereosinophilic syndrome (HES) lack recurrent gene mutations or known druggable targets. In systemic mastocytosis (SM), KIT D816V is identified in ∼ 90% of patients, but demonstrates imatinib resistance. Recently, the multikinase/KIT inhibitor midostaurin (PKC412) has demonstrated encouraging activity in patients with advanced SM, and selective KIT D816V inhibitors are entering clinical development. Pre-clinical rationale also exists for use of small molecule inhibitors of TK-linked pathways (e.g., BTK, JAK-STAT, PI3K/AKT, and FGFR1) that are implicated in normal or dysregulated signaling in eosinophils or mast cells. A complementary therapeutic approach is the use of naked antibody (e.g., mepolizumab and alemtuzumab) or antibody-based drug immunoconjugates (brentuximab vedotin) against targets expressed on the surface of eosinophils or mastocytes that can block proliferation and/or induce apoptosis of these cells. Ultimately, biologic and molecular characterization of eosinophilia and SM cases will help to optimize selection of TK inhibitors or therapeutic antibodies for individual patients.

    View details for DOI 10.1007/s11899-015-0280-3

    View details for Web of Science ID 000366354900003

    View details for PubMedID 26404639

  • World Health Organization-defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2015; 90 (11): 1078–89

    Abstract

    The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder.Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified, (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion.The goal of the therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

    View details for DOI 10.1002/ajh.24196

    View details for Web of Science ID 000363463600023

    View details for PubMedID 26486351

  • Effect of treatment with a JAK2-selective inhibitor, fedratinib, on bone marrow fibrosis in patients with myelofibrosis JOURNAL OF TRANSLATIONAL MEDICINE Jamieson, C., Hasserjian, R., Gotlib, J., Cortes, J., Stone, R., Talpaz, M., Thiele, J., Rodig, S., Pozdnyakova, O. 2015; 13

    Abstract

    Progressive bone marrow fibrosis (BMF) is a cardinal feature of many myeloproliferative neoplasms (MPNs) and there is a documented association between the severity of BMF and overall prognosis. We conducted an exploratory analysis of sequential BMF data from two phase I studies of long-term treatment with the Janus kinase 2 (JAK2) inhibitor fedratinib in patients with myelofibrosis.Bone marrow samples were obtained at baseline and after every six cycles (24 weeks) of daily fedratinib treatment. Fibrosis was centrally assessed by three independent haematopathologists, who were blinded to the patients' data, and graded according to European Consensus Myelofibrosis Grading Criteria. The analysis population comprised patients with a baseline BMF grade ≥1, and at least one post-baseline BMF grade assessment. Changes in BMF grade compared with baseline were classified as improvement (≥1 grade reduction), stabilisation (no change in any baseline BMF grade <3) or worsening (≥1 grade increase).Twenty-one patients were included in the analysis. A total of 153 bone marrow samples were analysed. Improvement or stabilisation of BMF from baseline was recorded in 15 of 18 (83%) evaluable patients at cycle 6 and in four of nine (44%) evaluable patients at cycle 30. Two patients achieved resolution of their BMF (grade = 0) by cycle 12.This exploratory analysis indicates that improvement or even resolution of BMF may be achievable with JAK2 inhibitor therapy in some patients with MPNs and myelofibrosis.

    View details for DOI 10.1186/s12967-015-0644-4

    View details for Web of Science ID 000361029500001

    View details for PubMedID 26357842

    View details for PubMedCentralID PMC4566296

  • A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis HAEMATOLOGICA Vannucchi, A. M., Kantarjian, H. M., Kiladjian, J., Gotlib, J., Cervantes, F., Mesa, R. A., Sarlis, N. J., Peng, W., Sandor, V., Gopalakrishna, P., Hmissi, A., Stalbovskaya, V., Gupta, V., Harrison, C., Verstovsek, S. 2015; 100 (9): 1139-1145

    Abstract

    Ruxolitinib, a potent Janus kinase 1/2 inhibitor, resulted in rapid and durable improvements in splenomegaly and disease-related symptoms in the 2 phase III COMFORT studies. In addition, ruxolitinib was associated with prolonged survival compared with placebo (COMFORT-I) and best available therapy (COMFORT-II). We present a pooled analysis of overall survival in the COMFORT studies using an intent-to-treat analysis and an analysis correcting for crossover in the control arms. Overall, 301 patients received ruxolitinib (COMFORT-I, n=155; COMFORT-II, n=146) and 227 patients received placebo (n=154) or best available therapy (n=73). After a median three years of follow up, intent-to-treat analysis showed that patients who received ruxolitinib had prolonged survival compared with patients who received placebo or best available therapy [hazard ratio=0.65; 95% confidence interval (95%CI): 0.46-0.90; P=0.01]; the crossover-corrected hazard ratio was 0.29 (95%CI: 0.13-0.63). Both patients with intermediate-2- or high-risk disease showed prolonged survival, and patients with high-risk disease in the ruxolitinib group had survival similar to that of patients with intermediate-2-risk disease in the control group. The Kaplan-Meier estimate of overall survival at week 144 was 78% in the ruxolitinib arm, 61% in the intent-to-treat control arm, and 31% in the crossover-adjusted control arm. While larger spleen size at baseline was prognostic for shortened survival, reductions in spleen size with ruxolitinib treatment correlated with longer survival. These findings are consistent with previous reports and support that ruxolitinib offers a survival benefit for patients with myelofibrosis compared with conventional therapies. (clinicaltrials.gov identifiers: COMFORT-I, NCT00952289; COMFORT-II, NCT00934544).

    View details for DOI 10.3324/haematol.2014.119545

    View details for PubMedID 26069290

  • Phase II evaluation of IPI-926, an oral Hedgehog inhibitor, in patients with myelofibrosis LEUKEMIA & LYMPHOMA Sasaki, K., Gotlib, J. R., Mesa, R. A., Newberry, K. J., Ravandi, F., Cortes, J. E., Kelly, P., Kutok, J. L., Kantarjian, H. M., Verstovsek, S. 2015; 56 (7): 2092-2097

    Abstract

    The clinical safety and efficacy of IPI-926 was evaluated in 14 patients with myelofibrosis in a phase II study. Patients received 160 mg IPI-926 orally in continuous 28-day cycles. The median treatment duration was 5.1 months, and all patients had discontinued treatment by 7.5 months. Nine patients discontinued due to lack of response as determined by the treating physician, two after developing acute leukemia and one due to disease progression/loss of response. Twelve patients had slight reductions in spleen size (less than 50% from baseline), but symptoms did not improve consistently. One patient achieved transfusion independence lasting 5 months. Reductions in GLI1 mRNA and protein levels, JAK2V617F allele burden, degree of fibrosis or cytokine levels were observed in some patients, but were not significant when evaluated for the cohort. Low-grade gastrointestinal/liver abnormalities were the most common toxicities. The results did not support continued evaluation of IPI-926 as a monotherapy in myelofibrosis.

    View details for DOI 10.3109/10428194.2014.984703

    View details for Web of Science ID 000359888700028

    View details for PubMedID 25641433

  • KIT mutation analysis in mast cell neoplasms: recommendations of the European Competence Network on Mastocytosis LEUKEMIA Arock, M., Sotlar, K., Akin, C., Broesby-Olsen, S., Hoermann, G., Escribano, L., Kristensen, T. K., Kluin-Nelemans, H. C., Hermine, O., Dubreuil, P., Sperr, W. R., Hartmann, K., Gotlib, J., Cross, N. C., Haferlach, T., Garcia-Montero, A., Orfao, A., Schwaab, J., Triggiani, M., Horny, H., Metcalfe, D. D., Reiter, A., Valent, P. 2015; 29 (6): 1223-1232
  • To Treat or Not to Treat: A Novel Stratification of Myelofibrosis Patients by Likelihood of Response to JAK2 Inhibitors Menghrajani, K., Boonstra, P. S., Weber, A., Perkins, C., Gowin, K., Huong Nguyen, Mesa, R., Gotlib, J. R., Talpaz, M. CIG MEDIA GROUP, LP. 2015: S236
  • Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations MODERN PATHOLOGY Ohgami, R. S., Ma, L., Merker, J. D., Gotlib, J. R., Schrijver, I., Zehnder, J. L., Arber, D. A. 2015; 28 (5): 706-714

    Abstract

    We assessed the frequency and clinicopathologic significance of 19 genes currently identified as significantly mutated in myeloid neoplasms, RUNX1, ASXL1, TET2, CEBPA, IDH1, IDH2, DNMT3A, FLT3, NPM1, TP53, NRAS, EZH2, CBL, U2AF1, SF3B1, SRSF2, JAK2, CSF3R, and SETBP1, across 93 cases of acute myeloid leukemia (AML) using capture target enrichment and next-generation sequencing. Of these cases, 79% showed at least one nonsynonymous mutation, and cases of AML with recurrent genetic abnormalities showed a lower frequency of mutations versus AML with myelodysplasia-related changes (P<0.001). Mutational analysis further demonstrated that TP53 mutations are associated with complex karyotype AML, whereas ASXL1 and U2AF1 mutations are associated with AML with myelodysplasia-related changes. Furthermore, U2AF1 mutations were specifically associated with trilineage morphologic dysplasia. Univariate analysis demonstrated that U2AF1 and TP53 mutations are associated with absence of clinical remission, poor overall survival (OS), and poor disease-free survival (DFS; P<0.0001), whereas TET2 and ASXL1 mutations are associated with poor OS (P<0.03). In multivariate analysis, U2AF1 and TP53 mutations retained independent prognostic significance in OS and DFS, respectively. Our results demonstrate unique relationships between mutations in AML, clinicopathologic prognosis, subtype categorization, and morphologic dysplasia.Modern Pathology advance online publication, 21 November 2014; doi:10.1038/modpathol.2014.160.

    View details for DOI 10.1038/modpathol.2014.160

    View details for Web of Science ID 000353774200010

    View details for PubMedID 25412851

  • Mast Cells in Systemic Mastocytosis Have Distinctly Brighter CD45 Expression by Flow Cytometry AMERICAN JOURNAL OF CLINICAL PATHOLOGY Chisholm, K. M., Merker, J. D., Gotlib, J. R., Gitana, G., Lefterova, M., Zehnder, J. L., George, T. I., Arber, D. A., Ohgami, R. S. 2015; 143 (4): 527-534

    Abstract

    We sought to determine the significance of bright CD45 expression on mast cells in cases of systemic mastocytosis vs mast cells in bone marrows uninvolved by systemic mastocytosis and compare this CD45 expression with CD25 and CD2 expression on mast cells.Multiparameter flow cytometry was performed on 31 cases of systemic mastocytosis and 70 bone marrow cases that were not involved by systemic mastocytosis. Bright expression of CD45 was defined as more than 20% of CD117+ mast cells showing brighter CD45 expression than the average expression level of lymphocytes.Mast cells with bright CD45 expression were seen in 26 systemic mastocytosis cases and three bone marrows uninvolved by systemic mastocytosis (sensitivity, 84%; specificity, 96%). CD25 alone had a greater sensitivity (100%) but lower specificity (93%) compared with bright CD45 for identifying abnormal mast cells, while CD2 alone had lower sensitivity but higher specificity. To reach a specificity of 100%, CD25 together with bright CD45 on mast cells was the optimal combination to detect cases of systemic mastocytosis.A combination of bright CD45 and CD25 appears to specifically identify abnormal mast cells in cases of systemic mastocytosis. Further studies will be necessary to confirm these results.

    View details for DOI 10.1309/AJCPZ3J4GEEYIRRA

    View details for PubMedID 25780004

  • Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I. Haematologica Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Raza, A., Vaddi, K., Sun, W., Peng, W., Sandor, V., Kantarjian, H. 2015; 100 (4): 479-488

    Abstract

    In the phase III COMFORT-I study, the Janus kinase 1 (JAK1)/JAK2 inhibitor ruxolitinib provided significant improvements in splenomegaly, key symptoms, and quality-of-life measures and was associated with an overall survival benefit relative to placebo in patients with intermediate-2 or high-risk myelofibrosis. This planned analysis assessed the long-term efficacy and safety of ruxolitinib at a median follow-up of 149 weeks. At data cutoff, approximately 50% of patients originally randomized to ruxolitinib remained on treatment whereas all patients originally assigned to placebo had discontinued or crossed over to ruxolitinib. At week 144, mean spleen volume reduction was 34% with ruxolitinib. Previously observed improvements in quality-of-life measures were sustained with longer-term ruxolitinib therapy. Overall survival continued to favor ruxolitinib despite the majority of placebo patients crossing over to ruxolitinib [hazard ratio 0.69 (95% confidence interval: 0.46-1.03); P=0.067]. Exploratory analyses suggest that crossover may have contributed to an underestimation of the true survival difference between the treatment groups. Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥3 anemia or thrombocytopenia with longer-term ruxolitinib exposure. These longer-term data continue to support the efficacy and safety of ruxolitinib in patients with myelofibrosis. The study is registered at clinicaltrials.gov: NCT00952289.

    View details for DOI 10.3324/haematol.2014.115840

    View details for PubMedID 25616577

  • Effects of Ruxolitinib Treatment on Metabolic and Nutritional Parameters in Patients With Myelofibrosis From COMFORT-I CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Mesa, R. A., Verstoysek, S., Gupta, V., Mascarenhas, J. O., Atallah, E., Burn, T., Sun, W., Sandor, V., Gotlib, J. 2015; 15 (4): 214-221

    Abstract

    In the COMFORT (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy)-I study, the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib provided significant reductions in splenomegaly, improvements in myelofibrosis (MF)-related symptoms, and a survival advantage relative to placebo in patients with intermediate-2 or high-risk MF. In this post hoc analysis, we assessed the effects of ruxolitinib treatment on measures of metabolic and nutritional status.Patients were randomized to receive ruxolitinib (n = 155; 15 or 20 mg twice a day for patients with baseline platelet counts of 100-200 × 10(9)/L or > 200 × 10(9)/L, respectively) or placebo (n = 154). The primary end point was the proportion of patients with a ≥ 35% spleen volume reduction from baseline to week 24. A secondary end point was the proportion of patients with ≥ 50% improvement in Total Symptom Score (TSS) from baseline to week 24, measured using the modified Myelofibrosis Symptom Assessment Form version 2.0. Weight, cholesterol, and albumin were measured at specified time points throughout the study.Compared with placebo, ruxolitinib treatment was associated with increased weight (mean change: 3.9 kg vs. -1.9 kg), total cholesterol (mean percentage change: 26.4% vs. -3.3%), and albumin levels (mean percentage change: 5.8% vs. -1.7%) at week 24; sustained improvements were observed with longer-term ruxolitinib therapy. Relative to placebo, increases in mean weight, total cholesterol, and albumin levels were observed with ruxolitinib treatment regardless of the degree of spleen volume and TSS reductions at 24 weeks.Treatment with ruxolitinib improved measures of metabolic and nutritional status of patients with intermediate-2 or high-risk MF.

    View details for DOI 10.1016/j.clml.2014.12.008

    View details for Web of Science ID 000352659300004

    View details for PubMedID 25682576

    View details for PubMedCentralID PMC4418454

  • Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I HAEMATOLOGICA Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Raza, A., Vaddi, K., Sun, W., Peng, W., Sandor, V., Kantarjian, H. 2015; 100 (4): 482-491
  • Historical Views, Conventional Approaches, and Evolving Management Strategies for Myeloproliferative Neoplasms JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Stein, B. L., Gotlib, J., Arcasoy, M., Nguyen, M. H., Shah, N., Moliterno, A., Jamieson, C., Pollyea, D. A., Scott, B., Wadleigh, M., Levine, R., Komrokji, R., Klisovic, R., Gundabolu, K., Kropf, P., Wetzler, M., Oh, S. T., Ribeiro, R., Paschal, R., Mohan, S., Podoltsev, N., Prchal, J., Talpaz, M., Snyder, D., Verstovsek, S., Mesa, R. A. 2015; 13 (4): 424-434

    Abstract

    The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.

    View details for PubMedID 25870379

  • Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance NATURE MEDICINE Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S., Kim, S. S., Liu, H., Tivey, T., Christie, A. L., Elpek, K. G., Card, J., Gritsman, K., Gotlib, J., Deininger, M. W., Makishima, H., Turley, S. J., Javidi-Sharifi, N., Maciejewski, J. P., Jaiswal, S., Ebert, B. L., Rodig, S. J., Tyner, J. W., Marto, J. A., Weinstock, D. M., Lane, A. A. 2015; 21 (1): 71-75

    Abstract

    Activating mutations in genes encoding G protein α (Gα) subunits occur in 4-5% of all human cancers, but oncogenic alterations in Gβ subunits have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors and disrupt Gα interactions with the Gβγ dimer. Different mutations in Gβ proteins clustered partly on the basis of lineage; for example, all 11 GNB1 K57 mutations were in myeloid neoplasms, and seven of eight GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 variants in Cdkn2a-deficient mouse bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K-mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, mutations in the gene encoding GNB1 co-occurred with oncogenic kinase alterations, including the BCR-ABL fusion protein, the V617F substitution in JAK2 and the V600K substitution in BRAF. Coexpression of patient-derived GNB1 variants with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 alterations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.

