Clinical Focus


  • Cancer > Hematology
  • Cancer > Lymphoma
  • Medical Oncology

Academic Appointments


Professional Education


  • Medical Education: Stanford University School of Medicine (2006) CA
  • Fellowship: Stanford University Hematology and Oncology Fellowship (2012) CA
  • Residency: Stanford University Internal Medicine Residency (2011) CA
  • Board Certification: American Board of Internal Medicine, Medical Oncology (2012)

Clinical Trials


  • (QuANTUM-R): An Open-label Study of Quizartinib Monotherapy vs. Salvage Chemotherapy in Acute Myeloid Leukemia (AML) Subjects Who Are FLT3-ITD Positive Not Recruiting

    The primary objective of the study is to determine whether quizartinib monotherapy prolongs overall survival (OS) compared to salvage chemotherapy in subjects with FMS-like tyrosine kinase 3 - Internal Tandem Duplication (FLT3-ITD) positive AML who are refractory to or have relapsed within 6 months, after first-line AML therapy.

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

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  • A Multi-Center Study of Ibrutinib in Combination With MEDI4736 in Subjects With Relapsed or Refractory Lymphomas Not Recruiting

    The purpose of this study is to evaluate the efficacy, safety and tolerability of the combination treatment of ibrutinib and MEDI4736 in subjects with relapsed or refractory lymphomas.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Phase 1 Study of Brentuximab Vedotin Given Sequentially and Combined With Multi-Agent Chemotherapy for CD30-Positive Mature T-Cell and NK-Cell Neoplasms Not Recruiting

    The purpose of this study is to assess the safety profile of brentuximab vedotin sequentially and in combination with multi-agent chemotherapy in front-line treatment for CD30-positive mature T-cell and NK-cell neoplasms, including systemic anaplastic large cell lymphoma. It is a phase 1, open-label, dose escalation study in three arms designed to define the MTD, PK, immunogenicity, and anti-tumor activity of brentuximab vedotin in sequence and in combination with multi-agent front-line chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, (650) 736 - 2563.

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  • A Study Being Conducted at Multiple Locations to Compare Safety and Efficacy of Three Different Regimens; (1) High-Dose Lenalidomide; (2) Lenalidomide + Azacitidine; or (3) Azacitidine in Subjects ≥ 65 Years With Newly-Diagnosed Acute Myeloid Leukemia Not Recruiting

    The study aim is to compare safety and efficacy of high-dose lenalidomide regimen, sequential azacitidine and lenalidomide and an azacitidine in persons ≥65 years with newly-diagnosed acute myeloid leukemia (AML).

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

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  • A Study of Atezolizumab (an Engineered Anti-Programmed Death-Ligand 1 [PDL1] Antibody) to Evaluate Safety, Tolerability and Pharmacokinetics in Participants With Locally Advanced or Metastatic Solid Tumors Not Recruiting

    This Phase I, multicenter, first-in-human, open-label, dose-escalation study will evaluate the safety, tolerability, and pharmacokinetics of atezolizumab (MPDL3280A) administered as single agent to participants with locally advanced or metastatic solid malignancies or hematologic malignancies. The study will be conducted in two cohorts: Dose-escalation cohort and Expansion cohort.

    Stanford is currently not accepting patients for this trial. For more information, please contact Maria Pitsiouni, 650-721-6977.

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  • A Study of Duvelisib in Combination With Rituximab or Obinutuzumab in Subjects With Previously Untreated CD20+ Follicular Lymphoma (CONTEMPO) Not Recruiting

    A Two-arm, Phase 1b/2 Study of duvelisib Administered in Combination with Rituximab or Obinutuzumab in Subjects with Previously Untreated CD20+ Follicular Lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • A Study of GDC-0853 in Patients With Resistant B-Cell Lymphoma or Chronic Lymphocytic Leukemia. Not Recruiting

    This open-label, Phase I study will evaluate the safety, tolerability, and pharmacokinetics of increasing doses of GDC-0853 in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma or chronic lymphocytic leukemia. In a dose-expansion part, GDC-0853 will be assessed in subsets of patients.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sabata Lund, 650-725-6432.

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  • A Study of JNJ-40346527 in Patients With Relapsed or Refractory Hodgkin Lymphoma Not Recruiting

    The purpose of this study is to determine the safety, pharmacokinetics, and preliminary efficacy information of JNJ-40346527 in patients with relapsed or refractory Hodgkin lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sarah Daadi, 650-725-6456 .

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  • A Study of PCI-32765 (Ibrutinib) in Patients With Refractory Follicular Lymphoma Not Recruiting

    The purpose of this study is to evaluate the efficacy and safety of PCI-32765 (ibrutinib) administered to patients with chemoimmunotherapy-resistant follicular lymphoma (FL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Lori Richards, 650-725-8589.

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  • A Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Given in Combination With Bendamustine and Rituximab in Patients With Newly Diagnosed Mantle Cell Lymphoma Not Recruiting

    The purpose of this study is to evaluate the efficacy and safety of ibrutinib given in combination with bendamustine and rituximab in patients 65 years of age or older with newly diagnosed mantle cell lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • A Study of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib), in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With Newly Diagnosed Non-Germinal Center B-Cell Subtype of Diffuse Large B-Cell Lymphoma Not Recruiting

    The purpose of this study is to evaluate if ibrutinib administered in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improves the clinical outcome in newly diagnosed patients with non-germinal center B-cell subtype (GCB) of diffuse large B-cell lymphoma (DLBCL) selected by immunohistochemistry (IHC) or newly diagnosed patients with activated B cell-like (ABC) subtype of DLBCL identified by gene expression profiling (GEP) or both populations.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • A Study of Vismodegib in Patients With Relapsed/Refractory Acute Myelogenous Leukemia and Relapsed Refractory High-Risk Myelodysplastic Syndrome Not Recruiting

    This study will assess the safety and efficacy of vismodegib in patients with relapsed/refractory acute myelogenous leukemia (AML) and relapsed/refractory high-risk myelodysplastic syndrome (MDS). Patients in Cohort 1 will receive single-agent vismodegib 150 mg orally daily. In Cohort 2, patients will receive vismodegib 150 mg orally daily in combination with cytarabine 20 mg subcutaneously for 10 days. Anticipated time on study treatment is until disease progression, intolerable toxicity, or patient withdrawal of consent.