    View details for DOI 10.1038/nm.3751

    View details for PubMedID 25485910

  • A New Prognostic Model for Response in Myelofibrosis Patients Treated with JAK2 Inhibitors: A Study from Three US Academic Centers Kamal, M., Boonstra, P. S., Weber, A. A., Perkins, C., Gowin, K. L., Huong (Marie) Nguyen, Mesa, R., Gotlib, J. R., Talpaz, M. AMER SOC HEMATOLOGY. 2014
  • GNB1 Activating Mutations Promote Myeloid and Lymphoid Neoplasms Targetable By Combined PI3K/mTOR Inhibition Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S., Kim, S. S., Liu, H., Tivey, T., Christie, A. L., Elpek, K. G., Card, J., Gritsman, K., Gotlib, J., Deininger, M. W., Makishima, H., Turley, S., Javidi-Sharifi, N., Maciejewski, J. P., Rodig, S. J., Tyner, J. W., Marto, J. A., Weinstock, D. M., Lane, A. A. AMER SOC HEMATOLOGY. 2014
  • Phase 2 Trial of PRM-151, an Anti-Fibrotic Agent, in Patients with Myelofibrosis: Stage 1 Results Verstovsek, S., Mesa, R. A., Foltz, L. M., Gupta, V., Mascarenhas, J. O., Ritchie, E. K., Hoffman, R., Silver, R. T., Kremyanskaya, M., Pozdnyakova, O., Hasserjian, R. P., Trehu, E., Kantarjian, H. M., Gotlib, J. R. AMER SOC HEMATOLOGY. 2014
  • Next Generation Sequencing to Delineate the Mutational Landscape of Chronic Myelomonocytic Leukemia (CMML): Novel Disease Genes and Correlations with Survival Mason, C. C., Khorashad, J. S., Tantravahi, S. K., Kelley, T. W., Pomicter, A. D., Iovino, A. J., Reynolds, K. R., Eiring, A. M., Zabriskie, M. S., Kronenberg, Z., Tyner, J. W., Dalley, B., Dao, K. T., O'Hare, T., Yandell, M., Druker, B. J., Gotlib, J. R., Deininger, M. W. AMER SOC HEMATOLOGY. 2014
  • Midostaurin (PKC412) Demonstrates a High Rate of Durable Responses in Patients with Advanced Systemic Mastocytosis: Results from the Fully Accrued Global Phase 2 CPKC412D2201 Trial Gotlib, J., Kluin-Nelemans, H. C., George, T. I., Akin, C., Sotlar, K., Hermine, O., Awan, F., Hexner, E. O., Mauro, M., Sternberg, D., Villeneuve, M., Emery-Salbert, F., Stanek, E., Hartmann, K., Horny, H., Valent, P., Reiter, A. AMER SOC HEMATOLOGY. 2014
  • A New International Multicenter-Based Model to Predict Survival in Myelofibrosis Secondary to Polycythemia and Thrombocythemia: The Mysec Prognostic Model (MYSEC-PM) Passamonti, F., Alessandro, V., Domenica, C., Alessandro, R., Enrica, M., Jacques, K., Komrokji, R. S., Maffioli, M., Gotlib, J., Francisco, C., Devos, T., Silver, R. T., Guglielmelli, P., Vianelli, N., De Stefano, V., Ruggeri, M., Specchia, G., Vitolo, U., Rumi, E., Mora, B., Barbui, T., Pieri, L., Pascutto, C., Cazzola, M. AMER SOC HEMATOLOGY. 2014
  • Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia LEUKEMIA RESEARCH Liedtke, M., Dunn, T., Dinner, S., Coutre, S. E., Berubea, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445

    Abstract

    The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ≥second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

    View details for DOI 10.1016/j.leukres.2014.09.018

    View details for Web of Science ID 000345614400011

  • Salvage therapy with mitoxantrone, etoposide and cytarabine in relapsed or refractory acute lymphoblastic leukemia. Leukemia research Liedtke, M., Dunn, T., Dinner, S., Coutré, S. E., Berube, C., Gotlib, J., Patel, S., Medeiros, B. 2014; 38 (12): 1441-1445

    Abstract

    The survival of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) is poor. We performed a retrospective analysis of 40 patients treated with five days of mitoxantrone 8mg/m(2)/day, etoposide 100mg/m(2)/day, and cytarabine 1000mg/m(2)/day (MEC). The complete remission rate was 30% and median remission duration was 11.2 months. Median overall survival was 6.5 months. In univariate analysis, patients in first relapse had improved overall survival compared to ≥second relapse (p=0.02). Thirty-day mortality rate was 7.5%. In relapsed or refractory ALL, MEC demonstrated moderate activity, but did not improve survival compared to published salvage chemotherapy regimens.

    View details for DOI 10.1016/j.leukres.2014.09.018

    View details for PubMedID 25449689

  • Chronic Myelogenous Leukemia, Version 1.2015 Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Radich, J. P., Abboud, C. N., Akhtari, M., Altman, J. K., Berman, E., Curtin, P., DeAngelo, D. J., Deininger, M., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Kropf, P., Moore, J. O., Pallera, A., Reddy, V. V., Shah, N. P., Smith, B. D., Snyder, D. S., Wetzler, M., Gregory, K., Sundar, H. 2014; 12 (11): 1590-1609

    Abstract

    Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML.

    View details for Web of Science ID 000344516200013

  • Chronic myelogenous leukemia, version 1.2015. Journal of the National Comprehensive Cancer Network O'Brien, S., Radich, J. P., Abboud, C. N., Akhtari, M., Altman, J. K., Berman, E., Curtin, P., DeAngelo, D. J., Deininger, M., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Kropf, P., Moore, J. O., Pallera, A., Reddy, V. V., Shah, N. P., Smith, B. D., Snyder, D. S., Wetzler, M., Gregory, K., Sundar, H. 2014; 12 (11): 1590-1610

    Abstract

    Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML.

    View details for PubMedID 25361806

  • The serum tryptase test: an emerging robust biomarker in clinical hematology EXPERT REVIEW OF HEMATOLOGY Valent, P., Sperr, W. R., Sotlar, K., Reiter, A., Akin, C., Gotlib, J., Horny, H., Arock, M. 2014; 7 (5): 683-690

    Abstract

    During the past few years, a number of molecular markers have been developed in clinical hematology, most of them related to specific gene defects. However, there is also an unmet need to develop novel serologic parameters to improve diagnostics and prognostication in daily practice. Among these, the serum tryptase appears to be a most reliable biomarker of myeloid neoplasms. Elevated tryptase levels are found in subgroups of patients with mastocytosis, myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia, chronic myeloid leukemia and chronic eosinophilic leukemia. In these patients, the tryptase level is of diagnostic and/or prognostic significance. In mastocytosis, an elevated tryptase level is a minor criterion of systemic disease and in BCR-ABL1(+) chronic myeloid leukemia, elevated tryptase at diagnosis correlates with treatment responses and overall survival. In patients with elevated tryptase, the enzyme also serves as follow-up parameter and can be employed to measure treatment-responses. In the current article, we review and update the perspectives of tryptase and provide recommendations for use of this conventional biomarker in daily practice.

    View details for DOI 10.1586/17474086.2014.955008

    View details for Web of Science ID 000342203200015

    View details for PubMedCentralID PMC4603354

  • Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis ALLERGY Valent, P., Escribano, L., Broesby-Olsen, S., Hartmann, K., Grattan, C., Brockow, K., Niedoszytko, M., NEDOSZYTKO, B., Elberink, J. N., Kristensen, T., Butterfield, J. H., Triggiani, M., Alvarez-Twose, I., Reiter, A., Sperr, W. R., Sotlar, K., Yavuz, S., Kluin-Nelemans, H. C., Hermine, O., Radia, D., van Doormaal, J. J., Gotlib, J., Orfao, A., Siebenhaar, F., SCHWARTZ, L. B., Castells, M., Maurer, M., Horny, H., Akin, C., Metcalfe, D. D., Arock, M. 2014; 69 (10): 1267-1274

    View details for DOI 10.1111/all.12436

    View details for Web of Science ID 000342759700003

  • Janus Kinase Inhibitors and Allogeneic Stem Cell Transplantation for Myelofibrosis BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Gupta, V., Gotlib, J., Radich, J. P., Kroeger, N. M., Rondelli, D., Verstovsek, S., Deeg, H. J. 2014; 20 (9): 1274-1281

    Abstract

    Myelofibrosis (MF) is a manifestation of several disorders of hematopoiesis, collectively referred to as myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (ASCT) is the only therapy with proven curative potential. However, most patients with MF are in their 6th or 7th decade of life, and only some of these patients have been considered suitable transplantation candidates. The development of reduced-intensity conditioning regimens with limited toxicity has allowed clinicians to offer ASCT to a growing number of older patients. The availability of Janus Kinase (JAK) 1/2 inhibitors allows clinicians to provide symptom relief and improved quality of life for MF patients. These drugs may also affect the decision regarding, in particular, the timing of ASCT. Future studies need to address the role of JAK1/2 inhibitors in patients who are transplantation candidates and determine their role before and, possibly, after transplantation. The identification of indications for the use of JAK1/2 inhibitors in the context of transplantation may lead to new therapeutic strategies for patients with MF.

    View details for DOI 10.1016/j.bbmt.2014.03.017

    View details for Web of Science ID 000340986200004

    View details for PubMedID 24680977

  • Refined diagnostic criteria and classification of mast cell leukemia (MCL) and myelomastocytic leukemia (MML): a consensus proposal ANNALS OF ONCOLOGY Valent, P., Sotlar, K., Sperr, W. R., Escribano, L., Yavuz, S., Reiter, A., George, T. I., Kluin-Nelemans, H. C., Hermine, O., Butterfield, J. H., Hagglund, H., Ustun, C., Hornick, J. L., Triggiani, M., Radia, D., Akin, C., Hartmann, K., Gotlib, J., SCHWARTZ, L. B., Verstovsek, S., Orfao, A., Metcalfe, D. D., Arock, M., Horny, H. 2014; 25 (9): 1691-1700
  • Acute myeloid leukemia with monosomal karyotype: morphologic, immunophenotypic, and molecular findings. American journal of clinical pathology Weinberg, O. K., Ohgami, R. S., Ma, L., Seo, K., Ren, L., Gotlib, J. R., Seetharam, M., Cherry, A., Arber, D. A. 2014; 142 (2): 190-195

    Abstract

    Acute myeloid leukemia (AML) with monosomal karyotype (MK) recently has been reported to be associated with worse outcome than the traditional complex karyotype.In this retrospective study of 111 patients with AML, we identified 14 patients with MK (13% of all patients with AML) using the definition proposed by Breems et al.Five (36%) of these 14 patients had a loss of a single chromosome in the presence of other structural abnormalities, and nine (64%) had a loss of two or more autosomal chromosomes. Patients with AML-MK presented at an older age, with lower bone marrow blasts, and their blasts less frequently expressed CD34. Most patients with AML-MK had morphologic multilineage dysplasia and were predominantly subclassified as having AML with myelodysplasia-related changes (AML-MRC). Molecular analysis showed a significant absence of NPM1 and FLT3 in patients with AML-MK.Outcome data showed that patients with AML-MK had significantly worse overall survival, disease-free survival, and complete response compared with the rest of the patients with AML as well as within the AML-MRC group.

    View details for DOI 10.1309/AJCPMLO84JDNVLNK

    View details for PubMedID 25015859

  • Altered translation of GATA1 in Diamond-Blackfan anemia NATURE MEDICINE Ludwig, L. S., Gazda, H. T., Eng, J. C., Eichhorn, S. W., Thiru, P., Ghazvinian, R., George, T. I., Gotlib, J. R., Beggs, A. H., Sieff, C. A., Lodish, H. F., Lander, E. S., Sankaran, V. G. 2014; 20 (7): 748-753

    Abstract

    Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA), congenital asplenia and T cell leukemia. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type- and tissue-specific defects remains unknown. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.

    View details for DOI 10.1038/nm.3557

    View details for PubMedID 24952648

  • Hereditary erythrocytosis, thrombocytosis and neutrophilia BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Hong, W., Gotlib, J. 2014; 27 (2): 95-106

    Abstract

    Hereditary erythrocytosis, thrombocytosis, and neutrophilia are rare inherited syndromes which exhibit Mendelian inheritance. Some patients with primary hereditary erythrocytosis exhibit a mutation in the erythropoietin receptor (EPOR) which is associated with low serum erythropoietin (EPO) levels. Secondary congenital erythrocytosis may be characterized by normal or high serum EPO levels, and is related to high oxygen affinity haemoglobin variants, mutation of the enzyme biphosphoglycerate mutase (BPGM), or defects in components of the oxygen-sensing pathway. Hereditary thrombocytosis was first linked to mutations in genes encoding thrombopoietin (THPO) or the thrombopoietin receptor, MPL. More recently, germline mutations in JAK2, distinct from JAK2 V617F, and mutation of the gelsolin gene, were uncovered in several pedigrees of hereditary thrombocytosis. Hereditary neutrophilia has been described in one family with an activating germline mutation in CSF3R. The mutational basis for most hereditary myeloproliferative disorders has yet to be identified.

    View details for DOI 10.1016/j.beha.2014.07.002

    View details for PubMedID 25189721

  • A phase 2 study of IPI-926, an oral hedgehog inhibitor, in patients with myelofibrosis. Sasaki, K., Gotlib, J. R., Mesa, R. A., Ravandi, F., Cortes, J. E., Kelly, P., Kutok, J., Kantarjian, H. M., Verstovsek, S. AMER SOC CLINICAL ONCOLOGY. 2014
  • Phase 2 trial of PRM-151, an antifibrotic agent, in patients with myelofibrosis: Stage 1 results. Verstovsek, S., Mesa, R. A., Foltz, L. M., Gupta, V., Mascarenhas, J., Ritchie, E. K., Hoffman, R., Silver, R. T., Hong, W., Kremyanskaya, M., Trehu, E. G., Kantarjian, H. M., Gotlib, J. R. AMER SOC CLINICAL ONCOLOGY. 2014
  • Intensive serial biomarker profiling for the prediction of neutropenic Fever in patients with hematologic malignancies undergoing chemotherapy: a pilot study. Hematology reports Chan, S. M., Chadwick, J., Young, D. L., Holmes, E., Gotlib, J. 2014; 6 (2): 5466-?

    Abstract

    Neutropenic fever (NF) is a life-threatening complication of myelosuppressive chemotherapy in patients with hematologic malignancies and triggers the administration of broad-spectrum antimicrobials. The ability to accurately predict NF would permit initiation of antimicrobials earlier in the course of infection with the goal of decreasing morbid complications and progression to septic shock and death. Changes in the blood level of inflammatory biomarkers may precede the occurrence of NF. To identify potential biomarkers for the prediction of NF, we performed serial measurements of nine biomarkers [C-reactive protein (CRP), protein C, interleukin (IL)-6, IL-8, IL-10, IL-1β, tumor necrosis factor-α, monocyte chemotactic protein-1, and intercellular adhesion molecule-1] using a multiplex ELISA array platform every 6-8 hours in patients undergoing myelosuppressive chemotherapy for hematologic malignancies. We found that the blood levels of IL-6 and CRP increased significantly 24 to 48 hours prior to the onset of fever. In addition, we showed that frequent biomarker monitoring is feasible using a bedside micro sample test device. The results of this pilot study suggest that serial monitoring of IL-6 and CRP levels using a bedside device may be useful in the prediction of NF. Prospective studies involving a larger cohort of patients to validate this observation are warranted. This trial is registered at ClinicalTrials.gov (NCT01144793).

    View details for DOI 10.4081/hr.2014.5466

    View details for PubMedID 25013718

    View details for PubMedCentralID PMC4091290

  • Two faces of ET: CALR and JAK2 BLOOD Chao, M. P., Gotlib, J. 2014; 123 (10): 1438–40

    Abstract

    In this issue of Blood, Rumi et al and Rotunno et al demonstrate that essential thrombocythemia (ET) patients with calreticulin mutations exhibit lower leukocyte and hemoglobin values, higher platelet counts, and a lower thrombosis risk vs JAK2-mutated ET. Calreticulin-mutated ET appears to be a distinct entity with a more indolent course.

    View details for DOI 10.1182/blood-2014-01-547596

    View details for Web of Science ID 000335844600005

    View details for PubMedID 24627549

  • CME Information: World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2014; 89 (3): 325-337

    Abstract

    The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder.Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion.The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3)) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second-line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited number of patients. Although clinical trials have been performed with anti-IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

    View details for DOI 10.1002/ajh.23664

    View details for Web of Science ID 000331941600016

  • Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies HAEMATOLOGICA Mesa, R. A., Kiladjian, J., Verstovsek, S., Al-Ali, H. K., Gotlib, J., Gisslinger, H., Levy, R., Siulnik, A., Gupta, V., Khan, M., DiPersio, J. F., McQuitty, M., Catalano, J. V., Hunter, D. S., Knoops, L., Deininger, M., Cervantes, F., Miller, C., Vannucchi, A. M., Silver, R. T., Barbui, T., Talpaz, M., Barosi, G., Winton, E. F., Mendeson, E., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Sun, W., Sandor, V., Kantarjian, H. M., Harrison, C. 2014; 99 (2): 292-298

    Abstract

    Prior to Janus kinase inhibitors, available therapies for myelofibrosis were generally supportive and did not improve survival. This analysis compares efficacy outcomes of patients with myelofibrosis in the control arms (placebo [n=154] and best available therapy [n=73]) from the two phase 3 COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (COMFORT) studies. Spleen volume was assessed by magnetic resonance imaging/computed tomography at baseline and every 12 weeks through week 72; spleen length was assessed by palpation at each study visit. Health-related quality of life and symptoms were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items at baseline and in weeks 4, 8, 12, 16 and 24 in COMFORT-I and in weeks 8, 16, 24 and 48 in COMFORT-II. The demographic and baseline characteristics were similar between the control arms of the two studies. One patient who received placebo and no patients who received best available therapy had a ≥35% reduction in spleen volume from baseline at week 24. At 24 weeks, neither placebo nor best available therapy had produced clinically meaningful changes in global quality of life or symptom scales. Non-hematologic adverse events were mostly grade 1/2; the most frequently reported adverse events in each group were abdominal pain, fatigue, peripheral edema and diarrhea. These data suggest that non-Janus kinase inhibitor therapies provide little improvement in splenomegaly, symptoms or quality of life as compared with placebo. Both COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies have been appropriately registered with clinicaltrials.gov.

    View details for DOI 10.3324/haematol.2013.087650

    View details for Web of Science ID 000336253900021

    View details for PubMedID 23911705

    View details for PubMedCentralID PMC3912959

  • Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes ONCOTARGETS AND THERAPY Verstovsek, S., Gotlib, J., Gupta, V., Atallah, E., Mascarenhas, J., Quintas-Cardama, A., Sun, W., Sarlis, N. J., Sandor, V., Levy, R. S., Kantarjian, H. M., Mesa, R. A. 2014; 7: 13-21

    Abstract

    Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 10(9)/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100-200 × 10(9)/L and >200 × 10(9)/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8-12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.

    View details for DOI 10.2147/OTT.S53348

    View details for Web of Science ID 000328610100001

    View details for PubMedCentralID PMC3869911

  • Eosinophilic myeloproliferative disorders CANCER CONSULT: EXPERTISE FOR CLINICAL PRACTICE Gotlib, J., Abutalib, S. A., Markman, M. 2014: 167–75
  • JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM Gotlib, J. 2013: 529-537

    Abstract

    The discovery of the JAK2 V617F mutation in the classic BCR-ABL1-negative myeloproliferative neoplasms in 2005 catalyzed a burst of research efforts that have culminated in substantial dividends for patients. Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation. Although these bench-top findings have informed the clinical development of JAK inhibitors in MF, they have also provided scientific context for some of their limitations. The JAK1/JAK2 inhibitor ruxolitinib is approved for treatment of MF in North America and Europe and other lead JAK inhibitors discussed herein (fedratinib [SAR302503], momelotinib [CYT387], and pacritinib [SB1518]), have entered advanced phases of trial investigation. Uniformly, these agents share the ability to reduce spleen size and symptom burden. A major challenge for practitioners is how to optimize dosing of these agents to secure clinically relevant and durable benefits while minimizing myelosuppression. Suboptimal responses have spurred a "return to the bench" to characterize the basis for disease persistence and to inform new avenues of drug therapy.