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

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  • A Study to Evaluate Safety, Pharmacokinetics, and Clinical Activity of Combination of RO6870810 and Venetoclax, With or Without Rituximab, in Participants With Relapsed/Refractory DLBCL and/or High-Grade B-Cell Lymphoma and/or High Grade B-Cell Lymphoma With MYC and/or BCL2 and/or BCL6 Not Recruiting

    The purpose of this study is to evaluate the safety, tolerability and clinical activity of RO6870810 in combination with venetoclax and when co-administered with rituximab in participants with relapse/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and/or high-grade B-cell lymphoma with myelocytomatosis oncogene (MYC) and/or B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) gene rearrangements (HGBL-DH/TH).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Escalating Doses of AGS67E Given as Monotherapy in Subjects With Refractory or Relapsed Lymphoid Malignancies Not Recruiting

    The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of AGS67E both without and with myeloid growth factor (GF) in subjects with refractory or relapsed lymphoid malignancies. Immunogenicity and anticancer activity of AGS67E will also be assessed.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • A Treatment-Option Protocol to Provide Brentuximab Vedotin to Eligible Patients Completing Studies SGN35-005 or C25001 Not Recruiting

    The purpose of this study is to provide the option of brentuximab vedotin treatment to eligible patients in studies SGN35-005 and C25001

    Stanford is currently not accepting patients for this trial.

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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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  • An Open Label Treatment Use Protocol for Ibrutinib in Subjects With Relapsed or Refractory Mantle Cell Lymphoma Not Recruiting

    The purpose of this study is to provide patients who have relapsed or refractory Mantle Cell Lymphoma (MCL) with early access to an investigational medication called ibrutinib (PCI-32765) and to collect safety information about the drug.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • Brentuximab Vedotin and Combination Chemotherapy in Treating Older Patients With Previously Untreated Stage II-IV Hodgkin Lymphoma Not Recruiting

    This phase II trial studies how well giving brentuximab vedotin together with combination chemotherapy works in treating older patients with previously untreated stage II-IV Hodgkin lymphoma (HL). Monoclonal antibody-drug conjugates, such as brentuximab vedotin, can block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine, and dacarbazine (AVD), work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving brentuximab vedotin, doxorubicin hydrochloride, vinblastine, and dacarbazine together may kill more cancer cells.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hapanowicz, 650-721-0273.

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  • Brentuximab Vedotin Combined With AVD Chemotherapy in Patients With Newly Diagnosed Early Stage, Unfavorable Risk Hodgkin Lymphoma Not Recruiting

    The purpose of this study is to compare the outcomes across the 4 different treatment groups. The investigators hope that this treatment will improve the ability to cure more patients with HL and also limit the long-term side effects from the treatment. Although eliminating radiation in cohort 4 will eliminate the risk for long-term side effects from radiation, it is also possible that with BV+AVD chemotherapy alone there may be an increased risk of the Hodgkin lymphoma coming back after initial treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ranjana Advani, MD, 650-498-6000.

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  • Combination 5-azacitidine and Gemtuzumab Ozogamicin Therapy for Treatment of Relapsed Acute Myeloid Leukemia (AML) Not Recruiting

    This study will test an experimental combination of the drugs Mylotarg and 5-azacitidine in the hopes of finding a treatment that may be effective against Acute Myeloid Leukemia that has come back after treatment.

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

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  • Combination Chemotherapy & Lenalidomide in Newly Diagnosed Stage II-IV Peripheral T-cell Non-Hodgkin's Lymphoma Not Recruiting

    This phase I/II trial studies the side effects and best dose of lenalidomide when given together with combination chemotherapy and to see how well they work in treating patients with newly diagnosed stage II-IV peripheral T-cell non-Hodgkin's lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and etoposide, 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. Lenalidomide may stop the growth of peripheral T-cell non-Hodgkin's lymphoma by blocking the growth of new blood vessels necessary for cancer growth. Giving combination chemotherapy with lenalidomide may be a better treatment for peripheral T-cell non-Hodgkin's lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ranjana H. Advani, 650-725-6456.

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  • Combination Chemotherapy and Pralatrexate as First-Line Therapy in Treating Patients With Non-Hodgkin Lymphoma Not Recruiting

    This phase II trial studies how well combination chemotherapy and pralatrexate works in treating patients with non-Hodgkin lymphoma (NHL). 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

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, (650) 736 - 2563.

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  • Combination Chemotherapy With or Without Blinatumomab in Treating Patients With Newly Diagnosed BCR-ABL-Negative B Lineage Acute Lymphoblastic Leukemia Not Recruiting

    This randomized phase III trial studies combination chemotherapy with blinatumomab to see how well it works compared to induction chemotherapy alone in treating patients with newly diagnosed breakpoint cluster region (BCR)-c-abl oncogene 1, non-receptor tyrosine kinase (ABL)-negative B lineage acute lymphoblastic leukemia. Drugs used in chemotherapy 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. Immunotherapy with monoclonal antibodies, such as blinatumomab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether combination chemotherapy is more effective with or without blinatumomab in treating 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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  • Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia Not Recruiting

    This phase II trial is studying the side effects of giving combination chemotherapy together with or without donor stem cell transplant and to see how well it works in treating patients with acute lymphoblastic leukemia. 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. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect).

    Stanford is currently not accepting patients for this trial. For more information, please contact Vani Jain, (650) 725 - 5459.

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  • Donor Peripheral Stem Cell Transplant in Treating Patients With Hematolymphoid Malignancies Not Recruiting

    This phase 1 trial studies the side effects and the best dose of donor CD8+ memory T-cells in treating patients with hematolymphoid malignancies. Giving low dose of chemotherapy before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-cancer effects). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • ECHELON-2: A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell Lymphomas Not Recruiting

    This is a double-blind, randomized, multicenter, phase 3 clinical trial to compare the efficacy and safety of brentuximab vedotin in combination with CHP with the standard-of-care CHOP in patients with CD30-positive mature T-cell lymphomas.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • Efficacy and Safety of Idelalisib (GS-1101) in Combination With Bendamustine and Rituximab for Previously Treated Indolent Non-Hodgkin Lymphomas Not Recruiting

    The primary objective of this study is to evaluate the addition of idelalisib to bendamustine/rituximab on progression-free survival (PFS) in adults with previously treated indolent non-Hodgkin lymphoma (iNHL). An increased rate of deaths and serious adverse events (SAEs) among participants with front-line chronic lymphocytic leukemia (CLL) and early-line iNHL treated with idelalisib in combination with standard therapies was observed by the independent data monitoring committee (DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data and terminated this study in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA).

    Stanford is currently not accepting patients for this trial. For more information, please contact Lori Richards, 650-725-8589.

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  • Efficacy and Safety of Idelalisib (GS-1101) in Combination With Rituximab for Previously Treated Indolent Non-Hodgkin Lymphomas Not Recruiting

    The primary objective of this study is to evaluate the effect of the addition of idelalisib to rituximab on progression-free survival (PFS) in adults with previously treated indolent non-Hodgkin lymphoma (iNHL). An increased rate of deaths and serious adverse events (SAEs) among participants with front-line chronic lymphocytic leukemia (CLL) and early-line iNHL treated with idelalisib in combination with standard therapies was observed by the independent data monitoring committee (DMC) during regular review of 3 Gilead Phase 3 studies. Gilead reviewed the unblinded data and terminated this study in agreement with the DMC recommendation and in consultation with the US Food and Drug Administration (FDA).

    Stanford is currently not accepting patients for this trial. For more information, please contact Lori Richards, 650-725-8589.

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  • Efficacy and Safety Study of Idelalisib in Participants With Indolent B-Cell Non-Hodgkin Lymphomas Not Recruiting

    The primary objective will be to assess the overall response rate and to evaluate the efficacy and safety of idelalisib (IDELA; GS-1101) in participants with previously treated indolent Non-Hodgkin Lymphoma (iNHL) that is refractory both to rituximab and to alkylating-agent-containing chemotherapy. Eligible participants will initiate oral therapy with idelalisib at a starting dose of 150 mg taken twice per day. Treatment with idelalisib can continue in compliant participants as long as the study is still ongoing and the participants appear to be benefiting from treatment with acceptable safety.

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

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  • Efficacy of Oral Azacitidine Plus Best Supportive Care as Maintenance Therapy in Subjects With Acute Myeloid Leukemia (AML) in Complete Remission Not Recruiting

    This study enrolled 472 participants, aged 55 or older, with a diagnosis of de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or chronic myelomonocytic leukemia (CMML), and who have achieved first complete remission (CR)/ complete remission with incomplete blood count recovery (CRi) following induction with or without consolidation chemotherapy. The study is amended to include an extension phase (EP). The EP allows participants who are currently receiving oral azacitidine and who are demonstrating clinical benefit as assessed by the investigator, to continue receiving oral azacitidine after unblinding by sponsor until the participant meets the criteria for study discontinuation or until oral azacitidine becomes commercially available and reimbursed. In addition, all participants in the placebo arm and participants who had been discontinued from the treatment phase (irrespective of randomization arm) and continuing in the follow-up phase will be followed for survival in the EP.

    Stanford is currently not accepting patients for this trial. For more information, please contact Jack Taw, 650-723-1269.

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  • Ibrutinib With Rituximab in Adults With Waldenström's Macroglobulinemia Not Recruiting

    The purpose of this study is to evaluate the safety and efficacy of ibrutinib in combination with rituximab in participants with Waldenström's macroglobulinemia (WM).

    Stanford is currently not accepting patients for this trial. For more information, please contact Kelsey Walters, 650-725-6432.