    View details for Web of Science ID 000331900300075

    View details for PubMedID 24319228

  • Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I HAEMATOLOGICA Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Sun, W., Sandor, V., Kantarjian, H. M. 2013; 98 (12): 1865-1871

    Abstract

    COMFORT-I is a randomized, double-blind, placebo-controlled trial of the Janus kinase 1/Janus kinase 2 inhibitor ruxolitinib in 309 patients with intermediate-2 or high-risk myelofibrosis. This analysis of COMFORT-I describes the long-term efficacy and safety of ruxolitinib (median follow-up, 2 years). Spleen volume was measured by magnetic resonance imaging, and quality of life was evaluated using the EORTC QLQ-C30. Overall survival was determined according to randomized treatment group. At the time of this analysis, 100 of 155 patients randomized to ruxolitinib were still receiving treatment. All patients randomized to placebo crossed over to ruxolitinib or discontinued within 3 months of the primary analysis (median time to crossover, 41 weeks). Mean spleen volume reductions in the ruxolitinib group were 31.6% at week 24 and 34.9% at week 96; improvements in quality of life measures were also maintained. Improved survival was observed for ruxolitinib (n=27 deaths) versus placebo (n=41 deaths) (hazard ratio=0.58; 95% confidence interval: 0.36, 0.95; P=0.03). The incidence of new-onset grade 3 or 4 anemia and thrombocytopenia decreased over time to levels observed in patients receiving placebo. These data indicate that ruxolitinib treatment provides durable reductions in spleen volume and improvements in quality of life and suggest a continued survival advantage for ruxolitinib over placebo.

    View details for DOI 10.3324/haematol.2013.092155

    View details for Web of Science ID 000328545500014

    View details for PubMedID 24038026

    View details for PubMedCentralID PMC3856961

  • Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes. Haematologica Merker, J. D., Roskin, K. M., Ng, D., Pan, C., Fisk, D. G., King, J. J., Hoh, R., Stadler, M., Okumoto, L. M., Abidi, P., Hewitt, R., Jones, C. D., Gojenola, L., Clark, M. J., Zhang, B., Cherry, A. M., George, T. I., Snyder, M., Boyd, S. D., Zehnder, J. L., Fire, A. Z., Gotlib, J. 2013; 98 (11): 1689-1696

    Abstract

    In order to identify novel somatic mutations associated with classic BCR/ABL1-negative myeloproliferative neoplasms, we performed high-coverage genome sequencing of DNA from peripheral blood granulocytes and cultured skin fibroblasts from a patient with MPL W515K-positive primary myelofibrosis. The primary myelofibrosis genome had a low somatic mutation rate, consistent with that observed in similar hematopoietic tumor genomes. Interfacing of whole-genome DNA sequence data with RNA expression data identified three somatic mutations of potential functional significance: a nonsense mutation in CARD6, implicated in modulation of NF-kappaB activation; a 19-base pair deletion involving a potential regulatory region in the 5'-untranslated region of BRD2, implicated in transcriptional regulation and cell cycle control; and a non-synonymous point mutation in KIAA0355, an uncharacterized protein. Additional mutations in three genes (CAP2, SOX30, and MFRP) were also evident, albeit with no support for expression at the RNA level. Re-sequencing of these six genes in 178 patients with polycythemia vera, essential thrombocythemia, and myelofibrosis did not identify recurrent somatic mutations in these genes. Finally, we describe methods for reducing false-positive variant calls in the analysis of hematologic malignancies with a low somatic mutation rate. This trial is registered with ClinicalTrials.gov (NCT01108159).

    View details for DOI 10.3324/haematol.2013.092379

    View details for PubMedID 23872309

  • Chronic Myelogenous Leukemia, Version 1.2014. Journal of the National Comprehensive Cancer Network O'Brien, S., Radich, J. P., Abboud, C. N., Akhtari, M., Altman, J. K., Berman, E., DeAngelo, D. J., Deininger, M., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Kropf, P., Moore, J. O., Pallera, A., Pinilla-Ibarz, J., Reddy, V. V., Shah, N. P., Smith, B. D., Snyder, D. S., Wetzler, M., Gregory, K., Sundar, H. 2013; 11 (11): 1327-1340

    Abstract

    The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ≤10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).

    View details for PubMedID 24225967

    View details for PubMedCentralID PMC4234105

  • Chronic Myelogenous Leukemia, Version 1.2014 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Radich, J. P., Abboud, C. N., Akhtari, M., Altman, J. K., Berman, E., DeAngelo, D. J., Deininger, M., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Kropf, P., Moore, J. O., Pallera, A., Pinilla-Ibarz, J., Reddy, V. V., Shah, N. P., Smith, B. D., Snyder, D. S., Wetzler, M., Gregory, K., Sundar, H. 2013; 11 (11): 1327-1340

    Abstract

    The 2014 NCCN Clinical Practice Guidelines in Oncology for Chronic Myelogenous Leukemia recommend quantitative reverse-transcription polymerase chain reaction (QPCR) standardized to International Scale (IS) as the preferred method for monitoring molecular response to tyrosine kinase inhibitor (TKI) therapy. A BCR-ABL1 transcript level of 10% or less (IS) is now included as the response milestone at 3 and 6 months. Change of therapy to an alternate TKI is recommended for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with imatinib. Continuing the same dose of TKI or switching to an alternate TKI are options for patients with BCR-ABL1 transcript levels greater than 10% (IS) at 3 months after primary treatment with dasatinib or nilotinib. The guidelines recommend 6-month evaluation with QPCR (IS) for patients with BCR-ABL1 transcript levels greater than 10% at 3 months. Monitoring with QPCR (IS) every 3 months is recommended for all patients, including those who meet response milestones at 3, 6, 12, and 18 months (BCR-ABL1 transcript level ≤10% [IS] at 3 and 6 months, complete cytogenetic response at 12 and 18 months).

    View details for Web of Science ID 000327066800003

    View details for PubMedCentralID PMC4234105

  • Hidden Mastocytosis in Acute Myeloid Leukemia With t(8;21)(q22;q22). American journal of clinical pathology Johnson, R. C., Savage, N. M., Chiang, T., Gotlib, J. R., Cherry, A. M., Arber, D. A., George, T. I. 2013; 140 (4): 525-535

    Abstract

    Objectives: To assess the frequency of systemic mastocytosis (SM) in a large series of acute myeloid leukemia (AML) with t(8;21)(q22;q22). Methods: We retrospectively characterized 40 bone marrow aspirate smears and biopsy specimens from patients with AML with t(8;21) for the presence of SM. Cases were assessed for mast cell morphology and immunohistochemistry, as well as KIT exon 8 and 17 mutational assessment by reverse transcription polymerase chain reaction. Results: Four patients met criteria for SM, 1 met criteria for myelomastocytic leukemia, and 8 demonstrated the benign finding of mast cell hyperplasia. Conclusions: We recommend examining all cases of AML with t(8;21) for the presence of SM via morphology, immunophenotyping, and KIT mutational analysis studies.

    View details for DOI 10.1309/AJCP1Q0YSXEAHNKK

    View details for PubMedID 24045550

  • Myeloid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, and FGFR1: a review INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Savage, N., George, T. I., Gotlib, J. 2013; 35 (5): 491-500

    Abstract

    Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of platelet-derived growth factor receptor alpha (PDGFRA), platelet-derived growth factor receptor beta (PDGFRB), and fibroblast growth factor receptor-1 (FGFR1) are a group of hematologic neoplasms resulting from the formation of abnormal fusion genes that encode constitutively activated tyrosine kinases. These entities are now separated into their own major category in the 2008 World Health Organization classification of hematolymphoid tumors. Although eosinophilia is characteristic of these diseases, the clinical presentation of the three entities is variable. Conventional cytogenetics (karyotyping) will detect the majority of abnormalities involving PDGFRB and FGFR1, but florescence in situ hybridization (FISH)/molecular studies are required to detect factor interacting with PAP (FIP1L1)-PDGFRA as the characteristic 4q12 interstitial deletion is cryptic. Imatinib mesylate (imatinib) is the first-line therapy for patients with abnormalities of PDGFRA/B, whereas patients with FGFR1 fusions are resistant to this therapy and carry a poor prognosis. The discovery of novel gene rearrangements associated with eosinophilia will further guide our understanding of the molecular pathobiology of these diseases and aid in the development of small-molecule inhibitors that inhibit deregulated hematopoiesis.

    View details for DOI 10.1111/ijlh.12057

    View details for Web of Science ID 000325079000016

    View details for PubMedID 23489324

  • Practical management of patients with myelofibrosis receiving ruxolitinib EXPERT REVIEW OF HEMATOLOGY Harrison, C., Mesa, R., Ross, D., Mead, A., Keohane, C., Gotlib, J., Verstovsek, S. 2013; 6 (5): 511-523

    Abstract

    Myelofibrosis (MF) is characterized by bone marrow fibrosis, progressive anemia and extramedullary hematopoiesis, primarily manifested as splenomegaly. Patients also experience debilitating constitutional symptoms, including sequelae of splenomegaly, night sweats and fatigue. Ruxolitinib (INC424, INCB18424, Jakafi, Jakavi), a JAK1 and JAK2 inhibitor, was approved in November 2011 by the US FDA for the treatment of intermediate- or high-risk MF, and more recently in Europe and Canada for the treatment of MF-related splenomegaly or symptoms. These approvals were based on data from two randomized Phase III studies: COMFORT-I randomized against placebo, and COMFORT-II randomized against best available therapy. In these studies, ruxolitinib rapidly improved multiple disease manifestations of MF, reducing splenomegaly and improving quality of life of patients and potentially prolonging survival. However, as with other chemotherapies, ruxolitinib therapy is associated with some adverse events, such as anemia and thrombocytopenia. The aims of this article are to provide a brief overview of ruxolitinib therapy, to discuss some common adverse events associated with ruxolitinib therapy and to provide clinical management recommendations to maximize patients' benefit from ruxolitinib.

    View details for DOI 10.1586/17474086.2013.827413

    View details for Web of Science ID 000325547100007

    View details for PubMedID 24083419

  • The new genetics of chronic neutrophilic leukemia and atypical CML: implications for diagnosis and treatment. Blood Gotlib, J., Maxson, J. E., George, T. I., Tyner, J. W. 2013; 122 (10): 1707-1711

    Abstract

    Although activation of tyrosine kinase pathways is a shared theme among myeloproliferative neoplasms, the pathogenetic basis of chronic neutrophilic leukemia (CNL) has remained elusive. Recently, we identified high-frequency oncogenic mutations in the granulocyte-colony stimulating factor receptor (CSF3R) in CNL and in some patients with atypical chronic myeloid leukemia. Inhibition of Janus kinase 2 or SRC kinase signaling downstream of mutated CSF3R is feasible and should be explored therapeutically. Herein, we discuss the potential impact of these findings for the classification and treatment of these disorders.

    View details for DOI 10.1182/blood-2013-05-500959

    View details for PubMedID 23896413

  • Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report BLOOD Tefferi, A., Cervantes, F., Mesa, R., Passamonti, F., Verstovsek, S., Vannucchi, A. M., Gotlib, J., Dupriez, B., Pardanani, A., Harrison, C., Hoffman, R., Gisslinger, H., Kroeger, N., Thiele, J., Barbui, T., Barosi, G. 2013; 122 (8): 1395-1398

    Abstract

    The current document is a revision of the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for treatment response in myelofibrosis (MF) and represents a collaborative effort by the IWG-MRT and the European LeukemiaNet to objectively assess the value of new drugs in inducing morphologic remission or improvement in MF-associated symptomatic burden (MF-SB). Some of the changes in the current revision include stricter definitions of red cell transfusion dependency and independency and consideration of the Myeloproliferative Neoplasm Symptom Assessment Form as a tool to quantify meaningful changes in disease-related symptoms. Six response categories are listed: complete remission (CR) and partial remission signify treatment effects that are consistent with disease modification, whereas drug-induced improvements in MF-SB were annotated as clinical improvement, anemia response, spleen response, or symptoms response. Additional criteria are provided for progressive disease, stable disease, and relapse. The document also includes recommendations for assessing cytogenetic and molecular remissions, without mandating their inclusion for CR assignment.

    View details for DOI 10.1182/blood-2013-03-488098

    View details for Web of Science ID 000323394300016

    View details for PubMedID 23838352

  • Editorial. Therapeutic advances in hematology Gotlib, J. 2013; 4 (4): 235-236

    View details for DOI 10.1177/2040620713498057

    View details for PubMedID 23926456

    View details for PubMedCentralID PMC3734904

  • Oncogenic CSF3R Mutations in Chronic Neutrophilic Leukemia and Atypical CML NEW ENGLAND JOURNAL OF MEDICINE Maxson, J. E., Gotlib, J., Pollyea, D. A., Fleischman, A. G., Agarwal, A., Eide, C. A., Bottomly, D., Wilmot, B., McWeeney, S. K., Tognon, C. E., Pond, J. B., Collins, R. H., Goueli, B., Oh, S. T., Deininger, M. W., Chang, B. H., Loriaux, M. M., Druker, B. J., Tyner, J. W. 2013; 368 (19): 1781-1790

    Abstract

    The molecular causes of many hematologic cancers remain unclear. Among these cancers are chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL1-negative) chronic myeloid leukemia (CML), both of which are diagnosed on the basis of neoplastic expansion of granulocytic cells and exclusion of genetic drivers that are known to occur in other myeloproliferative neoplasms and myeloproliferative-myelodysplastic overlap neoplasms.To identify potential genetic drivers in these disorders, we used an integrated approach of deep sequencing coupled with the screening of primary leukemia cells obtained from patients with CNL or atypical CML against panels of tyrosine kinase-specific small interfering RNAs or small-molecule kinase inhibitors. We validated candidate oncogenes using in vitro transformation assays, and drug sensitivities were validated with the use of assays of primary-cell colonies.We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family-TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib.Mutations in CSF3R are common in patients with CNL or atypical CML and represent a potentially useful criterion for diagnosing these neoplasms. (Funded by the Leukemia and Lymphoma Society and others.).

    View details for DOI 10.1056/NEJMoa1214514

    View details for PubMedID 23656643

  • The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo-controlled, Phase III study in patients with myelofibrosis BRITISH JOURNAL OF HAEMATOLOGY Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M., Miller, C., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Sun, W., Sandor, V., Kantarjian, H. M. 2013; 161 (4): 508-516

    Abstract

    Myelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT-I,) a double-blind trial, where patients with intermediate-2 or high-risk MF were randomized to twice-daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post-polycythaemia vera, post-essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100-200 × 10(9)/l, >200 × 10(9)/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan-Meier method according to original randomization group. In ruxolitinib-treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT-I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT-I.

    View details for DOI 10.1111/bjh.12274

    View details for Web of Science ID 000318172300007

    View details for PubMedID 23480528

    View details for PubMedCentralID PMC4055021

  • Myeloid and lymphoid Neoplasms with FGFR1 abnormalities: diagnostic and therapeutic challenges AMERICAN JOURNAL OF HEMATOLOGY Savage, N. M., Johnson, R. C., Gotlib, J., George, T. I. 2013; 88 (5): 427-430

    View details for DOI 10.1002/ajh.23296

    View details for Web of Science ID 000318043500430

    View details for PubMedID 22886804

  • Effect of Ruxolitinib Therapy on Myelofibrosis-Related Symptoms and Other Patient-Reported Outcomes in COMFORT-I: A Randomized, Double-Blind, Placebo-Controlled Trial JOURNAL OF CLINICAL ONCOLOGY Mesa, R. A., Gotlib, J., Gupta, V., Catalano, J. V., Deininger, M. W., Shields, A. L., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Hare, T., Erickson-Viitanen, S., Sun, W., Sandor, V., Levy, R. S., Kantarjian, H. M., Verstovsek, S. 2013; 31 (10): 1285-1292

    Abstract

    To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis.COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment-I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC).Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either "Much improved" or "Very much improved" on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs.Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

    View details for DOI 10.1200/JCO.2012.44.4489

    View details for Web of Science ID 000317003300015

    View details for PubMedID 23423753

  • Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia. Haematologica Pollyea, D. A., Zehnder, J., Coutre, S., Gotlib, J. R., Gallegos, L., Abdel-Wahab, O., Greenberg, P., Zhang, B., Liedtke, M., Berube, C., Levine, R., Mitchell, B. S., Medeiros, B. C. 2013; 98 (4): 591-596

    Abstract

    There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ≥ 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ≥ 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

    View details for DOI 10.3324/haematol.2012.076414

    View details for PubMedID 23242596

  • International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis BLOOD Gotlib, J., Pardanani, A., Akin, C., Reiter, A., George, T., Hermine, O., Kluin-Nelemans, H., Hartmann, K., Sperr, W. R., Brockow, K., Schwartz, L. B., Orfao, A., DeAngelo, D. J., Arock, M., Sotlar, K., Horny, H., Metcalfe, D. D., Escribano, L., Verstovsek, S., Tefferi, A., Valent, P. 2013; 121 (13): 2393-2401

    Abstract

    Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.

    View details for DOI 10.1182/blood-2012-09-458521

    View details for PubMedID 23325841

  • A Pan-BCL2 Inhibitor Renders Bone-Marrow-Resident Human Leukemia Stem Cells Sensitive to Tyrosine Kinase Inhibition CELL STEM CELL Goff, D. J., Recart, A. C., Sadarangani, A., Chun, H., Barrett, C. L., Krajewska, M., Leu, H., Low-Marchelli, J., Ma, W., Shih, A. Y., Wei, J., Zhai, D., Geron, I., Pu, M., Bao, L., Chuang, R., Balaian, L., Gotlib, J., Minden, M., Martinelli, G., Rusert, J., Dao, K., Shazand, K., Wentworth, P., Smith, K. M., Jamieson, C. A., Morris, S. R., Messer, K., Goldstein, L. S., Hudson, T. J., Marra, M., Frazer, K. A., Pellecchia, M., Reed, J. C., Jamieson, C. H. 2013; 12 (3): 316-328

    Abstract

    Leukemia stem cells (LSCs) play a pivotal role in the resistance of chronic myeloid leukemia (CML) to tyrosine kinase inhibitors (TKIs) and its progression to blast crisis (BC), in part, through the alternative splicing of self-renewal and survival genes. To elucidate splice-isoform regulators of human BC LSC maintenance, we performed whole-transcriptome RNA sequencing, splice-isoform-specific quantitative RT-PCR (qRT-PCR), nanoproteomics, stromal coculture, and BC LSC xenotransplantation analyses. Cumulatively, these studies show that the alternative splicing of multiple prosurvival BCL2 family genes promotes malignant transformation of myeloid progenitors into BC LSCS that are quiescent in the marrow niche and that contribute to therapeutic resistance. Notably, sabutoclax, a pan-BCL2 inhibitor, renders marrow-niche-resident BC LSCs sensitive to TKIs at doses that spare normal progenitors. These findings underscore the importance of alternative BCL2 family splice-isoform expression in BC LSC maintenance and suggest that the combinatorial inhibition of prosurvival BCL2 family proteins and BCR-ABL may eliminate dormant LSCs and obviate resistance.