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  • Immunostimulatory CpG SD-101 + RT in Recurrent/Progressive Lymphoma After Allogeneic Hematopoietic Cell Transplantation (HCT) Not Recruiting

    For patients with lymphoma that recurs after chemotherapy, bone marrow transplantation using cells from a healthy donor represents potentially curative treatment. In these individuals, cure is possible because transplantation of healthy donor immune cells can fight the lymphoma in the patient. The goal of this work is to test a strategy that activates the healthy donor immune cells so that they more effectively fight lymphoma and can result in an increased cure rate for these patients. Our group has previously studied CpG, an immune activating medication, in patients with lymphoma and demonstrated modest anti-tumor responses. We now have a more potent form of CpG which we intend to test to see if it will better activate the donor immune cells and result in shrinkage of tumor throughout the entire body, not just at the injected site.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Investigation of Tipifarnib in Treatment of Subjects With PTCL That Have Not Responded to Standard Therapy. Not Recruiting

    Phase II study designed to investigate antitumor activity in terms of objective response rate (ORR) of tipifarnib subjects with advanced Peripheral T-Cell Lymphoma (PTCL). Tipifarnib will be administered orally until disease progression.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • Ipilimumab and Local Radiation for Selected Solid Tumors Not Recruiting

    This pilot phase 1-2 trial studies the side effects and best of dose ipilimumab when given together with local radiation therapy and to see how well it works in treating patients with recurrent melanoma, non-Hodgkin lymphoma, colon, or rectal cancer. Monoclonal antibodies, such as ipilimumab, 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. Radiation therapy uses high energy x rays to kill cancer cells. Giving monoclonal antibody therapy together with radiation therapy may be an effective treatment for melanoma, non-Hodgkin lymphoma, colon, or rectal cancer. - The phase 1 component ("safety") of this study is ipilimumab 25 mg monotherapy. - The phase 2 component ("treatment-escalation") of this study is ipilimumab 25 mg plus radiation combination therapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Erin Waller, 650-725-0379.

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  • Nivolumab and Brentuximab Vedotin in Treating Older Patients With Untreated Hodgkin Lymphoma Not Recruiting

    This phase II trial studies how well nivolumab and brentuximab vedotin work in treating older patients with untreated Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Biological therapies, such as brentuximab vedotin, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Nivolumab and brentuximab vedotin may work better in treating older patients with untreated Hodgkin lymphoma.

    Stanford is currently not accepting patients for this trial.

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  • Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma Not Recruiting

    First study, at multiple clinical centers, exploring the effects of different combinations of compounds (CC-122, CC-223 ,CC-292 and rituximab) to treat Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hapanowicz, 650-721-4096.

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  • Phase 1-2 of a CpG-Activated Whole Cell Vaccine Followed by Autologous Immunotransplant for MCL Not Recruiting

    Mantle cell lymphoma (MCL) is a sub-type of non-Hodgkin's lymphoma (NHL) which is generally considered incurable with current therapy. Participants will receive an autologous vaccine against their individual lymphoma after undergoing stem cell transplantation. This vaccination may prolong the time which patients will stay in remission from their disease.

    Stanford is currently not accepting patients for this trial. For more information, please contact Ami Okada, (650) 725 - 4968.

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  • Phase 1/2 Dose Escalation Study in Patients With Relapsed or Refractory Waldenstrom's Macroglobulinemia Not Recruiting

    Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 90% of the patients with Waldenström's macroglobulinemia. MYD88 is a key linker protein in the signaling pathway of Toll Like Receptors (TLRs) 7, 8, and 9, and IMO-8400 is an oligonucleotide specifically designed to inhibit TLRs 7,8, and 9. The scientific hypothesis for use of IMO-8400 to treat patients with Waldenström's macroglobulinemia depends on the inhibition of mutant MYD88 signaling in the TLR pathway, thereby interrupting the proliferation of cell populations responsible for the propagation of the disease.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia Not Recruiting

    This randomized phase III trial studies rituximab with bendamustine hydrochloride or ibrutinib to see how well they work compared to ibrutinib alone in treating older patients with previously untreated chronic lymphocytic leukemia. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as bendamustine hydrochloride, 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. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether rituximab with bendamustine hydrochloride may work better than rituximab and ibrutinib or ibrutinib alone in treating chronic lymphocytic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kevin Morrison, 650-725-5459.

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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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  • S0919 Idarubicin, Cytarabine, and Pravastatin in Treating Patients With Relapsed Acute Myeloid Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Pravastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Pravastatin may also help idarubicin and cytarabine work better by making cancer cells more sensitive to the drugs. Giving idarubicin and cytarabine together with pravastatin may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving idarubicin and cytarabine together with pravastatin works in treating patients with relapsed acute myeloid leukemia (AML). ADDITIONAL BACKGROUND: S0919 was initially designed for patients with relapsed acute myeloid leukemia (AML), where the patient's preceding remission had lasted ≥ 3 months. The null response rate was 30%. The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study; and the results are being submitted to the American Society of Clinical Oncology meeting. Based on the promising results from this trial, the trial has now been amended to evaluate this therapeutic regimen in poor-risk patients (patients with newly diagnosed acute myeloid leukemia (AML) arising out of myelodysplastic syndrome (MDS), primary refractory acute myeloid leukemia (AML), and relapsed acute myeloid leukemia (AML) with the patient's preceding remission lasting < 6 months).

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

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  • S1312, Inotuzumab Ozogamicin and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Acute Leukemia Not Recruiting

    This phase I trial studies the side effects and best dose of inotuzumab ozogamicin when given together with combination chemotherapy in treating patients with relapsed or refractory acute leukemia. Immunotoxins, such as inotuzumab ozogamicin, can find cancer cells that express cluster of differentiation (CD)22 and kill them without harming normal cells. Drugs used in chemotherapy, such as cyclophosphamide, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving inotuzumab ozogamicin together with combination chemotherapy may kill more cancer cells.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kevin Morrison, 650-725-5450.

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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 Pracinostat With Azacitadine in Elderly Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) Not Recruiting

    The purpose of this study is to determine the safety and effectiveness of pracinostat when combined with azacitadine for patients who are 65 years of age or older and have Acute Myelogenous Leukemia (AML)

    Stanford is currently not accepting patients for this trial. For more information, please contact Leilani Hong Lien, 650-725-0437.

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  • Study of Effectiveness of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Patients With Relapsed/Refractory Diffuse Large B Cell Lymphoma Not Recruiting

    The goal of this clinical study is to assess whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Study of Ibrutinib in Combination With Rituximab in Previously Untreated Subjects With Follicular Lymphoma Not Recruiting

    This is an open-label, Phase 2 study designed to assess the efficacy and safety of ibrutinib combined with rituximab in previously untreated subjects with Follicular Lymphoma (FL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Sabata Lund, 650-725-6432.

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  • Study of Pembrolizumab (MK-3475) in Participants With Relapsed or Refractory Classical Hodgkin Lymphoma (MK-3475-087/KEYNOTE-087) Not Recruiting

    This is a study of pembrolizumab (MK-3475) for participants with relapsed/refractory classical Hodgkin Lymphoma (RRcHL) who: 1) have failed to achieve a response or progressed after autologous stem cell transplant (auto-SCT) and have relapsed after treatment with or failed to respond to brentuximab vedotin (BV) post auto-SCT or 2) were unable to achieve a Complete Response (CR) or Partial Response (PR) to salvage chemotherapy and did not receive auto-SCT, but have relapsed after treatment with or failed to respond to BV or 3) have failed to achieve a response to or progressed after auto-SCT and have not received BV post auto-SCT. The primary study hypothesis is that treatment with single agent pembrolizumab will result in a clinically meaningful overall response rate.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hapanowicz, 650-721-4096.

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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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  • Study to Investigate the Safety and Tolerability of Odronextamab in Patients With CD20+ B-Cell Malignancies Not Recruiting

    This study has two parts with distinct study objectives and study design. In part A, odronextamab is studied as an intravenous (IV) administration with a dose escalation and a dose expansion phase for B-NHL and CLL. The dose escalation phase for B-NHL and the CLL study are closed at the time of protocol amendment 17. In part B, odronextamab is studied as a subcutaneous (SC) administration with a dose finding and a dose expansion phase for B-NHL.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sipra Choudhury, 650-736-2563.

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  • Trial of Magrolimab (Hu5F9-G4) in Combination With Rituximab or Rituximab + Chemotherapy in Participants With Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma Not Recruiting

    The primary objectives of this study are: - To investigate the safety and tolerability, and to define the recommended Phase 2 dose and schedule (RP2DS) for magrolimab in combination with rituximab and for magrolimab in combination with rituximab, gemcitabine, and oxaliplatin (R-GemOx). - To evaluate the efficacy of magrolimab in combination with rituximab in participants with indolent lymphoma and diffuse large B-cell lymphoma (DLBCL) and to evaluate the efficacy of magrolimab in combination with R-GemOx in autologous stem cell transplant (ASCT) ineligible DLBCL participants.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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All Publications


  • A clinical trial of therapeutic vaccination in lymphoma with serial tumor sampling and single cell analysis. Blood advances Shree, T., Haebe, S. E., Czerwinski, D. K., Eckhert, E., Day, G., Sathe, A., Grimes, S. M., Frank, M. J., Maeda, L., Alizadeh, A. A., Advani, R. H., Hoppe, R. T., Long, S. R., Martin, B. A., Ozawa, M. G., Khodadoust, M. S., Ji, H. P., Levy, R. 2023

    Abstract

    In situ vaccination (ISV) triggers an immune response to tumor-associated antigens at one tumor site that can then tackle disease throughout the body. Here we report clinical and biological results of a phase I/II ISV trial in patients with low-grade lymphoma (NCT02927964) combining an intratumoral TLR9 agonist with local low-dose radiation, and ibrutinib (an inhibitor of B and T cell kinases). Adverse events were predominately low grade. The overall response rate was 50%, including one complete response. All patients experienced tumor reduction at distant sites. Single cell analyses of serial fine needle aspirates from injected and uninjected tumors revealed correlates of clinical response, such as lower CD47 and higher MHCII expression on tumor cells, enhanced T and NK cell effector function, and reduced immune suppression from TGFß and inhibitory T regulatory 1 cells. While changes at the local injected site were more pronounced, changes at distant uninjected sites more often associated with clinical responses. Functional immune response assays and tracking of T cell receptor sequences provided evidence of treatment-induced tumor-specific T cell responses. Induction of immune effectors and reversal of negative regulators were both important in producing clinically meaningful tumor responses. NCT02927964.

    View details for DOI 10.1182/bloodadvances.2023011589

    View details for PubMedID 37939259

  • Activating Immune Effectors and Dampening Immune Suppressors Generates Successful Therapeutic Cancer Vaccination in Patients with Lymphoma Shree, T., Haebe, S., Czerwinski, D. K., Eckhert, E., Day, G., Sathe, A., Grimes, S. M., Frank, M. J., Maeda, L. S., Alizadeh, A. A., Advani, R. H., Hoppe, R., Long, S. R., Martin, B., Ozawa, M. G., Khodadoust, M. S., Ji, H. P., Levy, R. AMER SOC HEMATOLOGY. 2022: 6450-6451
  • CD20-Targeted Therapy Ablates De Novo Antibody Response to Vaccination but Spares Pre-Established Immunity. Blood cancer discovery Shree, T., Shankar, V., Lohmeyer, J. J., Czerwinski, D. K., Schroers-Martin, J. G., Rodriguez, G. M., Beygi, S., Kanegai, A. M., Corbelli, K. S., Gabriel, E., Kurtz, D. M., Khodadoust, M. S., Gupta, N. K., Maeda, L. S., Advani, R. H., Alizadeh, A. A., Levy, R. 2022

    Abstract

    To obtain a deeper understanding of poor responses to COVID-19 vaccination in lymphoma patients, we assessed blocking antibodies, total anti-spike IgG, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months after COVID-19 vaccination. Fifty-five percent of patients developed blocking antibodies post-vaccination, compared to 100% of controls. Evaluating patients last treated from days to nearly 18 years prior to vaccination, time since last anti-CD20 was a significant independent predictor of vaccine response. None of 31 patients who had received anti-CD20 treatment within 6 months prior to vaccination developed blocking antibodies. In contrast, patients who initiated anti-CD20 treatment shortly after achieving a vaccine-induced antibody response tended to retain that response during treatment, suggesting a policy of immunizing prior to treatment whenever possible.