    View details for DOI 10.1016/j.stem.2012.12.011

    View details for Web of Science ID 000329569400010

    View details for PubMedID 23333150

  • Accessory splenules in autoimmune hemolytic anemia. American journal of hematology Logan, A., Berube, C., Gotlib, J. 2013; 88 (2): 156-?

    View details for DOI 10.1002/ajh.23335

    View details for PubMedID 23027373

  • A Detailed Flow Cytometry Analysis of the Immune System in Non-Leukemic Cells of Acute Myeloid Leukemia Demonstrates the Prognostic Significance of Lymphocyte Subsets 102nd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) Ohgami, R. S., Alcasid, M., Ren, L., Gotlib, J. R., Arber, D. A. NATURE PUBLISHING GROUP. 2013: 353A–354A
  • Kinase Pathway Dependence in Primary Human Leukemias Determined by Rapid Inhibitor Screening CANCER RESEARCH Tyner, J. W., Yang, W. F., Bankhead, A., Fan, G., Fletcher, L. B., Bryant, J., Glover, J. M., Chang, B. H., Spurgeon, S. E., Fleming, W. H., Kovacsovics, T., Gotlib, J. R., Oh, S. T., Deininger, M. W., Zwaan, C. M., den Boer, M. L., van den Heuvel-Eibrink, M. M., O'Hare, T., Druker, B. J., Loriaux, M. M. 2013; 73 (1): 285-296

    Abstract

    Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options.

    View details for DOI 10.1158/0008-5472.CAN-12-1906

    View details for PubMedID 23087056

  • Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. OncoTargets and therapy Verstovsek, S., Gotlib, J., Gupta, V., Atallah, E., Mascarenhas, J., Quintas-Cardama, A., Sun, W., Sarlis, N. J., Sandor, V., Levy, R. S., Kantarjian, H. M., Mesa, R. A. 2013; 7: 13-21

    Abstract

    Ruxolitinib is an oral Janus kinase (JAK) 1/JAK2 inhibitor approved in the US for the treatment of intermediate-or high-risk myelofibrosis (MF). Because thrombopoietin and erythropoietin signal through JAK2, dose-dependent cytopenias are expected with treatment. In the COMFORT-I (COntrolled Myelofibrosis study with ORal JAK inhibitor Treatment I) trial, these cytopenias were effectively managed with dose adjustments. These analyses were conducted to evaluate the relationship between ruxolitinib titrated doses and changes in platelet count and hemoglobin level as well as efficacy measures.COMFORT-I was a randomized, placebo-controlled trial in 309 patients with intermediate-2 or high-risk MF and a platelet count ≥100 × 10(9)/L. Ruxolitinib starting doses were 15 and 20 mg twice daily (bis in die [BID]) for patients with baseline platelet counts of 100-200 × 10(9)/L and >200 × 10(9)/L, respectively. Percentage changes from baseline to week 24 in spleen volume and MF-related symptoms were assessed in subgroups defined by final titrated dose (average daily dose during weeks 21 to 24).The median final titrated doses for patients starting at doses of 15 and 20 mg BID were 10 and 20 mg BID, respectively, at week 24. Most dose reductions occurred in the first 8-12 weeks of treatment and coincided with decreases in platelet count and hemoglobin level. Subsequently, platelet counts stabilized and hemoglobin levels gradually returned to near baseline levels (red blood cell transfusion rates followed a similar trend). Final titrated doses of ≥10 mg BID were associated with clinically meaningful improvements in MF-related symptoms that were comparable across doses, while marginally greater reductions in spleen volume were observed at higher doses.This COMFORT-I analysis shows that dose-dependent cytopenias were effectively managed with ruxolitinib dose adjustments, and titrated doses of ≥10 mg BID were associated with clinically meaningful reductions in spleen volume and symptom improvement at week 24.

    View details for DOI 10.2147/OTT.S53348

    View details for PubMedID 24368888

  • ICON: Eosinophil Disorders. The World Allergy Organization journal Valent, P., Klion, A. D., Rosenwasser, L. J., Arock, M., Bochner, B. S., Butterfield, J. H., Gotlib, J., Haferlach, T., Hellmann, A., Horny, H., Leiferman, K. M., Metzgeroth, G., Matsumoto, K., Reiter, A., Roufosse, F., Rothenberg, M. E., Simon, H., Sotlar, K., Vandenberghe, P., Weller, P. F., Gleich, G. J. 2012; 5 (12): 174-181

    View details for DOI 10.1097/WOX.0b013e31827f4192

    View details for PubMedID 23282419

  • Next-generation sequencing in hematologic malignancies: what will be the dividends? Therapeutic advances in hematology Merker, J. D., Valouev, A., Gotlib, J. 2012; 3 (6): 333-339

    Abstract

    The application of high-throughput, massively parallel sequencing technologies to hematologic malignancies over the past several years has provided novel insights into disease initiation, progression, and response to therapy. Here, we describe how these new DNA sequencing technologies have been applied to hematolymphoid malignancies. With further improvements in the sequencing and analysis methods as well as integration of the resulting data with clinical information, we expect these technologies will facilitate more precise and tailored treatment for patients with hematologic neoplasms.

    View details for DOI 10.1177/2040620712458948

    View details for PubMedID 23606936

    View details for PubMedCentralID PMC3627325

  • Correlation of Symptom Assessment with Genotyping Analysis of Saliva Samples in a Large Cohort of Myeloproliferative Neoplasm Patients 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Nguyen, H. (., Hinds, D. A., Barnholt, K. E., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. A., Levine, R. L., Zehnder, J. L., Gotlib, J., Mesa, R. A. AMER SOC HEMATOLOGY. 2012
  • KIT Inhibitor Midostaurin in Patients with Advanced Systemic Mastocytosis: Results of a Planned Interim Analysis of the Global CPKC412D2201 Trial Gotlib, J., Kluin-Nelemans, H. C., George, T. I., Akin, C., Sotlar, K., Hermine, O., Awan, F., Hexner, E., Mauro, M. J., Morariu, R., Squier, M., Villeneuve, M., Emery-Salbert, F., Hartmann, K., Horny, H., Valent, P., Reiter, A. AMER SOC HEMATOLOGY. 2012
  • Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. N., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Sun, W., Sandor, V. A., Kantarjian, H. M. AMER SOC HEMATOLOGY. 2012
  • A Germline Variant in the TERT Gene Is a Novel Predisposition Allele Associated with Myeloproliferative Neoplasms Hinds, D. A., Barnholt, K. E., Zehnder, J. L., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. A., Huong (Marie) Nguyen, Levine, R. L., Mesa, R. A., Gotlib, J. AMER SOC HEMATOLOGY. 2012
  • Phase I/II Study of CYT387, a JAK1/JAK2 Inhibitor for the Treatment of Myelofibrosis Pardanani, A., Gotlib, J., Gupta, V., Roberts, A. W., Wadleigh, M., Sirhan, S., Bavisotto, L. M., Kawashima, J., Kowalski, M., Tefferi, A. AMER SOC HEMATOLOGY. 2012
  • Effect of Ruxolitinib On the Incidence of Splenectomy in Patients with Myelofibrosis: A Retrospective Analysis of Data From Ruxolitinib Clinical Trials Verstovsek, S., Kiladjian, J., Mesa, R. A., Vannucchi, A. M., Gotlib, J., Barosi, G., Kantarjian, H. M., Sirulnik, A., Peng, W., Sandor, V. A., Harrison, C. N. AMER SOC HEMATOLOGY. 2012
  • Clinical Benefits of Ruxolitinib Therapy in Myelofibrosis Patients with Varying Degrees of Splenomegaly and Symptoms Mesa, R. A., Gotlib, J., Kantarjian, H. M., Sun, W., Verstovsek, S. AMER SOC HEMATOLOGY. 2012
  • Improvement in Weight and Total Cholesterol and Their Association with Survival in Ruxolitinib-Treated Patients with Myelofibrosis From COMFORT-I Mesa, R. A., Verstovsek, S., Gupta, V., Mascarenhas, J., Atallah, E., Sun, W., Sandor, V. A., Gotlib, J. AMER SOC HEMATOLOGY. 2012
  • Azacitidine Plus Lenalidomide for Untreated AML Patients Ineligible for Conventional Chemotherapy Pollyea, D. A., Zehnder, J. L., Coutre, S., Gotlib, J., Gallegos, L., Greenberg, P., Zhang, B., Liedtke, M., Levine, R. L., Medeiros, B. C. AMER SOC HEMATOLOGY. 2012
  • Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012
  • FDA-Approved Ruxolitinib in Patients with Myelofibrosis: the Stanford Experience 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Nguyen, H. (., Anh Pham, A., Perkins, C., Linder, A., Fechter, L., Gotlib, J. AMER SOC HEMATOLOGY. 2012
  • Whole Genome Sequence Analysis of Primary Myelofibrosis. 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Merker, J. D., Roskin, K., Ng, D., Pan, C., Fisk, D. G., Jones, C. D., Gojenola, L., Clark, M. J., Zhang, B., Cherry, M., Snyder, M., Boyd, S. D., Zehnder, J. L., Fire, A. Z., Gotlib, J. AMER SOC HEMATOLOGY. 2012
  • A Phase I/II Study of Bortezomib (VELCADE) in Combination with Pralatrexate in Relapsed/Refractory Multiple Myeloma 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Dunn, T. J., Dinner, S. N., Berube, C., Gotlib, J., Coutre, S. E., Medeiros, B. C., Liedtke, M. AMER SOC HEMATOLOGY. 2012
  • Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012
  • Sabutoclax, a Novel Pan BCL2 Family Inhibitor, Sensitizes Dormant Blast Crisis Chronic Myeloid Leukemia Stem Cells to Dasatinib 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Leu, H. S., Goff, D. J., Low-Marchelli, J., Recart, A. C., Smith, K. M., Ma, W., Sadarangani, A., Shih, A. Y., Wei, J., Zhai, D., Gotlib, J., Minden, M. D., Martinelli, G., Marra, M. A., Frazer, K. A., Pellecchia, M., Reed, J. C., Jamieson, C. AMER SOC HEMATOLOGY. 2012
  • Estimation of JAK2 V617F Prevalence by Detection of the Mutation in Saliva Samples From Online MPN and General Population Cohorts 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Barnholt, K. E., Hinds, D. A., Kiefer, A. K., Do, C. B., Eriksson, N., Mountain, J. L., Francke, U., Tung, J. A., Nguyen, H. (., Levine, R. L., Mesa, R. A., Gotlib, J., Zehnder, J. L. AMER SOC HEMATOLOGY. 2012
  • DNA methylation analysis of ALOX12 and GSTM1 in acute myeloid leukaemia identifies prognostically significant groups BRITISH JOURNAL OF HAEMATOLOGY Ohgami, R. S., Ma, L., Ren, L., Weinberg, O. K., Seetharam, M., Gotlib, J. R., Arber, D. A. 2012; 159 (2): 182-190

    Abstract

    To determine the role of DNA methylation in the progression of acute myeloid leukaemia (AML), we analysed the methylation status of ALOX12, GSTM1, HS3ST2 and FZD9 in 127 AML patients. Aberrant methylation of ALOX12 was associated with the subcategory AML with myelodysplasia-related changes (P = 0·0439) and specifically with megakaryocytic dysplasia (P = 0·0003). An association between HS3ST2 and AML patients with favourable cytogenetic risk was identified (P = 0·0469). In univariate and multivariate analysis, methylation of GSTM1 was associated with worse overall survival (OS) and disease-free survival (DFS), with hazard ratios of 2·57 and 1·86, respectively. Furthermore, the significance of methylation of GSTM1 in predicting poor prognosis was maintained within the subcategories of AML not otherwise specified (NOS), AML with intermediate cytogenetic risk and normal karyotype AML. Finally, patients with both GSTM1 and ALOX12 methylated, demonstrated worse outcomes when all AML patients were assessed (OS; P = 0·000411) as well as within AML NOS (DFS; P = 0·0023), AML with intermediate cytogenetic risk (OS; P = 0·0104) and normal karyotype AML (OS; P = 0·00636). This study implicates methylation of specific genes in the classification and prognostication of AML and suggests that the morphological feature of multilineage dysplasia may be a surrogate marker of gene methylation in at least a subset of AML cases.

    View details for DOI 10.1111/bjh.12029

    View details for Web of Science ID 000309242000009

    View details for PubMedID 22924777

  • World Health Organization-defined eosinophilic disorders: 2012 update on diagnosis, risk stratification, and management. American journal of hematology Gotlib, J. 2012; 87 (9): 903-914

    Abstract

    DISEASE OVERVIEW: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1," chronic eosinophilic leukemia, not otherwise specified' (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established.

    View details for DOI 10.1002/ajh.23293

    View details for PubMedID 22926771

  • Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Valent, P., Klion, A. D., Horny, H., Roufosse, F., Gotlib, J., Weller, P. F., Hellmann, A., Metzgeroth, G., Leiferman, K. M., Arock, M., Butterfield, J. H., Sperr, W. R., Sotlar, K., Vandenberghe, P., Haferlach, T., Simon, H., Reiter, A., Gleich, G. J. 2012; 130 (3): 607-?

    Abstract

    Eosinophilia is an important indicator of various neoplastic and nonneoplastic conditions. Depending on the underlying disease and mechanisms, eosinophil infiltration can lead to organ dysfunction, clinical symptoms, or both. During the past 2 decades, several different classifications of eosinophilic disorders and related syndromes have been proposed in various fields of medicine. Although criteria and definitions are, in part, overlapping, no global consensus has been presented to date. The Year 2011 Working Conference on Eosinophil Disorders and Syndromes was organized to update and refine the criteria and definitions for eosinophilic disorders and to merge prior classifications in a contemporary multidisciplinary schema. A panel of experts from the fields of immunology, allergy, hematology, and pathology contributed to this project. The expert group agreed on unifying terminologies and criteria and a classification that delineates various forms of hypereosinophilia, including primary and secondary variants based on specific hematologic and immunologic conditions, and various forms of the hypereosinophilic syndrome. For patients in whom no underlying disease or hypereosinophilic syndrome is found, the term hypereosinophilia of undetermined significance is introduced. The proposed novel criteria, definitions, and terminologies should assist in daily practice, as well as in the preparation and conduct of clinical trials.

    View details for DOI 10.1016/j.jaci.2012.02.019

    View details for Web of Science ID 000308463500005

    View details for PubMedID 22460074

  • Adverse events (AEs) and the return of myelofibrosis (MF)-related symptoms after interruption or discontinuation of ruxolitinib (RUX) therapy. Verstovsek, S., Mesa, R. A., Gotlib, J. R., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M. N., Miller, C., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J., Arcasoy, M. O., Hexner, E. O., Lyons, R. M., Paquette, R., Raza, A., Sun, W., Kantarjian, H., COMFORT-I Investigators AMER SOC CLINICAL ONCOLOGY. 2012
  • Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia LEUKEMIA Pollyea, D. A., Kohrt, H. E., Gallegos, L., Figueroa, M. E., Abdel-Wahab, O., Zhang, B., Bhattacharya, S., Zehnder, J., Liedtke, M., Gotlib, J. R., Coutre, S., Berube, C., Melnick, A., Levine, R., Mitchell, B. S., Medeiros, B. C. 2012; 26 (5): 893-901

    Abstract

    Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

    View details for DOI 10.1038/leu.2011.294

    View details for Web of Science ID 000303883500005

    View details for PubMedID 22033493

  • Unraveling the genetic underpinnings of myeloproliferative neoplasms and understanding their effect on disease course and response to therapy: Proceedings from the 6th international post-ASH symposium AMERICAN JOURNAL OF HEMATOLOGY Abdel-Wahab, O., Pardanani, A., Bernard, O. A., Finazzi, G., Crispino, J. D., Gisslinger, H., Kralovics, R., Odenike, O., Bhalla, K., Gupta, V., Barosi, G., Gotlib, J., Guglielmelli, P., Kiladjian, J., Noel, P., Cazzola, M., Vannucchi, A. M., Hoffman, R., Barbui, T., Thiele, J., Van Etten, R. A., Mughal, T., Tefferi, A. 2012; 87 (5): 562-568

    Abstract

    Immediately after the annual scientific meeting of the American Society of Hematology (ASH), a select group of clinical and laboratory investigators in myeloproliferative neoplasms (MPN) is summoned to a post-ASH conference on chronic myeloid leukemia and the BCR-ABL1-negative MPN. The 6th such meeting occurred on December 13–14,2011, in La Jolla, California, USA, under the direction of its founder,Dr. Tariq Mughal. The current document is the first of two reports on this post-ASH event and summarizes the most recent preclinical and clinical advances in polycythemia vera, essential thrombocythemia,and primary myelofibrosis.

    View details for DOI 10.1002/ajh.23169

    View details for Web of Science ID 000302899900028

    View details for PubMedID 22460584

    View details for PubMedCentralID PMC3491640

  • Mast Cells and Eosinophils in Mastocytosis, Chronic Eosinophilic Leukemia, and Non-clonal Disorders SEMINARS IN HEMATOLOGY Gotlib, J., Akin, C. 2012; 49 (2): 128-137

    Abstract

    Mast cells and eosinophils often travel in the same biologic circles. In non-clonal states, such as allergic and inflammatory conditions, cell-to-cell contact and the pleiotropic actions of multiple cytokines and chemokines, derived from local tissues or mast cells themselves, foster the co-recruitment of these cells to the same geographic cellular niche. While eosinophils and mast cells serve critical roles as part of the host immune response and in maintenance of normal homeostasis, these cell types can undergo neoplastic transformation due to the development of clonal molecular abnormalities that arise in early hematopoietic progenitors. The dysregulated tyrosine kinases, D816V KIT and FIP1L1-PDGFRA, are the prototypic oncogenic lesions resulting in systemic mastocytosis (SM) and chronic eosinophilic leukemia, respectively. We review the pathobiology of these myeloproliferative neoplasms (MPNs) with a focus on the relationship between mast cells and eosinophils, and discuss murine models, which further elucidate how the phenotype of these diseases can be influenced by stem cell factor (SCF) and expression of the potent eosinophilopoietic cytokine, interleukin-5 (IL-5). Therapy of SM and FIP1L1-PDGFRA-positive disease and the prognostic relevance of increased peripheral blood and tissue mast cells in hematolymphoid malignancies will also be addressed.