    View details for DOI 10.1158/2643-3230.BCD-21-0222

    View details for PubMedID 35015688

  • Time Since Last Anti-CD20 Treatment Is a Major Determinant of Sars-Cov-2 Vaccine Response in a Large Cohort of Patients with B-Cell Lymphoma Shree, T., Shankar, V., Czerwinski, D. K., Rodriguez, G., Beygi, S., Schroers-Martin, J. G., Advani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Kurtz, D. M., Corbelli, K. S., Gabriel, E., Kanegai, A. M., Alizadeh, A. A., Levy, R. AMER SOC HEMATOLOGY. 2021
  • Characteristics and Outcome of Extranodal NK/T-cell Lymphoma in North America: A Retrospective Multi-Institutional Experience. Clinical lymphoma, myeloma & leukemia Bennani, N. N., Tun, A. M., Carson, K. R., Geiger, J. L., Maeda, L. S., Savage, K. J., Rose, J., Pinter-Brown, L., Lunning, M. A., Abramson, J. S., Bartlett, N. L., Vose, J. M., Evens, A. M., Smith, S. M., Horwitz, S. M., Ansell, S. M., Advani, R. H. 2021

    Abstract

    BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinical data from non-Asian countries are lacking. It is unclear whether outcomes and disease natural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers.PATIENTS AND METHODS: We retrospectively identified patients with newly-diagnosed CD56+ENKTL and studied disease characteristics and clinical outcomes.RESULTS: One hundred and twenty-one patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treated with combined modality therapy (CMT) (n=53), chemotherapy alone (CT) (n=14) or radiotherapy alone (RT) (n=16). Thirty-eight patients (31%) had stage III/IV disease and were treated with CMT (n=12), CT (n=23), or RT (n=3). The median follow-up for the entire cohort was 51 months. Patients with stage I/II disease, compared to those with stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs 19% (P=.03) and overall survival (OS) 59% vs. 29% (P= .004). Outcomes were similar for stage I/II patients who received CMT vs. RT alone with 2-year PFS (53% vs. 47%; P= .91) and OS (67% vs. 67%; P= .58). No significant differences in outcomes were noted based on race/ethnicity.CONCLUSIONS: This series represents a large experience of ENKTL treated at several major North American academic centers. Our data are consistent with Asian studies: (1) majority of patients present with early-stage disease; (2) overall poor outcome regardless of race/ethnicity; (3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease.

    View details for DOI 10.1016/j.clml.2021.10.018

    View details for PubMedID 34848181

  • Characteristics and Outcome of Extranodal NK/T-Cell Lymphoma in North America: A Retrospective Multi-Institutional Experience. Clinical lymphoma, myeloma & leukemia Bennani, N. N., Tun, A. M., Carson, K. R., Geiger, J. L., Maeda, L. S., Savage, K. J., Rose, J., Pinter-Brown, L., Lunning, M. A., Abramson, J. S., Bartlett, N. L., Vose, J. M., Evens, A. M., Smith, S. M., Horwitz, S. M., Ansell, S. M., Advani, R. H. 2021

    Abstract

    BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) is rare and clinicaldata from non-Asian countries are lacking. It is unclear whether outcomes and diseasenatural history is similar to reported Asian series. We assessed characteristics and outcomes of patients with ENKTL from major North American centers.PATIENTS AND METHODS: We retrospectively identified patients with newly-diagnosedCD56 + ENKTL and studied disease characteristics and clinical outcomes.RESULTS: 121 patients with ENKTL diagnosed between June 1990 and November 2012 were identified. Eighty-three patients (69%) had stage I/II disease and were treatedwith combined modality therapy (CMT) (n=53), chemotherapy alone (CT) (n=14) orradiotherapy alone (RT) (n=16). Thirty-eight patients (31%) had stage III/IV diseaseand were treated with CMT (n=12), CT (n=23), or RT (n=3). The median follow-up forthe entire cohort was 51 months. Patients with stage I/II disease, compared to thosewith stage III/IV disease, had superior 2-year progression free survival (PFS) 43% vs19% (p=0.03) and overall survival (OS) 59% vs 29% (p=0.004). Outcomes were similarfor stage I/II patients who received CMT vs RT alone with 2-year PFS (53% vs 47%;p=0.91) and OS (67% vs 67%; p=0.58). No significant differences in outcomes werenoted based on race/ethnicity.CONCLUSIONS: This series represents a large experience of ENKTL treated at several major North American academic centers.OUR DATA ARE CONSISTENT WITH ASIAN STUDIES: 1) majority of patients present with early-stage disease; 2) overall poor outcome regardless of race/ethnicity; 3) CMT likely yields favorable outcomes for suitable candidates with early-stage disease.