    View details for DOI 10.1053/j.seminhematol.2012.01.007

    View details for Web of Science ID 000302427300004

    View details for PubMedID 22449623

  • Pathogenesis and classification of eosinophil disorders: a review of recent developments in the field EXPERT REVIEW OF HEMATOLOGY Valent, P., Gleich, G. J., Reiter, A., Roufosse, F., Weller, P. F., Hellmann, A., Metzgeroth, G., Leiferman, K. M., Arock, M., Sotlar, K., Butterfield, J. H., Cerny-Reiterer, S., Mayerhofer, M., Vandenberghe, P., Haferlach, T., Bochner, B. S., Gotlib, J., Horny, H., Simon, H., Klion, A. D. 2012; 5 (2): 157-176

    Abstract

    Eosinophils and their products play an essential role in the pathogenesis of various reactive and neoplastic disorders. Depending on the underlying disease, molecular defect and involved cytokines, hypereosinophilia may develop and may lead to organ damage. In other patients, persistent eosinophilia is accompanied by typical clinical findings, but the causative role and impact of eosinophilia remain uncertain. For patients with eosinophil-mediated organ pathology, early therapeutic intervention with agents reducing eosinophil counts can be effective in limiting or preventing irreversible organ damage. Therefore, it is important to approach eosinophil disorders and related syndromes early by using established criteria, to perform all appropriate staging investigations, and to search for molecular targets of therapy. In this article, we review current concepts in the pathogenesis and evolution of eosinophilia and eosinophil-related organ damage in neoplastic and non-neoplastic conditions. In addition, we discuss classifications of eosinophil disorders and related syndromes as well as diagnostic algorithms and standard treatment for various eosinophil-related disorders.

    View details for DOI 10.1586/EHM.11.81

    View details for Web of Science ID 000303629400013

    View details for PubMedID 22475285

    View details for PubMedCentralID PMC3625626

  • A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis NEW ENGLAND JOURNAL OF MEDICINE Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J. V., Deininger, M., Miller, C., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Koumenis, I. L., Sun, W., Sandor, V., Kantarjian, H. M. 2012; 366 (9): 799-807

    Abstract

    Ruxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.In this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.The primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.Ruxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

    View details for Web of Science ID 000300874300006

    View details for PubMedID 22375971

  • Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: A case review AMERICAN JOURNAL OF HEMATOLOGY Ustun, C., Savage, N. M., Gotlib, J., Bhalla, K., Manaloor, E., George, T. I. 2012; 87 (2): 191-193

    View details for DOI 10.1002/ajh.22208

    View details for Web of Science ID 000299098100014

    View details for PubMedID 22081475

  • Loss of CD25 Expression in Advanced Systemic Mastocytosis Patients Treated with Midostaurin (PKC412) 101st Annual Meeting of United-States-and-Canadian-Academy-of-Pathology (USCAP) Kunder, C. A., DeAngelo, D. J., Gotlib, J. R., Gitana, G., Atwater, S. K., George, T. I. NATURE PUBLISHING GROUP. 2012: 349A–349A
  • Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Kohrt, H. E., Gotlib, J., Coutre, S. E., Zhang, B., Arber, D. A., Zehnder, J. L. 2012; 87 (1): 45-50

    Abstract

    Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.

    View details for DOI 10.1002/ajh.22191

    View details for Web of Science ID 000298257700010

    View details for PubMedID 22052619

  • Insights into the molecular genetics of myeloproliferative neoplasms. American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting Nguyen, H. M., Gotlib, J. 2012: 411-418

    Abstract

    The molecular biology of the BCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) has witnessed unprecedented advances since the discovery of the acquired JAK2 V617F mutation in 2005. Despite the high prevalence of JAK2 V617F in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), and the common finding of dysregulated JAK-STAT signaling in these disorders, it is now appreciated that MPN pathogenesis can reflect the acquisition of multiple genetic mutations that alter several biologic pathways, including epigenetic control of gene expression. Although certain gene mutations are identified at higher frequencies with disease evolution to the blast phase, MPN initiation and progression are not explained by a single, temporal pattern of clonal changes. A complex interplay between acquired molecular abnormalities and host genetic background, in addition to the type and allelic burden of mutations, contributes to the phenotypic heterogeneity of MPNs. At the population level, an inherited predisposition to developing MPNs is linked to a relatively common JAK2-associated haplotype (referred to as '46/1'), but it exhibits a relatively low penetrance. This review details the current state of knowledge of the molecular genetics of the classic MPNs PV, ET, and PMF and discusses the clinical implications of these findings.

    View details for DOI 10.14694/EdBook_AM.2012.32.411

    View details for PubMedID 24451773

  • Treatment advances have not improved the early death rate in acute promyelocytic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL McClellan, J. S., Kohrt, H. E., Coutre, S., Gotlib, J. R., Majeti, R., Alizadeh, A. A., Medeiros, B. C. 2012; 97 (1): 133-136

    Abstract

    Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.

    View details for DOI 10.3324/haematol.2011.046490

    View details for Web of Science ID 000299870500022

    View details for PubMedID 21993679

    View details for PubMedCentralID PMC3248942

  • Chronic Myelogenous Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Abboud, C. N., Akhtari, M., Altman, J., Berman, E., DeAngelo, D. J., Devine, S., Fathi, A. T., Gotlib, J., Jagasia, M., Moore, J. O., Pinilla-Ibarz, J., Radich, J. P., Reddy, V. V., Shah, N. P., Shami, P. J., Smith, B. D., Snyder, D. S., Wetzler, M., Yunus, F. 2012; 10 (1): 64-110

    View details for Web of Science ID 000299007500009

    View details for PubMedID 22223870

  • Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Liedtke, M., Twist, C. J., Medeiros, B. C., Gotlib, J. R., Berube, C., Bieber, M. M., Bhat, N. M., Teng, N. N., Coutre, S. E. 2012; 97 (1): 30-37

    Abstract

    This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

    View details for DOI 10.3324/haematol.2011.045997

    View details for Web of Science ID 000299870500009

    View details for PubMedID 21993685

    View details for PubMedCentralID PMC3248928

  • A novel splice donor mutation in the thrombopoietin gene leads to exon 2 skipping in a Filipino family with hereditary thrombocythemia. Blood Zhang, B., Ng, D., Jones, C., Oh, S. T., Nolan, G. P., Salehi, S., Wong, W., Zehnder, J. L., Gotlib, J. 2011; 118 (26): 6988-6990

    View details for DOI 10.1182/blood-2011-10-386177

    View details for PubMedID 22194398

  • A novel splice donor mutation in the thrombopoietin gene leads to exon 2 skipping in a Filipino family with hereditary thrombocythemia BLOOD Ng, D., Jones, C., Oh, S. T., Nolan, G. P., Salehi, S., Wong, W., Zehnder, J. L., Gotlib, J. 2011; 118 (26): 6988-?
  • Consistent Benefit of Ruxolitinib Over Placebo in Spleen Volume Reduction and Symptom Improvement Across Subgroups and Overall Survival Advantage: Results From COMFORT-I 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Verstovsek, S., Mesa, R. A., Gotlib, J., Levy, R. S., Gupta, V., DiPersio, J. F., Catalano, J., Deininger, M. W., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Arcasoy, M. O., Hexner, E., Lyons, R. M., Paquette, R., Raza, A., Vaddi, K., Erickson-Viitanen, S., Sun, W., Sandor, V. A., Kantarjian, H. M. AMER SOC HEMATOLOGY. 2011: 128–29
  • Cycling Toward Leukemia Stem Cell Elimination Wtih a Selective Sonic Hedgehog Antagonist Shih, A. Y., Schairer, A., Barrett, C. L., Geron, I., Recart, A., Goff, D., Prashad, S., Wu, J., Jiang, Q., Gotlib, J., Balaian, L., Minden, M. D., Leu, H., Wall, R., Ma, W., Shazand, K., McPherson, J. D., Kornblau, S. M., Deichaite, I., Pu, M., Bao, L., Martinelli, G., Reya, T., Morris, S. R., VanArsdale, T., Hudson, T. J., Messer, K., Mikkola, H., Levin, W. J., Frazer, K. A., Sadarangani, A., Jamieson, C. AMER SOC HEMATOLOGY. 2011: 1613
  • Associations Between Improvements in Myelofibrosis (MF) Symptoms and Quality of Life Measures with Splenomegaly Reduction in COMFORT-I: A Randomized, Double-Blind, Phase III Trial of the JAK1 and JAK2 Inhibitor Ruxolitinib Versus Placebo in Patients with MF Mesa, R. A., Gotlib, J., Gupta, V., DiPersio, J. F., Catalano, J., Deininger, M. W., Shields, A., Miller, C. B., Silver, R. T., Talpaz, M., Winton, E. F., Harvey, J. H., Hare, T., Erickson-Viitanen, S., Sun, W., Sandor, V. A., Levy, R. S., Kantarjian, H. M., Verstovsek, S. AMER SOC HEMATOLOGY. 2011: 1642–43
  • An Expanded Multicenter Phase I/II Study of CYT387, a JAK-1/2 Inhibitor for the Treatment of Myelofibrosis Pardanani, A., Gotlib, J., Gupta, V., Roberts, A. W., Wadleigh, M., Sirhan, S., Litzow, M. R., Hogan, W. J., Begna, K., Smith, G., Bavisotto, L. M., Kowalski, M., Tefferi, A. AMER SOC HEMATOLOGY. 2011: 1645
  • SAR302503: Interim Safety, Efficacy and Long-Term Impact on JAK2 V617F Allele Burden in a Phase I/II Study in Patients with Myelofibrosis 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Pardanani, A., Gotlib, J., Jamieson, C., Cortes, J. E., Talpaz, M., Stone, R., Gao, G., Zhang, J. (., Neumann, F., Tefferi, A. AMER SOC HEMATOLOGY. 2011: 1640–40
  • BCL2 Splice Isoform Switching Promotes Leukemia Stem Cell Survival and Sensitivity to a Novel Pan BCL2 Inhibitor 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Goff, D., Smith, K. M., Shih, A. Y., Court-Recart, A., Sadarangani, A., Geron, I., Chuang, R., Balaian, L., Wei, J., Kitada, S., Zhai, D., Gotlib, J., Minden, M. D., Martinelli, G., Schairer, A., Leu, H., Ma, W., Jiang, Q., Rusert, J., Dao, K. T., Shazand, K., Volar, M., De Borja, R., McPherson, J. D., Hudson, T. J., Barrett, C. L., Frazer, K. A., Wentworth, P., Jamieson, C., Morris, S. R., Goldstein, L. S., Pellechia, M., Reed, J. C., Jamieson, C. AMER SOC HEMATOLOGY. 2011: 1176–76
  • Impact of TET2 mutations on mRNA expression and clinical outcomes in MDS patients treated with DNA methyltransferase inhibitors HEMATOLOGICAL ONCOLOGY Pollyea, D. A., Raval, A., Kusler, B., Gotlib, J. R., Alizadeh, A. A., Mitchell, B. S. 2011; 29 (3): 157-160

    View details for DOI 10.1002/hon.976

    View details for Web of Science ID 000300148700010

    View details for PubMedID 21922510

  • KIT-D816V-independent oncogenic signaling in neoplastic cells in systemic mastocytosis: role of Lyn and Btk activation and disruption by dasatinib and bosutinib BLOOD Gleixner, K. V., Mayerhofer, M., Cerny-Reiterer, S., Hoermann, G., Rix, U., Bennett, K. L., Hadzijusufovic, E., Meyer, R. A., Pickl, W. F., Gotlib, J., Horny, H., Reiter, A., Mitterbauer-Hohendanner, G., Superti-Furga, G., Valent, P. 2011; 118 (7): 1885-1898

    Abstract

    Systemic mastocytosis (SM) either presents as a malignant neoplasm with short survival or as an indolent disease with normal life expectancy. In both instances, neoplastic mast cells (MCs) harbor D816V-mutated KIT, suggesting that additional oncogenic mechanisms are involved in malignant transformation. We here describe that Lyn and Btk are phosphorylated in a KIT-independent manner in neoplastic MCs in advanced SM and in the MC leukemia cell line HMC-1. Lyn and Btk activation was not only detected in KIT D816V-positive HMC-1.2 cells, but also in the KIT D816V-negative HMC-1.1 subclone. Moreover, KIT D816V did not induce Lyn/Btk activation in Ba/F3 cells, and deactivation of KIT D816V by midostaurin did not alter Lyn/Btk activation. siRNAs against Btk and Lyn were found to block survival in neoplastic MCs and to cooperate with midostaurin in producing growth inhibition. Growth inhibitory effects were also obtained with 2 targeted drugs, dasatinib which blocks KIT, Lyn, and Btk activation in MCs, and bosutinib, a drug that deactivates Lyn and Btk without blocking KIT activity. Together, KIT-independent signaling via Lyn/Btk contributes to growth of neoplastic MCs in advanced SM. Dasatinib and bosutinib disrupt Lyn/Btk-driven oncogenic signaling in neoplastic MC, which may have clinical implications and explain synergistic drug interactions.

    View details for DOI 10.1182/blood-2010-06-289959

    View details for Web of Science ID 000294011500028

    View details for PubMedID 21680801

  • World Health Organization-defined eosinophilic disorders: 2011 update on diagnosis, risk stratification, and management. American journal of hematology Gotlib, J. 2011; 86 (8): 677-688

    Abstract

    DISEASE OVERVIEW: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic niche in primary eosinophilic diseases and HES have yet to be established.

    View details for DOI 10.1002/ajh.22062

    View details for PubMedID 21761433

  • World Health Organization-defined eosinophilic disorders: 2011 update on diagnosis, risk stratification, and management AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2011; 86 (8): 678-688

    Abstract

    DISEASE OVERVIEW: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ-hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. RISK STRATIFICATION: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semi-molecular classification scheme of disease subtypes including myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1, chronic eosinophilic leukemia, not otherwise specified (CEL, NOS), lymphocyte-variant hypereosinophilia, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. RISK-ADAPTED THERAPY: The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g. < 1,500/mm(3) ) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant hypereosinophilia and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited numbers of patients. Although clinical trials have been performed with anti IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic niche in primary eosinophilic diseases and HES have yet to be established.

    View details for DOI 10.1002/ajh.22062

    View details for Web of Science ID 000293508600009

  • Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis JOURNAL OF CLINICAL ONCOLOGY Pardanani, A., Gotlib, J. R., Jamieson, C., Cortes, J. E., Talpaz, M., Stone, R. M., Silverman, M. H., Gilliland, D. G., Shorr, J., Tefferi, A. 2011; 29 (7): 789-796

    Abstract

    Myelofibrosis is a myeloid malignancy associated with anemia, splenomegaly, and constitutional symptoms. Patients frequently harbor JAK-STAT activating mutations that are sensitive to TG101348, a selective small-molecule Janus kinase 2 (JAK2) inhibitor.In a multicenter phase I trial, oral TG101348 was administered once a day to patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Results: Fifty-nine patients were treated, including 28 in the dose-escalation phase. The maximum-tolerated dose was 680 mg/d, and dose-limiting toxicity was a reversible and asymptomatic increase in the serum amylase level. Forty-three patients (73%) continued treatment beyond six cycles; the median cumulative exposure to TG101348 was 380 days. Adverse events included nausea, vomiting, diarrhea, anemia, and thrombocytopenia; corresponding grades 3 to 4 incidence rates were 3%, 3%, 10%, 35%, and 24%. TG101348 treatment had modest effect on serum cytokine levels, but greater than half of the patients with early satiety, night sweats, fatigue, pruritus, and cough achieved rapid and durable improvement in these symptoms. By six and 12 cycles of treatment, 39% and 47% of patients, respectively, had achieved a spleen response per International Working Group criteria. The majority of patients with leukocytosis or thrombocytosis at baseline (n = 28 and n = 10, respectively) achieved normalization of blood counts after six (57% and 90%, respectively) and 12 (56% and 88%, respectively) cycles. A significant decrease in JAK2 V617F allele burden was observed at 6 months in mutation-positive patients (n = 51; P = .04), particularly in the subgroup with allele burden greater than 20% (n = 23; P < .01); the decrease was durable at 12 months.TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis.

    View details for DOI 10.1200/JCO.2010.32.8021

    View details for Web of Science ID 000287729900018

    View details for PubMedID 21220608

  • Mutations with epigenetic effects in myeloproliferative neoplasms and recent progress in treatment: Proceedings from the 5th International Post-ASH Symposium BLOOD CANCER JOURNAL Tefferi, A., Abdel-Wahab, O., Cervantes, F., Crispino, J. D., Finazzi, G., Girodon, F., Gisslinger, H., Gotlib, J., Kiladjian, J., Levine, R. L., Licht, J. D., Mullally, A., Odenike, O., Pardanani, A., Silver, R. T., Solary, E., Mughal, T. 2011; 1

    Abstract

    Immediately following the 2010 annual American Society of Hematology (ASH) meeting, the 5th International Post-ASH Symposium on Chronic Myelogenous Leukemia and BCR-ABL1-Negative Myeloproliferative Neoplasms (MPNs) took place on 7-8 December 2010 in Orlando, Florida, USA. During this meeting, the most recent advances in laboratory research and clinical practice, including those that were presented at the 2010 ASH meeting, were discussed among recognized authorities in the field. The current paper summarizes the proceedings of this meeting in BCR-ABL1-negative MPN. We provide a detailed overview of new mutations with putative epigenetic effects (TET oncogene family member 2 (TET2), additional sex comb-like 1 (ASXL1), isocitrate dehydrogenase (IDH) and enhancer of zeste homolog 2 (EZH2)) and an update on treatment with Janus kinase (JAK) inhibitors, pomalidomide, everolimus, interferon-α, midostaurin and cladribine. In addition, the new 'Dynamic International Prognostic Scoring System (DIPSS)-plus' prognostic model for primary myelofibrosis (PMF) and the clinical relevance of distinguishing essential thrombocythemia from prefibrotic PMF are discussed.