    View details for DOI 10.1016/j.clml.2021.10.004

    View details for PubMedID 34794912

  • Stereotactic Radiotherapy for Recurrent Post- Transplant Primary Central Nervous System Lymphoma CUREUS Benitez, C. M., Rahimy, E., Panjwani, N., Maeda, L. S., Soltys, S. G. 2021; 13 (7)
  • Stereotactic Radiotherapy for Recurrent Post-Transplant Primary Central Nervous System Lymphoma. Cureus Benitez, C. M., Rahimy, E., Panjwani, N., Maeda, L. S., Soltys, S. G. 2021; 13 (7): e16537

    Abstract

    Post-transplant primary central nervous system lymphoma (PCNSL) is a rare complication of solid organ transplantation. The optimal therapy for post-transplant PCNSL is not well established and generally includes reduction of immunosuppression and chemotherapy. Progression after front-line chemotherapy is common, and whole-brain radiotherapy (WBRT) is a standard salvage treatment as there is a concern that localized treatment fields would not prevent out-of-field recurrences. However, WBRT is associated with neurotoxicity and morbidity in these patients with inherently poor prognoses. Here, we report a patient with local recurrence of post-transplant PCNSL who was treated with fractionated stereotactic radiotherapy (SRT). He had no clinical toxicity from treatment and maintained pre-treatment neurocognition and performance status. Local control was achieved for 20 months following SRT, at which point he developed an in-field recurrence. He restarted lymphoma therapy but died one month later from fungal pneumonia. For central nervous system (CNS) lymphoma, further data are needed to optimize tumor control and toxicity outcomes and identify patients in whom localized radiotherapy fields may be beneficial, avoiding the potential toxicity of WBRT.

    View details for DOI 10.7759/cureus.16537

    View details for PubMedID 34430145

    View details for PubMedCentralID PMC8378593

  • Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial. The Journal of experimental medicine Frank, M. J., Khodadoust, M. S., Czerwinski, D. K., Haabeth, O. A., Chu, M. P., Miklos, D. B., Advani, R. H., Alizadeh, A. A., Gupta, N. K., Maeda, L. S., Reddy, S. A., Laport, G. G., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Weng, W. K., Sheehan, K. n., Faham, M. n., Okada, A. n., Moore, A. H., Phillips, D. L., Wapnir, I. L., Brody, J. D., Levy, R. n. 2020; 217 (9)

    Abstract

    Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

    View details for DOI 10.1084/jem.20191712

    View details for PubMedID 32558897

  • Prognostic Value of Circulating Tumor DNA in Diffuse Large B-Cell Lymphoma Reply JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019; 37 (9): 755-+
  • Reply to J. Wang et al. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, O., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2019: JCO1801907

    View details for PubMedID 30753108

  • Central Nervous System Lymphoma in a Patient with Chronic Lymphocytic Leukemia: A Case Report and Literature Review. Cureus Albakr, A., Alhothali, W., Samghabadi, P., Maeda, L., Nagpal, S., Ajlan, A. 2018; 10 (11): e3660

    Abstract

    Chronic lymphocytic leukemia (CLL) is the most common type of leukemia that affects older adults in the Western world. Symptomatic nervous system invasion in undiagnosed CLL is rare, poorly understood, challenging to treat, and associated with decreased survival. The average survival of CLL patients with central nervous system (CNS) involvement is 3.79 years as compared to six years in CLL patients without CNS involvement. Autopsy studies demonstrated ahigh incidence of undiagnosed CLL with CNS involvement, suggesting that CNS involvement is either underdiagnosed or subclinical. Although the most common site of CNS involvement is the leptomeninges, our case demonstrates an extremely rare form of CNS diffuse large B-cell parenchymal involvement in a patient with a concurrent diagnosis of systemic CLL.

    View details for PubMedID 30755837

  • Noninvasive Genotyping and Monitoring of Classical Hodgkin Lymphoma Jin, M. C., Schroers-Martin, J. G., Kurtz, D. M., Buedts, L., Esfahani, M. S., Macaulay, C., Sworder, B., Soo, J., Glover, C., Roschewski, M., Wilson, W. H., Duhrsen, U., Huettmann, A., Rossi, D., Gaidano, G., Westin, J. R., Maeda, L. S., Advani, R. H., Vandenberghe, P., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2018
  • Central Nervous System Lymphoma in a Patient with Chronic Lymphocytic Leukemia: A Case Report and Literature Review CUREUS Albakr, A., Alhothali, W., Samghabadi, P., Maeda, L., Nagpal, S., Ajlan, A. 2018; 10 (11)
  • Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma JOURNAL OF CLINICAL ONCOLOGY Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. M., Esfahani, M., Chabon, J. J., Stehr, H., Liu, C., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duehrsen, U., Huettmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018; 36 (28): 2845-+
  • Circulating tumor DNA (ctDNA) in B-cell lymphoma Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. M., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Green, M. R., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Davis, R., Levy, R., Ohgami, R. S., Kunder, C. A., Rossi, D., Westin, J., Diehn, M., Alizadeh, A. A. WILEY. 2018: 16–17
  • Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Kurtz, D. M., Scherer, F., Jin, M. C., Soo, J., Craig, A. F., Esfahani, M. S., Chabon, J. J., Stehr, H., Liu, C. L., Tibshirani, R., Maeda, L. S., Gupta, N. K., Khodadoust, M. S., Advani, R. H., Levy, R., Newman, A. M., Duhrsen, U., Huttmann, A., Meignan, M., Casasnovas, R., Westin, J. R., Roschewski, M., Wilson, W. H., Gaidano, G., Rossi, D., Diehn, M., Alizadeh, A. A. 2018: JCO2018785246