    View details for DOI 10.1038/bcj.2011.4

    View details for Web of Science ID 000298815400001

    View details for PubMedID 23471017

    View details for PubMedCentralID PMC3255279

  • Eosinophilic Disorders: Differential Diagnosis and Management MYELOPROLIFERATIVE NEOPLASMS- BIOLOGY AND THERAPY Gotlib, J., Verstovsek, S., Tefferi, A. 2011: 181–203
  • Temozolomide In Acute Myeloid Leukemia: A MGMT Promoter Methylation Status-Based Treatment Stratification 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Medeiros, B. C., Kohrt, H. E., Rajwanshi, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Zhang, M., Arber, D. A., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 1357–58
  • KIT Inhibitor Midostaurin Exhibits a High Rate of Clinically Meaningful and Durable Responses in Advanced Systemic Mastocytosis: Report of a Fully Accrued Phase II Trial Gotlib, J., DeAngelo, D. J., George, T. I., Corless, C. L., Linder, A., Langford, C., Dutreix, C., Gross, S., Nikolova, Z., Graubert, T. AMER SOC HEMATOLOGY. 2010: 144
  • Longer-Term Follow up with TG101348 Therapy In Myelofibrosis Confirms Sustained Improvement In Splenomegaly,, Disease-Related Symptoms, and JAK2V617F Allele Burden Pardanani, A., Gotlib, J. R., Jamieson, C., Cortes, J. E., Talpaz, M., Stone, R. M., Silverman, M. H., Shorr, J., Gilliland, D., Tefferi, A. AMER SOC HEMATOLOGY. 2010: 205–6
  • A Novel Missense Mutation In An MDS Patient and Effects on TET2 mRNA Expression and Clinical Outcomes Pollyea, D. A., Raval, A., Kusler, B., Gotlib, J. R., Alizadeh, A. A., Mitchell, B. S. AMER SOC HEMATOLOGY. 2010: 788
  • Identification of a Novel Splice Donor Mutation In the Thrombopoietin Gene In a Philippine Family with Hereditary Thrombocythemia 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Gotlib, J., Zhang, B., Jones, C. D., Riess, J., Wong, W. B., Simonds, E. F., Hale, M. B., Abidi, P., McClung, J., Nolan, G. P., Oh, S. T., Zehnder, J. L. AMER SOC HEMATOLOGY. 2010: 1272–72
  • A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML) 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Pollyea, D. A., Kohrt, H. E., Gallegos, L., Berube, C., Coutre, S., Gotlib, J., Liedtke, M., Mitchell, B. S., Medeiros, B. C. AMER SOC HEMATOLOGY. 2010: 1347–47
  • Identification of Novel LNK Mutations In Patients with Chronic Myeloproliferative Neoplasms and Related Disorders 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Oh, S. T., Zahn, J. M., Jones, C. D., Zhang, B., Loh, M. L., Kantarjian, H., Simonds, E. F., Bruggner, R. V., Abidi, P., Natsoulis, G., Bell, J., Buenrostro, J., Nolan, G. P., Zehnder, J. L., Ji, H. P., Gotlib, J. AMER SOC HEMATOLOGY. 2010: 143–44
  • Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience AMERICAN JOURNAL OF HEMATOLOGY Kohrt, H. E., Patel, S., Ho, M., Owen, T., Pollyea, D. A., Majeti, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Alizadeh, A. A., Medeiros, B. C. 2010; 85 (11): 877-881

    Abstract

    The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.

    View details for DOI 10.1002/ajh.21857

    View details for Web of Science ID 000283568200010

    View details for PubMedID 20872554

  • LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations LEUKEMIA Pardanani, A., Lasho, T., Finke, C., Oh, S. T., Gotlib, J., Tefferi, A. 2010; 24 (10): 1713-1718

    Abstract

    LNK mutation analysis was performed in 61 patients with blast-phase myeloproliferative neoplasms (MPN); post-primary myelofibrosis (PMF) in 41, post-polycythemia vera in 11 and post-essential thrombocythemia in 9 patients. Paired chronic-blast phase sample analysis was possible in 26 cases. Nine novel heterozygous LNK mutations were identified in eight (13%) patients: six exon 2 missense mutations involving codons 215, 220, 223, 229 and 234, a synonymous mutation involving codon 208, and two deletion mutations involving exon 2 (685-691_delGGCCCCG) or exon 5 (955_delA); eight affected the pleckstrin homology (PH) domain. Mutations were detected in six (9.8%) blast-phase samples; chronic-phase sample analysis in four of these revealed the same mutation in one. Mutant LNK was detected in chronic-phase only in two patients and in both chronic-blast phases in one. JAK2V617F was documented in three and IDH2R140Q in one LNK-mutated patients. LNK mutations were not detected in 78 additional patients with chronic-phase MPN enriched for TET2, IDH, JAK2V617F, or MPL-mutated cases. We conclude that LNK mutations (i) target an exon 2 'hot spot' in the PH domain spanning residues E208-D234, (ii) might be more prevalent in blast-phase PMF and (iii) are not mutually exclusive of other MPN-associated mutations but rarely occur in their presence in chronic-phase disease.

    View details for DOI 10.1038/leu.2010.163

    View details for Web of Science ID 000283056200006

    View details for PubMedID 20724988

  • Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms BLOOD Oh, S. T., Simonds, E. F., Jones, C., Hale, M. B., Goltsev, Y., Gibbs, K. D., Merker, J. D., Zehnder, J. L., Nolan, G. P., Gotlib, J. 2010; 116 (6): 988-992

    Abstract

    Dysregulated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling due to activation of tyrosine kinases is a common feature of myeloid malignancies. Here we report the first human disease-related mutations in the adaptor protein LNK, a negative regulator of JAK-STAT signaling, in 2 patients with JAK2 V617F-negative myeloproliferative neoplasms (MPNs). One patient exhibited a 5 base-pair deletion and missense mutation leading to a premature stop codon and loss of the pleckstrin homology (PH) and Src homology 2 (SH2) domains. A second patient had a missense mutation (E208Q) in the PH domain. BaF3-MPL cells transduced with these LNK mutants displayed augmented and sustained thrombopoietin-dependent growth and signaling. Primary samples from MPN patients bearing LNK mutations exhibited aberrant JAK-STAT activation, and cytokine-responsive CD34(+) early progenitors were abnormally abundant in both patients. These findings indicate that JAK-STAT activation due to loss of LNK negative feedback regulation is a novel mechanism of MPN pathogenesis.

    View details for DOI 10.1182/blood-2010-02-270108

    View details for Web of Science ID 000280881700021

    View details for PubMedID 20404132

    View details for PubMedCentralID PMC2924231

  • Myelomastocytic leukemia versus mast cell leukemia versus systemic mastocytosis associated with acute myeloid leukemia: A diagnostic challenge AMERICAN JOURNAL OF HEMATOLOGY Arredondo, A. R., Gotlib, J., Shier, L., Medeiros, B., Wong, K., Cherry, A., Corless, C., Arber, D. A., Valent, P., George, T. I. 2010; 85 (8): 600-606

    View details for DOI 10.1002/ajh.21713

    View details for PubMedID 20658589

  • JAK2 V617F and beyond: role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms EXPERT REVIEW OF HEMATOLOGY Oh, S. T., Gotlib, J. 2010; 3 (3): 323-337

    Abstract

    Dysregulated signaling is a hallmark of chronic myeloproliferative neoplasms (MPNs), as evidenced by the identification of the activating JAK2 V617F somatic mutation in almost all patients with polycythemia vera (PV) and 50-60% of essential thrombocythemia and primary myelofibrosis patients. These disorders are clinically distinct, raising the question of how a single mutation can result in such phenotypic diversity. Mouse models have demonstrated that the level of JAK2 V617F expression can modulate the phenotype, and clinical studies of JAK2 V617F allele burden have reported similar findings. It has also been hypothesized that one or more pre-JAK2 V617F events may modify the MPN phenotype. However, the molecular basis of JAK2 V617F-negative essential thrombocythemia and primary myelofibrosis remains largely unexplained. Mutations in the TET2 gene have been identified in both JAK2 V617F-positive and -negative MPNs and other myeloid neoplasms, but their functional and clinical significance have yet to be clarified. In addition, recent reports have identified a specific germline haplotype that increases the predisposition to MPNs. The role of inhibitory pathways (e.g., SOCS and LNK) in regulating JAK-STAT signaling in MPNs is being increasingly recognized. The implications of these findings and their clinical relevance are the focus of this article.

    View details for DOI 10.1586/EHM.10.28

    View details for Web of Science ID 000284801600015

    View details for PubMedID 21082983

  • Eosinophilic myeloid disorders: new classification and novel therapeutic strategies CURRENT OPINION IN HEMATOLOGY Gotlib, J. 2010; 17 (2): 117-124

    Abstract

    The aim of this brief review is to evaluate recent developments in the classification and treatment of eosinophilic myeloid disorders in the context of reactive, lymphocyte-variant, and idiopathic eosinophilias.The revised 2008 WHO classification recognizes both molecularly defined ('myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1') and undefined (chronic eosinophilic leukemia, not otherwise specified) eosinophilic myeloid disorders. An increasingly sophisticated understanding of the molecular underpinnings of eosinophilia has translated into rational use of biologically targeted therapies such as imatinib mesylate. Conventional cytotoxics and interferon-alpha still have an established role in treating these diseases. Although studied in idiopathic hypereosinophilic syndrome, the therapeutic niche of anti-interleukin-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibody therapy in eosinophilic myeloid diseases has yet to be established.Molecular/genetic analysis is now mandatory for the diagnosis, classification, and treatment of eosinophilic myeloid disorders. The finding of rearranged, constitutively activated PDGFRA/B identifies patients who are eminently treatable with tyrosine kinase inhibitors.

    View details for DOI 10.1097/MOH.0b013e3283366c70

    View details for Web of Science ID 000275198000008

    View details for PubMedID 20071982

  • Hypereosinophilic Syndrome and Clonal Eosinophilia: Point-of-Care Diagnostic Algorithm and Treatment Update MAYO CLINIC PROCEEDINGS Tefferi, A., Gotlib, J., Pardanani, A. 2010; 85 (2): 158-164

    Abstract

    Acquired eosinophilia is operationally categorized into secondary, clonal, and idiopathic types. Causes of secondary eosinophilia include parasite infections, allergic or vasculitis conditions, drugs, and lymphoma. Clonal eosinophilia is distinguished from idiopathic eosinophilia by the presence of histologic, cytogenetic, or molecular evidence of an underlying myeloid malignancy. The World Health Organization classification system for hematologic malignancies recognizes 2 distinct subcategories of clonal eosinophilia: chronic eosinophilic leukemia, not otherwise specified and myeloid/lymphoid neoplasms with eosinophilia and mutations involving platelet-derived growth factor receptor alpha/beta or fibroblast growth factor receptor 1. Clonal eosinophilia might also accompany other World Health Organization-defined myeloid malignancies, including chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and systemic mastocytosis. Hypereosinophilic syndrome, a subcategory of idiopathic eosinophilia, is defined by the presence of a peripheral blood eosinophil count of 1.5 x 10(9)/L or greater for at least 6 months (a shorter duration is acceptable in the presence of symptoms that require eosinophil-lowering therapy), exclusion of both secondary and clonal eosinophilia, evidence of organ involvement, and absence of phenotypically abnormal and/or clonal T lymphocytes. The presence of the latter defines lymphocytic variant hyper eosinophilia, which is best classified under secondary eosinophilia. In the current review, we provide a simplified algorithm for distinguishing the various causes of clonal and idiopathic eosinophilia and discuss current therapy, including new drugs (imatinib mesylate, alemtuzumab, and mepolizumab).

    View details for DOI 10.4065/mcp.2009.0503

    View details for Web of Science ID 000274607200009

    View details for PubMedID 20053713

    View details for PubMedCentralID PMC2813824

  • Design and Evaluation of a Real-Time PCR Assay for Quantification of JAK2 V617F and Wild-Type JAK2 Transcript Levels in the Clinical Laboratory JOURNAL OF MOLECULAR DIAGNOSTICS Merker, J. D., Jones, C. D., Oh, S. T., Schrijver, I., Gotlib, J., Zehnder, J. L. 2010; 12 (1): 58-64

    Abstract

    The somatic mutation JAK2 V617F is associated with BCR-ABL1-negative myeloproliferative neoplasms. Detection of this mutation aids diagnosis of these neoplasms, and quantification of JAK2 V617F may provide a method to monitor response to therapy. For these reasons, we designed a clinical assay that uses allele-specific PCR and real-time detection with hydrolysis probes for the quantification of JAK2 V617F, wild-type JAK2, and GAPDH transcripts. Mutant and wild-type JAK2 were quantified by using external plasmid standards that contain the relevant JAK2 V617F or JAK2 sequence, respectively. We tested 55 peripheral blood specimens from patients with suspected myeloproliferative neoplasms and 55 peripheral blood specimens from patients not known to have myeloproliferative neoplasms. Low-level, nonspecific amplification was detected in reactions containing a high copy number of plasmid standards and in specimens from patients not known to have myeloproliferative neoplasms, necessitating the use of a laboratory-established mutant to wild-type cutoff. The limit of detection established by using cell line dilutions is 0.1%, and this method identified three JAK2 V617F-positive patients who were not detected by a less sensitive method. The assay characteristics and our initial evaluation indicate this method can be used for the detection and quantification of JAK2 V617F, which should be useful for diagnosis of myeloproliferative neoplasms and potentially for monitoring minimal residual disease in future trials of therapies targeted to myeloproliferative neoplasms.

    View details for DOI 10.2353/jmoldx.2010.090068

    View details for Web of Science ID 000273664100009

    View details for PubMedID 19959796

    View details for PubMedCentralID PMC2797719

  • Fusion of PDGFRB to two distinct loci at 3p21 and a third at 12q13 in imatinib-responsive myeloproliferative neoplasms BRITISH JOURNAL OF HAEMATOLOGY Hidalgo-Curtis, C., Apperley, J. F., Stark, A., Jeng, M., Gotlib, J., Chase, A., Cross, N. C., Grand, F. H. 2010; 148 (2): 268-273

    Abstract

    We identified four patients who presented with BCR-ABL1 negative myeloproliferative neoplasms and cytogenetically visible abnormalities of chromosome band 5q31-35. Fluorescence in situ hybridization indicated that the platelet-derived growth factor receptor beta gene (PDGFRB) was disrupted in all four cases and 5' rapid amplification of cDNA ends identified in-frame mRNA fusions between PDGFRB and WDR48 (3p21), GOLGA4 (3p21) and BIN2 (12q13). Strikingly, all three genes encode proteins involving intracellular trafficking. Imatinib, a known inhibitor of PDGFRbeta, selectively blocked the growth of t(3;5) myeloid colonies and produced clinically significant responses in all patients. We conclude that PDGFRB fuses to diverse partner genes in atypical myeloproliferative neoplasms (MPNs). Although very rare, identification of these fusions is critical for proper management of affected individuals.

    View details for DOI 10.1111/j.1365-2141.2009.07955.x

    View details for Web of Science ID 000272884100009

    View details for PubMedID 20085582

  • When yellow jackets attack: recurrent and severe anaphylactic reactions to insect bites and stings AMERICAN JOURNAL OF HEMATOLOGY Pollyea, D. A., George, T. I., Corless, C., Gotlib, J. 2009; 84 (12): 843-846

    View details for DOI 10.1002/ajh.21551

    View details for PubMedID 19862831

  • On being metachromatic: mystique and misunderstanding in mastocytosis AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J. 2009; 84 (12): 779-781

    View details for DOI 10.1002/ajh.21575

    View details for Web of Science ID 000272481500001

    View details for PubMedID 19899132

  • NPM1 Haploinsufficiency Results in Increased Numbers of Hematopoietic Stem Cells and Progenitor Cells 51st Annual Meeting and Exposition of the American-Society-of-Hematology Raval, A., Park, C. Y., Pang, W. W., Kusler, B., Sridhar, K. J., Gotlib, J. R., Greenberg, P. L., Weissman, I. L., Mitchell, B. S. AMER SOC HEMATOLOGY. 2009: 307–
  • Development of a Small-Molecule Inhibitor Screen to Rapidly Identify Key Signaling Pathways in Leukemogenesis Tyner, J. W., Fletcher, L., Yang, W., Oh, S. T., Gotlib, J. R., Deininger, M. N., Druker, B. J., Loriaux, M. AMER SOC HEMATOLOGY. 2009: 295–96
  • A Phase I Evaluation of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis: Clinical Response Is Accompanied by Significant Reduction in JAK2V617F Allele Burden Pardanani, A. D., Gotlib, J. R., Jamieson, C., Cortes, J., Talpaz, M., Stone, R., Silverman, M. H., Shorr, J., Gilliland, D., Tefferi, A. AMER SOC HEMATOLOGY. 2009: 314–15
  • AML Patients with Monosomal Karyotype Are Characterized by Absence of NPM1 and FLT3 Mutations and Worse Clinical Outcome. Seetharam, M., Weinberg, O. K., Ren, L., Ma, L., Seo, K., Zehnder, J. L., Gotlib, J. R., Arber, D. A. AMER SOC HEMATOLOGY. 2009: 1035
  • RAPID siRNA Screen for Identification of Therapeutic Gene Targets in Patients with Hematologic Malignancies Tyner, J. W., Loriaux, M., Willis, S. G., Chang, B. H., Bicocca, V. T., Oh, S. T., Hollink, I. M., Segers, S., DenBoer, M. L., van den Heuvel-Eibrink, M. M., Zwaan, C., Gotlib, J. R., Deininger, M., Druker, B. J. AMER SOC HEMATOLOGY. 2009: 1529
  • Is Time of the Essence in Adult Acute Myeloid Leukemia (AML)? Time to Blast Clearance and Time to Induction Therapy Fail to Predict Overall Survival (OS). 51st Annual Meeting and Exposition of the American-Society-of-Hematology Kohrt, H. E., Patel, S., Ho, M., Owen, T., Majeti, R., Gotlib, J. R., Coutre, S., Medeiros, B. C., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2009: 646–47
  • Early Mortality in Acute Promyelocytic Leukemia May Be Higher Than Previously Reported. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Alizadeh, A. A., McClellan, J. S., Gotlib, J. R., Coutre, S., Majeti, R., Kohrt, H. E., Medeiros, B. C. AMER SOC HEMATOLOGY. 2009: 420–21
  • Chronic Myelogenous Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Brien, S., Berman, E., Borghaei, H., DeAngelo, D. J., Devetten, M. P., Devine, S., Erba, H. P., Gotlib, J., Jagasia, M., Moore, J. O., Mughal, T., Mughal, T., Radich, J. P., Radich, J. P., Shah, N. P., Smith, B. D., Snyder, D. S., Snyder, D. S., Talpaz, M., Wetzler, M. 2009; 7 (9): 984-1023
  • NCCN clinical practice guidelines in oncology: chronic myelogenous leukemia. Journal of the National Comprehensive Cancer Network O'Brien, S., Berman, E., Borghaei, H., DeAngelo, D. J., Devetten, M. P., Devine, S., Erba, H. P., Gotlib, J., Jagasia, M., Moore, J. O., Mughal, T., Pinilla-Ibarz, J., Radich, J. P., Shah Md, N. P., Shami, P. J., Smith, B. D., Snyder, D. S., Tallman, M. S., Talpaz, M., Wetzler, M. 2009; 7 (9): 984-1023

    View details for PubMedID 19878641

  • Monoclonal antibodies against IREM-1: potential for targeted therapy of AML LEUKEMIA Korver, W., Zhao, X., Singh, S., Pardoux, C., Zhao, J., Guzman, M. L., Sen, S., Yonkovich, S., Liu, S., Zhan, X., Tomasevic, N., Zhou, C., Gros, D., Jordan, C. T., Gotlib, J., Hsi, E. D., Abo, A. 2009; 23 (9): 1587-1597

    Abstract

    IREM-1 is an inhibitory cell surface receptor with an unknown function and is expressed on myeloid cell lineages, including cell lines derived from acute myeloid leukemia (AML) patients. We have generated a series of monoclonal antibodies (mAbs) against the extracellular domain of IREM-1 and further assessed its expression in normal and AML cells. IREM-1 was restricted to cells from myeloid origin and extensive expression analysis in primary cells obtained from AML patients showed IREM-1 expression in leukemic blasts of 72% (39/54) of samples. We therefore searched for specific IREM-1 mAbs with activity in functional complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). Lead mAbs against IREM-1 showed specific cytotoxic activity against a variety of AML-derived cell lines and freshly isolated blasts from AML patients. Internalization of mAbs upon IREM-1 binding was also shown. In vivo anticancer activity of lead mAbs was observed in an established HL-60 xenograft model with a tumor growth delay of up to 40% and in a model using primary human AML cells, where treatment with anti-IREM-1 mAb resulted in a significant reduction of engrafted human cells. These results demonstrate IREM-1 as a potential novel target for immunotherapy of AML.

    View details for DOI 10.1038/leu.2009.99

    View details for Web of Science ID 000269674200007

    View details for PubMedID 19440216

  • RNAi screen for rapid therapeutic target identification in leukemia patients PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tyner, J. W., Deininger, M. W., Loriaux, M. M., Chang, B. H., Gotlib, J. R., Willis, S. G., Erickson, H., Kovacsovics, T., O'Hare, T., Heinrich, M. C., Druker, B. J. 2009; 106 (21): 8695-8700

    Abstract

    Targeted therapy has vastly improved outcomes in certain types of cancer. Extension of this paradigm across a broad spectrum of malignancies will require an efficient method to determine the molecular vulnerabilities of cancerous cells. Improvements in sequencing technology will soon enable high-throughput sequencing of entire genomes of cancer patients; however, determining the relevance of identified sequence variants will require complementary functional analyses. Here, we report an RNAi-assisted protein target identification (RAPID) technology that individually assesses targeting of each member of the tyrosine kinase gene family. We demonstrate that RAPID screening of primary leukemia cells from 30 patients identifies targets that are critical to survival of the malignant cells from 10 of these individuals. We identify known, activating mutations in JAK2 and K-RAS, as well as patient-specific sensitivity to down-regulation of FLT1, CSF1R, PDGFR, ROR1, EPHA4/5, JAK1/3, LMTK3, LYN, FYN, PTK2B, and N-RAS. We also describe a previously undescribed, somatic, activating mutation in the thrombopoietin receptor that is sensitive to down-stream pharmacologic inhibition. Hence, the RAPID technique can quickly identify molecular vulnerabilities in malignant cells. Combination of this technique with whole-genome sequencing will represent an ideal tool for oncogenic target identification such that specific therapies can be matched with individual patients.

    View details for DOI 10.1073/pnas.0903233106

    View details for PubMedID 19433805

  • Interim results of protracted low doses of temozolomide in high-risk acute myeloid leukemia 45th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Medeiros, B. C., Gotlib, J. R., Coutre, S. E., Jones, C., Khan, S. A., Rajwanshi, R., Rajwanshi, R., Zehnder, J., Zehnder, J. AMER SOC CLINICAL ONCOLOGY. 2009
  • Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens NATURE MEDICINE Fan, A. C., Deb-Basu, D., Orban, M. W., Gotlib, J. R., Natkunam, Y., O'Neill, R., Padua, R., Xu, L., Taketa, D., Shirer, A. E., Beer, S., Yee, A. X., Voehringer, D. W., Felsher, D. W. 2009; 15 (5): 566-571

    Abstract

    Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie key cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nanofluidic proteomic immunoassay (NIA) to quantify total and low-abundance protein isoforms in nanoliter volumes. Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal-related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and detect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin. Therefore, we have described a new and highly sensitive method for determining oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.

    View details for DOI 10.1038/nm.1903

    View details for PubMedID 19363496

  • Glycogen synthase kinase 3 beta missplicing contributes to leukemia stem cell generation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Abrahamsson, A. E., Geron, I., Gotlib, J., Dao, K. T., Barroga, C. F., Newton, I. G., Giles, F. J., Durocher, J., Creusot, R. S., Karimi, M., Jones, C., Zehnder, J. L., Keating, A., Negrin, R. S., Weissman, I. L., Jamieson, C. H. 2009; 106 (10): 3925-3929

    Abstract

    Recent evidence suggests that a rare population of self-renewing cancer stem cells (CSC) is responsible for cancer progression and therapeutic resistance. Chronic myeloid leukemia (CML) represents an important paradigm for understanding the genetic and epigenetic events involved in CSC production. CML progresses from a chronic phase (CP) in hematopoietic stem cells (HSC) that harbor the BCR-ABL translocation, to blast crisis (BC), characterized by aberrant activation of beta-catenin within granulocyte-macrophage progenitors (GMP). A major barrier to predicting and inhibiting blast crisis transformation has been the identification of mechanisms driving beta-catenin activation. Here we show that BC CML myeloid progenitors, in particular GMP, serially transplant leukemia in immunocompromised mice and thus are enriched for leukemia stem cells (LSC). Notably, cDNA sequencing of Wnt/beta-catenin pathway regulatory genes, including adenomatous polyposis coli, GSK3beta, axin 1, beta-catenin, lymphoid enhancer factor-1, cyclin D1, and c-myc, revealed a novel in-frame splice deletion of the GSK3beta kinase domain in the GMP of BC samples that was not detectable by sequencing in blasts or normal progenitors. Moreover, BC CML progenitors with misspliced GSK3beta have enhanced beta-catenin expression as well as serial engraftment potential while reintroduction of full-length GSK3beta reduces both in vitro replating and leukemic engraftment. We propose that CP CML is initiated by BCR-ABL expression in an HSC clone but that progression to BC may include missplicing of GSK3beta in GMP LSC, enabling unphosphorylated beta-catenin to participate in LSC self-renewal. Missplicing of GSK3beta represents a unique mechanism for the emergence of BC CML LSC and might provide a novel diagnostic and therapeutic target.

    View details for DOI 10.1073/pnas.0900189106

    View details for Web of Science ID 000264036900051

    View details for PubMedID 19237556

    View details for PubMedCentralID PMC2646624

  • Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Weinberg, O. K., Seetharam, M., Ren, L., Seo, K., Ma, L., Merker, J. D., Gotlib, J., Zehnder, J. L., Arber, D. A. AMER SOC HEMATOLOGY. 2009: 1906–8

    Abstract

    Although some studies have validated the 2001 World Health Organization (WHO) classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification has expanded this category into "AML with myelodysplasia-related changes" (AML-MRC). We evaluated the clinical, pathologic, cytogenetic, and molecular features of 100 AML patients using the 2008 WHO criteria. Patients underwent genetic screening for NPM1, FLT3-ITD, FLT3-D835, and CEBPA mutations. Compared with patients with AML, not otherwise specified, patients with AML-MRC were significantly older (P= .014), presented with a lower hemoglobin (P= .044), more frequently expressed CD14 (P= .048), and exhibited a decreased frequency of CEBPA mutations (P= .001). Multivariate analysis indicated that patients with AML-MRC had a significantly worse overall survival, progression-free survival, and complete response compared with AML-not otherwise specified (all P< .001). These data support the clinical, morphologic, and cytogenetic criteria for this 2008 WHO AML category.

    View details for DOI 10.1182/blood-2008-10-182782

    View details for Web of Science ID 000263723700007

    View details for PubMedID 19131546

  • A phase II intra-patient dose-escalation trial of weight-based darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes AMERICAN JOURNAL OF HEMATOLOGY Gotlib, J., Lavori, P., Quesada, S., Stein, R. S., Shahnia, S., Greenberg, P. L. 2009; 84 (1): 15-20

    Abstract

    This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level non-neutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients.

    View details for DOI 10.1002/ajh.21316

    View details for PubMedID 19006226

  • Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Weinberg, O. K., Seetharam, M., Ren, L., Ma, L., Seo, K., Merker, J., Gotlib, J., Zehnder, J., Arber, D. A. NATURE PUBLISHING GROUP. 2009: 291A–291A
  • Myelomastocytic Leukemia: A Clinical, Pathologic, and Molecular Genetic Study 98th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology McGuire, A., Shier, L. R., Gotlib, J., Medeiros, B., Wong, K., Corless, C., Arber, D. A., George, T. I. NATURE PUBLISHING GROUP. 2009: 277A–277A
  • Molecular stratification of patients with normal karyotype acute myeloid leukemia based on initial assessment of FLT3-internal tandem duplication status at first complete remission LEUKEMIA & LYMPHOMA Medeiros, B. C., Gotlib, J., Zehnder, J. 2009; 50 (5): 851-853

    View details for DOI 10.1080/10428190902838400

    View details for Web of Science ID 000266201800029

    View details for PubMedID 19452323

  • Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System 50th Annual Meeting of the American-Society-of-Hematology/ASH/ASCO Joint Symposium Weinberg, O. K., Seetharam, M., Ren, L., Ma, L., Seo, K., Merker, J. D., Gotlib, J. R., Zehnder, J. L., Arber, D. A. AMER SOC HEMATOLOGY. 2008: 341–42
  • Tailored Temozolomide Therapy for Elderly Patients with Acute Myeloid Leukemia. Medeiros, B. C., Gotlib, J. R., Coutre, S. E., Mignea, A., Zehnder, J. AMER SOC HEMATOLOGY. 2008: 351
  • A Phase I Study of TG101348, An Orally Bioavailable JAK2-Selective Inhibitor, in Patients with Myelofibrosis Pardanani, A. D., Gotlib, J., Jamieson, C., Cortes, J., Talpaz, M., Stone, R. M., Silverman, M. H., Shorr, J., Gilliland, D., Tefferi, A. AMER SOC HEMATOLOGY. 2008: 43–44
  • RNAi Screening of the Tyrosine Kinome Identifies Therapeutic Targets in Leukemia Patients Tyner, J. W., Loriaux, M., Willis, S. G., Chang, B., Bicocca, V. T., Oh, S., Hollink, I. M., Segers, S., den Boer, M. L., Zwaan, C. M., Gotlib, J. R., Deininger, M. N., Druker, B. J. AMER SOC HEMATOLOGY. 2008: 281
  • Small-Molecule Inhibitor Screen Rapidly Identifies Key Signaling Pathways in Leukemogenesis. Tyner, J. W., Erickson, H., Oh, S., Gotlib, J. R., Deininger, M. N., Druker, B. J., Loriaux, M. AMER SOC HEMATOLOGY. 2008: 874
  • Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias LEUKEMIA Gotlib, J., Cools, J. 2008; 22 (11): 1999-2010

    Abstract

    The year 2008 marks the fifth anniversary since the publication which identified the FIP1L1-PDGFRA fusion gene in patients with idiopathic hypereosinophilia. With the benefit of time, a more comprehensive picture has emerged regarding several characteristics of the fusion, including its incidence, biological features and the clinical profile of patients who carry the molecular rearrangement. A few prospective trials have now better defined the natural history of imatinib-treated FIP1L1-PDGFRA-positive patients, from which some basic conclusions can be drawn: the prognosis is outstanding, acquired resistance is exceedingly rare, but ongoing imatinib treatment is likely required to prevent relapse. The emergence of genetically assigned eosinophilias has led the World Health Organization in 2008 to adopt a semi-molecular classification scheme, with one subcategory named 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1.' Molecular rearrangements involving other partner genes, such as ETV6 and JAK2, have also been associated with eosinophilic disorders, and will likely be assimilated into such classifications over time. Despite the molecularly defined eosinophilias comprising a small proportion of cases compared to the aggregate of other subtypes of hypereosinophilia, their recognition is critical because of the availability of highly effective molecularly targeted therapy.

    View details for DOI 10.1038/leu.2008.287

    View details for Web of Science ID 000260832800003

    View details for PubMedID 18843283

  • Design and Validation of a Real-Time PCR Assay for Quantification of JAK2 V617F and Wild-type JAK2 Transcript Levels 14th Annual Meeting of the Association-for-Molecular-Pathology Merker, J. D., Jones, C. D., Oh, S. T., Khan, S., Schrijver, I., Gotlib, J., Zehnder, J. L. ELSEVIER SCIENCE INC. 2008: 581–81
  • Selective inhibition of JAK2-Driven erythroid differentiation of polycythemia vera progenitors CANCER CELL Geron, I., Abrahamsson, A. E., Barroga, C. F., Kavalerchik, E., Gotlib, J., Hood, J. D., Durocher, J., Mak, C. C., Noronha, G., Soll, R. M., Tefferi, A., Kaushansky, K., Jamieson, C. H. 2008; 13 (4): 321-330

    Abstract

    Polycythemia Vera (PV) is a myeloproliferative disorder (MPD) that is commonly characterized by mutant JAK2 (JAK2V617F) signaling, erythrocyte overproduction, and a propensity for thrombosis, progression to myelofibrosis, or acute leukemia. In this study, JAK2V617F expression by human hematopoietic progenitors promoted erythroid colony formation and erythroid engraftment in a bioluminescent xenogeneic immunocompromised mouse transplantation model. A selective JAK2 inhibitor, TG101348 (300 nM), significantly inhibited JAK2V617F+ progenitor-derived colony formation as well as engraftment (120 mg/kg) in xenogeneic transplantation studies. TG101348 treatment decreased GATA-1 expression, which is associated with erythroid-skewing of JAK2V617F+ progenitor differentiation, and inhibited STAT5 as well as GATA S310 phosphorylation. Thus, TG101348 may be an effective inhibitor of JAK2V617F+ MPDs in clinical trials.

    View details for DOI 10.1016/j.ccr.2008.02.017

    View details for Web of Science ID 000254817400007

    View details for PubMedID 18394555

  • A 2-gene classifier for predicting response to the famesyltransferase inhibitor tipifarnib in acute myeloid leukemia BLOOD Raponi, M., Lancet, J. E., Fan, H., Dossey, L., Lee, G., Gojo, I., Feldman, E. J., Gotlib, J., Morris, L. E., Greenberg, P. L., Wright, J. J., Harousseau, J., Loewenberg, B., Stone, R. M., De Porre, P., Wang, Y., Karp, J. E. 2008; 111 (5): 2589-2596

    Abstract

    At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.

    View details for DOI 10.1182/blood-2007-09-112730

    View details for Web of Science ID 000253671600023

    View details for PubMedID 18160667

  • Gene expression and pathway analysis of immune thrombocytopenic purpura BRITISH JOURNAL OF HAEMATOLOGY Sood, R., Wong, W., Gotlib, J., Jeng, M., Zehnder, J. L. 2008; 140 (1): 99-103

    Abstract

    A global expression profile of peripheral blood from patients with immune thrombocytopenic purpura (ITP) was performed that identified an ITP-specific signature, which also included interferon (IFN)-induced genes. Several genes correlated with ITP have been shown to be associated with expression signatures in systemic lupus erythematosis and rheumatoid arthritis, indicating an overlap with other autoimmune disorders. Pathway analysis demonstrated that IFN signalling, death receptor and protein ubiquitination pathways were associated with ITP. These results provide the first glimpse of the genes and pathways consistently aberrant in ITP, identifying new targets for investigations of pathogenesis and treatment of ITP.

    View details for DOI 10.1111/j.1365-2141.2007.06881.x

    View details for PubMedID 18005267

  • Significance of NPM1 and FLT3 mutations in acute myeloid leukemia with multilineage dysplasia: Does NPM1 identify a lower risk group? 97th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology Weinberg, O., Merker, J., Beck, A., Seetharam, M., Gotlib, J., Zehnder, J., Arber, D. A. NATURE PUBLISHING GROUP. 2008: 281A–281A
  • Antiangiogenic therapy in myelodysplastic syndromes: is there a role? Current hematologic malignancy reports Oh, S. T., Gotlib, J. 2008; 3 (1): 10-18

    Abstract

    Angiogenesis has been shown to play a pivotal role in the growth and metastasis of solid tumors. Numerous in vitro and translational research studies have implicated a role for angiogenesis in the pathogenesis of myelodysplastic syndrome (MDS). Although the role of angiogenesis inhibitors in the treatment of solid tumors has evolved significantly over the past 5 years, their role in the treatment of hematologic malignancies such as MDS remains investigational. MDS treatment historically has been challenging, but the US Food and Drug Administration in the past 4 years has approved the hypomethylating agents 5-azacitidine and decitabine and the immunomodulatory agent lenalidomide for the 5q-syndrome. These approvals highlight recent successes in identifying and targeting pathobiologic abnormalities that contribute to MDS. Drugs such as lenalidomide and the first-generation analogue from which it was derived, thalidomide, exert multiple mechanisms of action but partially act via inhibition of angiogenesis. Over the next 5 to 10 years, preclinical and clinical evaluation of agents with more strictly defined antiangiogenic activity, such as inhibitors of vascular endothelial growth factor, or agents with partial antiangiogenesis activity, such as multitargeted tyrosine kinase inhibitors, will ultimately help define the utility of angiogenic blockade in MDS.

    View details for DOI 10.1007/s11899-008-0003-0

    View details for PubMedID 20425441

  • Chronic eosinophilic leukemia/hypereosinophilic syndrome. Cancer treatment and research Gotlib, J. 2008; 142: 69-106

    Abstract

    Although HES and CEL are indeed rare clinical entities, interest in these disorders has been reborn due to a renaissance in uncovering the biologic basis of previously idiopathic cases. Unmasking the molecular basis for such cases has, in turn, led to the development of semimolecular classification schemes for categorizing patients based on recurrent genetic alterations, usually related to constitutively activated tyrosine kinases. In turn, increasing sophistication in unmasking the molecular underpinnings of eosinophilia in patients heretofore classified as idiopathic HES now permits the rationale use biologically targeted therapies such as imatinib mesylate and recombinant anti-IL-5 antibody. The WHO convenes in 2007 to review prior diagnostic criteria for both HES and CEL. It will be of interest to see how the new genetic information becomes integrated with traditional histopathologic criteria in establishing a practical road map for clinicians who treat these diseases.

    View details for PubMedID 18283783

  • Missplicing of glycogen synthase kinase 3 beta: A potential mechanism of blast crisis chronic myeloid leukemia stem cell generation 49th Annual Meeting of the American-Society-of-Hematology Abrahamsson, A., Geron, I., Gotlib, J., Dao, K., Giles, F., Newton, I., Kavaterchik, E., Durocher, J., Creusot, R., Karimi, M., Jones, C., Zehnder, J., Keating, A., Negrin, R., Weissman, I. L., Jamieson, C. H. AMER SOC HEMATOLOGY. 2007: 238A–239A
  • The KIT tyrosine kinase inhibitor midostaurine (PKC412) exhibits a high response rate in aggressive systemic mastocytosis (ASM): Interim results of a phase II trial 49th Annual Meeting of the American-Society-of-Hematology Gotlib, J., George, T. I., Corless, C., Linder, A., Ruddell, A., Akin, C., DeAngelo, D. J., Kepten, I., Lanza, C., Heinemann, H., Yin, O., Gallagher, N., Graubert, T. AMER SOC HEMATOLOGY. 2007: 1035A–1035A
  • A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia BLOOD Lancet, J. E., Gojo, I., Gotlib, J., Feldman, E. J., Greer, J., Liesveld, J. L., Bruzek, L. M., Morris, L., Park, Y., Adjei, A. A., Kaufmann, S. H., Garrett-Mayer, E., Greenberg, P. L., Wright, J. J., Karp, J. E. 2007; 109 (4): 1387-1394

    Abstract

    Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response.

    View details for DOI 10.1182/blood-2006-04-014357

    View details for Web of Science ID 000244219400013

    View details for PubMedID 17082323

    View details for PubMedCentralID PMC1794070

  • Gene expression profile of idiopathic thrombocytopenic purpura (ITP) reveals elevated expression of interferon regulated genes. 48th Annual Meeting of the American-Society-of-Hematology Sood, R., Wong, W., Gotlib, J., Jeng, M., Zehnder, J. L. AMER SOC HEMATOLOGY. 2006: 211A–211A
  • Aberrant regulation of Wnt/beta-catenin pathway mediators in chronic myelogenous leukemia stem cells 48th Annual Meeting of the American-Society-of-Hematology Abrahamsson, A., Geron, I., Gotlib, J., Durocher, J., Creusot, R., Kavalerchik, E., Goff, D., Fathman, C. G., Lilleberg, S. L., Giles, F., Weissman, I., Jamieson, C. AMER SOC HEMATOLOGY. 2006: 605A–605A
  • Inhibition of JAK2 V617F-Induced erythroid skewing of hematopoietic stem cell differentiation with a selective JAK2 antagonist. 48th Annual Meeting of the American-Society-of-Hematology Geron, I., Barroga, C., Gotlib, J., Kavalerchik, E., Abrahamsson, A., Goff, D., Cacalano, N., Hood, J., Soll, R., Noronha, G., Tefferi, A., Weissman, I. L., Kaushansky, K., Jamieson, C. AMER SOC HEMATOLOGY. 2006: 1033A–1033A
  • Inhibition of chronic myelogenous leukemia stem cells with novel wnt antagonists. 48th Annual Meeting of the American-Society-of-Hematology Kavalerchik, E., Gotlib, J., Geron, I., Abrahamsson, A., Wrasidlo, W., Goff, D., Lu, D., Molinski, T., Giles, F., Weissman, I., Carson, D., Jamieson, C. AMER SOC HEMATOLOGY. 2006: 74A–75A
  • A patient with paroxysmal nocturnal hemoglobinuria, T cell large granular lymphocyte clonal expansion, and monoclonal gammopathy of undetermined significance AMERICAN JOURNAL OF HEMATOLOGY Fukumoto, J. S., Gotlib, J. 2006; 81 (11): 870-874

    Abstract

    Paroxysmal nocturnal hemoglobinuria (PNH) has been described in association separately with T cell large granular lymphocyte (LGL) clonal expansions and plasma cell dyscrasias. We describe a patient with anemia related to hemolytic PNH, with concurrent T cell LGL oligoclonal expansion and IgG lambda monoclonal gammopathy of undetermined significance. Peripheral blood flow cytometry revealed decreased expression of CD55 and CD59 on erythrocytes and decreased expression of CD55 and CD66 on neutrophils. An LGL population was present in the peripheral blood and was characterized as oligoclonal by polymerase chain reaction-based analysis of the T cell receptor gamma-chain variable region. Serum protein electrophoresis with immunofixation showed a low level IgG lambda monoclonal protein. We describe the diagnostic evaluation of this patient and provide a brief review of the reported associations among PNH, LGL clonal expansion, and monoclonal gammopathy.

    View details for DOI 10.1002/ajh.20634

    View details for Web of Science ID 000241906700010

    View details for PubMedID 16929542

  • Use of urine flow cytometry to verify relapse of Burkitt's lymphoma in the genitourinary system JOURNAL OF CLINICAL ONCOLOGY Dormady, S. P., Mariappan, M. R., Kao, D., Gotlib, J. 2006; 24 (27): 4515-4516

    View details for DOI 10.1200/JCO.2006.06.1598

    View details for Web of Science ID 000240708200023

    View details for PubMedID 16983121

  • KIT mutations in mastocytosis and their potential as therapeutic targets IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Gotlib, J. 2006; 26 (3): 575-?

    Abstract

    Deregulation of the KIT receptor TK by the prevalent activation loop mutation D816V has served as a focal point in therapeutic strategies aimed curbing neoplastic mast cell growth. Perhaps the most important development in this era of targeted therapy, and certainly relevant to KIT-driven diseases like mastocytosis, is the realization that small molecule inhibitors with varied chemical structure (eg, PKC412, dasatinib, AP23464) can circumvent the resistance of TKs to first-generation agents such as imatinib. Genuine opportunity now exists to effectively treat mastocytosis, and the arsenal consists of several orally bioavailable drugs with promising preclinical activity against D816V and other KIT mutants that promote mast cell growth. Because KIT mutations may not act as fully transforming oncogenic events in SM, it is prudent to evaluate combinations of TK inhibitors with drugs with activity in mast cell disease, such as cladribine, interferon-alpha, and corticosteroids. The identification of novel "drug-able" targets within mast cells should aid in the development of complementary therapies that promote enhanced cytotoxicity of mast cells through blockade of nonredundant signaling pathways. In addition, the generation of murine models that recapitulate human mastocytosis should accelerate preclinical testing of novel agents.

    View details for DOI 10.1016/j.iac.2006.05.003

    View details for Web of Science ID 000240967200012

    View details for PubMedID 16931294

  • Detection of the JAK2 V617F mutation by LightCycler PCR and probe dissociation analysis JOURNAL OF MOLECULAR DIAGNOSTICS Lay, M., Mariappan, R., Gotlib, J., Dietz, L., Sebastian, S., Schrijver, I., Zehnder, J. L. 2006; 8 (3): 330-334

    Abstract

    A point mutation in the JAK2 gene, a member of the tyrosine kinase family, was recently identified and shown to be associated with several myeloproliferative disorders. Several studies identified the same JAK2 point mutation (1,849G>T), resulting in the substitution of a valine to phenylalanine at codon 617 (V617F). We developed a simple and sensitive method to detect this mutation via polymerase chain reaction and probe dissociation analysis using the LightCycler platform, and we compared this method to existing restriction fragment-length polymorphism, direct sequencing, and amplification refractory mutation system methods. We found that the LightCycler method offered advantages of speed, reliability, and more straightforward interpretation over the restriction fragment-length polymorphism and sequencing approaches.

    View details for DOI 10.2353/jmoldx.2006.050130

    View details for Web of Science ID 000239106800006

    View details for PubMedID 16825505

    View details for PubMedCentralID PMC1867612

  • Eosinophilic disorders: Molecular pathogenesis, new classification, and modern therapy BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Gotlib, J., Cross, N. C., Gilliland, D. G. 2006; 19 (3): 535-569

    Abstract

    Before the 1990s, lack of evidence for a reactive cause of hypereosinophilia or chronic eosinophilic leukemia (e.g. presence of a clonal cytogenetic abnormality or increased blood or bone marrow blasts) resulted in diagnosticians characterizing such nebulous cases as 'idiopathic hypereosinophilic syndrome (HES)'. However, over the last decade, significant advances in our understanding of the molecular pathophysiology of eosinophilic disorders have shifted an increasing proportion of cases from this idiopathic HES 'pool' to genetically defined eosinophilic diseases with recurrent molecular abnormalities. The majority of these genetic lesions result in constitutively activated fusion tyrosine kinases, the phenotypic consequence of which is an eosinophilia-associated myeloid disorder. Most notable among these is the recent discovery of the cryptic FIP1L1-PDGFRA gene fusion in karyotypically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES, redefining these diseases as clonal eosinophilias. Rearrangements involving PDGFRA and PDGFRB in eosinophilic chronic myeloproliferative disorders, and of fibroblast growth factor receptor 1 (FGFR1) in the 8p11 stem cell myeloproliferative syndrome constitute additional examples of specific genetic alterations linked to clonal eosinophilia. The identification of populations of aberrant T-lymphocytes secreting eosinophilopoietic cytokines such as interleukin-5 establish a pathophysiologic basis for cases of lymphocyte-mediated hypereosinophilia. This recent revival in understanding the biologic basis of eosinophilic disorders has permitted more genetic specificity in the classification of these diseases, and has translated into successful therapeutic approaches with targeted agents such as imatinib mesylate and recombinant anti-IL-5 antibody.

    View details for DOI 10.1016/j.beha.2005.07.013

    View details for Web of Science ID 000238903900012

    View details for PubMedID 16781488

  • Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation BLOOD Gotlib, J., Berube, C., Growney, J. D., Chen, C. C., George, T. I., Williams, C., Kajiguchi, T., Ruan, J., Lilleberg, S. L., Durocher, J. A., Lichy, J. H., Wang, Y. F., Cohen, P. S., Arber, D. A., Heinrich, M. C., Neckers, L., GALLI, S. J., Gilliland, D. G., Coutre, S. E. 2005; 106 (8): 2865-2870

    Abstract

    The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.

    View details for DOI 10.1182/blood-2005-04-1568

    View details for PubMedID 15972446

  • Farnesyltransferase inhibitor therapy in acute myelogenous leukemia. Current hematology reports Gotlib, J. 2005; 4 (1): 77-84

    Abstract

    Acute myelogenous leukemia (AML) remains a clinical challenge with poor long-term survival. Low remission rates and high treatment-related mortality persist as major obstacles, particularly in older patients. The design of novel agents based on the identification of genetic lesions and aberrant signaling pathways provides opportunity to improve the standard treatment paradigm of intensive cytotoxic chemotherapy. Farnesyltransferase inhibitors (FTIs) show potential to fill this niche. The preclinical concept of farnesyltransferase blockade as a targeted therapy against oncogenic Ras has clearly evolved with the recognition that many proteins involved signaling pathways in tumor cells undergo farnesylation. Phase I/II trials of FTI monotherapy in AML demonstrate encouraging responses and good tolerability. The FTI tipifarnib (R115777, Zarnestra; Johnson & Johnson, Titusville, NJ) has advanced the furthest in clinical trials, with the most promising activity in previously untreated, high-risk AML patients. A major emphasis of current clinical studies has been to analyze potential candidate genes and signaling pathways modified by FTIs in order to identify mechanisms of response and resistance. Preclinical concepts related to the development of FTIs, the rationale for their use in AML, and efficacy and safety results from recent clinical trials are evaluated in this paper.

    View details for PubMedID 15610664

  • Molecular classification and pathogenesis of eosinophilic disorders: 2005 update ACTA HAEMATOLOGICA Gotlib, J. 2005; 114 (1): 7-25

    Abstract

    Use of the term "idiopathic hypereosinophilic syndrome (HES)" has highlighted our basic lack of understanding of the molecular pathophysiology of eosinophilic disorders. However, over the last 10 years, the study of hypereosinophilia has enjoyed a revival. This interest has been rekindled by two factors: (1) the development of increasingly sophisticated molecular biology techniques that have unmasked recurrent genetic abnormalities linked to eosinophilia, and (2) the successful application of targeted therapy with agents such as imatinib to treat eosinophilic diseases. To date, most of these recurrent molecular abnormalities have resulted in constitutively activated fusion tyrosine kinases whose phenotypic consequence is an eosinophilia-associated myeloid disorder. Most notable among these are rearrangements of platelet-derived growth factor receptors alpha and beta (PDGFRalpha, PDGFRbeta), which define a small subset of patients with eosinophilic chronic myeloproliferative disorders (MPDs) and/or overlap myelodysplastic syndrome/MPD syndromes, including chronic myelomonocytic leukemia. Discovery of the cryptic FIP1L1-PDGFRA gene fusion in cytogenetically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES has redefined these diseases as clonal eosinophilias. A growing list of fibroblast growth factor receptor 1 fusion partners has similarly emerged in the 8p11 myeloproliferative syndromes, which are often characterized by elevated eosinophil counts. Herein the focus is on the molecular gains made in these MPD-type eosinophilias, and the classification and clinicopathological issues related to hypereosinophilic syndromes, including the lymphocyte variant. Success in establishing the molecular basis of a group of once seemingly heterogeneous diseases has now the laid the foundation for establishing a semi-molecular classification scheme of eosinophilic disorders.

    View details for DOI 10.1159/000085559

    View details for Web of Science ID 000230306500002

    View details for PubMedID 15995322

  • Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML NEW ENGLAND JOURNAL OF MEDICINE Jamieson, C. H., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., Gotlib, J., Li, K., Manz, M. G., Keating, A., Sawyers, C. L., Weissman, I. L. 2004; 351 (7): 657-667

    Abstract

    The progression of chronic myelogenous leukemia (CML) to blast crisis is supported by self-renewing leukemic stem cells. In normal mouse hematopoietic stem cells, the process of self-renewal involves the beta-catenin-signaling pathway. We investigated whether leukemic stem cells in CML also use the beta-catenin pathway for self-renewal.We used fluorescence-activated cell sorting to isolate hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage progenitors, and megakaryocyte-erythroid progenitors from marrow during several phases of CML and from normal marrow. BCR-ABL, beta-catenin, and LEF-1 transcripts were compared by means of a quantitative reverse-transcriptase-polymerase-chain-reaction assay in normal and CML hematopoietic stem cells and granulocyte-macrophage progenitors. Confocal fluorescence microscopy and a lymphoid enhancer factor/T-cell factor reporter assay were used to detect nuclear beta-catenin in these cells. In vitro replating assays were used to identify self-renewing cells as candidate leukemic stem cells, and the dependence of self-renewal on beta-catenin activation was tested by lentiviral transduction of hematopoietic progenitors with axin, an inhibitor of the beta-catenin pathway.The granulocyte-macrophage progenitor pool from patients with CML in blast crisis and imatinib-resistant CML was expanded, expressed BCR-ABL, and had elevated levels of nuclear beta-catenin as compared with the levels in progenitors from normal marrow. Unlike normal granulocyte-macrophage progenitors, CML granulocyte-macrophage progenitors formed self-renewing, replatable myeloid colonies, and in vitro self-renewal capacity was reduced by enforced expression of axin.Activation of beta-catenin in CML granulocyte-macrophage progenitors appears to enhance the self-renewal activity and leukemic potential of these cells.

    View details for PubMedID 15306667

  • Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. Seminars in cancer biology Coutré, S., Gotlib, J. 2004; 14 (4): 307-315

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

    View details for PubMedID 15305431

  • The HP1L1-PDIGFR alpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management BLOOD Gotlib, J., Cools, J., Malone, J. M., Schrier, S. L., Gilliland, D. G., Coutre, S. E. 2004; 103 (8): 2879-2891

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.

    View details for DOI 10.1182/blood-2003-06-1824

    View details for Web of Science ID 000222163500012

    View details for PubMedID 15070659

  • Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis BLOOD Loh, M. L., Vattikuti, S., Schubbert, S., Reynolds, M. G., Carlson, E., Lieuw, K. H., Cheng, J. W., Lee, C. M., Stokoe, D., Bonifas, J. M., Curtiss, N. P., Gotlib, J., Meshinchi, S., Le Beau, M. M., Emanuel, P. D., Shannon, K. M. 2004; 103 (6): 2325-2331

    Abstract

    The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that relays signals from activated growth factor receptors to p21Ras (Ras) and other signaling molecules. Mutations in PTPN11 cause Noonan syndrome (NS), a developmental disorder characterized by cardiac and skeletal defects. NS is also associated with a spectrum of hematologic disorders, including juvenile myelomonocytic leukemia (JMML). To test the hypothesis that PTPN11 mutations might contribute to myeloid leukemogenesis, we screened the entire coding region for mutations in 51 JMML specimens and in selected exons from 60 patients with other myeloid malignancies. Missense mutations in PTPN11 were detected in 16 of 49 JMML specimens from patients without NS, but they were less common in other myeloid malignancies. RAS, NF1, and PTPN11 mutations are largely mutually exclusive in JMML, which suggests that mutant SHP-2 proteins deregulate myeloid growth through Ras. However, although Ba/F3 cells engineered to express leukemia-associated SHP-2 proteins cells showed enhanced growth factor-independent survival, biochemical analysis failed to demonstrate hyperactivation of the Ras effectors extracellular-regulated kinase (ERK) or Akt. We conclude that SHP-2 is an important cellular PTPase that is mutated in myeloid malignancies. Further investigation is required to clarify how these mutant proteins interact with Ras and other effectors to deregulate myeloid growth.

    View details for DOI 10.1182/blood-2003-09-3287

    View details for Web of Science ID 000220123400053

    View details for PubMedID 14644997

  • Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate SEMINARS IN CANCER BIOLOGY Coutre, S., Gotlib, J. 2004; 14 (1): 23-31

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

    View details for DOI 10.1016/j.semcancer.2003.11.004

    View details for Web of Science ID 000189081200004

    View details for PubMedID 14757533

  • PTPN11 mutations are rare in adult patients with chronic myelomonocytic leukemia (CMML). 45th Annual Meeting and Exhibition of the American-Society-of-Hematology Loh, M. L., Vattikuti, S., Reynolds, M. G., Cheng, J. W., Lee, C. M., Gotlib, J., Beran, M. AMER SOC HEMATOLOGY. 2003: 328B–328B
  • Novel biospecific agents for the treatment of myelodysplastic syndromes. Journal of the National Comprehensive Cancer Network Gotlib, J., Greenberg, P. L. 2003; 1 (4): 473-480

    Abstract

    Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term "biospecific" has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS.

    View details for PubMedID 19774739

  • Soluble TNF receptor fusion protein (etanercept) for the treatment of myelodysplastic syndrome: A pilot study LEUKEMIA Deeg, H. J., Gotlib, J., Beckham, C., Dugan, K., Holmberg, L., Schubert, M., Appelbaum, F., Greenberg, P. 2002; 16 (2): 162-164

    Abstract

    Blockade of tumor necrosis factor (TNF)alpha by a soluble TNF receptor fusion protein (etanercept; Enbrel) improved in vitro hemopoiesis from the marrow of patients with myelodysplastic syndrome (MDS). Therefore, we enrolled 14 MDS patients (4 RA, 2 RARS, 6 RAEB, 2 CMML), 44-80 (median 60) years old, in a pilot trial. Etanercept, 25 mg, was given twice a week s.c. for 16 weeks (increased to three times a week if no response at 8 weeks). Among 12 evaluable patients, four had rises in hemoglobin by 1-1.5 gm/dl (three) or decreased transfusion requirements (one). Two patients had increased platelet counts (54% and 73%), and two increased neutrophils (63% and 120%). Baseline TNFalpha levels, determined in all patients, did not correlate with responses. Among eight marrows available for sequential in vitro assays, four showed increases in CFU-GM of 1.5- to 5-fold at 8 weeks, whereas three showed 3- to 10-fold decrements relative to baseline. Thus, etanercept treatment resulted in moderate improvements of cytopenias in some patients, while cell counts declined in others. Additional trials are needed to evaluate its clinical efficacy in MDS.

    View details for Web of Science ID 000173710800003

    View details for PubMedID 11840280