    Abstract

    Purpose Outcomes for patients with diffuse large B-cell lymphoma remain heterogeneous, with existing methods failing to consistently predict treatment failure. We examined the additional prognostic value of circulating tumor DNA (ctDNA) before and during therapy for predicting patient outcomes. Patients and Methods We studied the dynamics of ctDNA from 217 patients treated at six centers, using a training and validation framework. We densely characterized early ctDNA dynamics during therapy using cancer personalized profiling by deep sequencing to define response-associated thresholds within a discovery set. These thresholds were assessed in two independent validation sets. Finally, we assessed the prognostic value of ctDNA in the context of established risk factors, including the International Prognostic Index and interim positron emission tomography/computed tomography scans. Results Before therapy, ctDNA was detectable in 98% of patients; pretreatment levels were prognostic in both front-line and salvage settings. In the discovery set, ctDNA levels changed rapidly, with a 2-log decrease after one cycle (early molecular response [EMR]) and a 2.5-log decrease after two cycles (major molecular response [MMR]) stratifying outcomes. In the first validation set, patients receiving front-line therapy achieving EMR or MMR had superior outcomes at 24 months (EMR: EFS, 83% v 50%; P = .0015; MMR: EFS, 82% v 46%; P < .001). EMR also predicted superior 24-month outcomes in patients receiving salvage therapy in the first validation set (EFS, 100% v 13%; P = .011). The prognostic value of EMR and MMR was further confirmed in the second validation set. In multivariable analyses including International Prognostic Index and interim positron emission tomography/computed tomography scans across both cohorts, molecular response was independently prognostic of outcomes, including event-free and overall survival. Conclusion Pretreatment ctDNA levels and molecular responses are independently prognostic of outcomes in aggressive lymphomas. These risk factors could potentially guide future personalized risk-directed approaches.

    View details for PubMedID 30125215

  • Development and Validation of Biopsy-Free Genotyping for Molecular Subtyping of Diffuse Large B-Cell Lymphoma 58th Annual Meeting and Exposition of the American-Society-of-Hematology Scherer, F., Kurtz, D. M., Newman, A. M., Esfahani, M. S., Craig, A., Stehr, H., Lovejoy, A. F., Chabon, J. J., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Davis, E. R., Gaidano, G., Kunder, C. A., Rossi, D., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016
  • Noninvasive Detection of BCL2, BCL6, and MYC Translocations in Diffuse Large B-Cell Lymphoma Kurtz, D. M., Scherer, F., Newman, A. M., Craig, A., Jin, M., Stehr, H., Chabon, J. J., Esfahani, M., Liu, C., Zhou, L., Glover, C., Visser, B. C., Poultsides, G., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Davis, R., Kunder, C. A., Westin, J. R., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016
  • Absence of Evidence Implicating Hematopoietic Stem Cells As Common Progenitors for DLBCL Mutations Jan, M., Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Liu, C., Zhou, L., Glover, C., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Kunder, C. A., Sanchez-Garcia, I., Diehn, M., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2016
  • Distinct biological subtypes and patterns of genome evolution in lymphoma revealed by circulating tumor DNA SCIENCE TRANSLATIONAL MEDICINE Scherer, F., Kurtz, D. M., Newman, A. M., Stehr, H., Craig, A. F., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C. L., Zhou, L., Glover, C., Visser, B. C., Poultsides, G. A., Advani, R. H., Maeda, L. S., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C. A., Diehn, M., Alizadeh, A. A. 2016; 8 (364)

    Abstract

    Patients with diffuse large B cell lymphoma (DLBCL) exhibit marked diversity in tumor behavior and outcomes, yet the identification of poor-risk groups remains challenging. In addition, the biology underlying these differences is incompletely understood. We hypothesized that characterization of mutational heterogeneity and genomic evolution using circulating tumor DNA (ctDNA) profiling could reveal molecular determinants of adverse outcomes. To address this hypothesis, we applied cancer personalized profiling by deep sequencing (CAPP-Seq) analysis to tumor biopsies and cell-free DNA samples from 92 lymphoma patients and 24 healthy subjects. At diagnosis, the amount of ctDNA was found to strongly correlate with clinical indices and was independently predictive of patient outcomes. We demonstrate that ctDNA genotyping can classify transcriptionally defined tumor subtypes, including DLBCL cell of origin, directly from plasma. By simultaneously tracking multiple somatic mutations in ctDNA, our approach outperformed immunoglobulin sequencing and radiographic imaging for the detection of minimal residual disease and facilitated noninvasive identification of emergent resistance mutations to targeted therapies. In addition, we identified distinct patterns of clonal evolution distinguishing indolent follicular lymphomas from those that transformed into DLBCL, allowing for potential noninvasive prediction of histological transformation. Collectively, our results demonstrate that ctDNA analysis reveals biological factors that underlie lymphoma clinical outcomes and could facilitate individualized therapy.

    View details for DOI 10.1126/scitranslmed.aai8545

    View details for PubMedID 27831904

  • Noninvasive molecular subtyping and risk stratification of DLBCL. Scherer, F., Kurtz, D., Newman, A. M., Stehr, H., Craig, A. M., Esfahani, M. S., Lovejoy, A. F., Chabon, J. J., Klass, D. M., Liu, C., Zhou, L., Glover, C., Advani, R. H., Maeda, L., Gupta, N. K., Levy, R., Ohgami, R. S., Kunder, C., Diehn, M., Alizadeh, A. A. AMER SOC CLINICAL ONCOLOGY. 2016
  • Phase I/II Clinical Trial of CpG-Activated Whole Cell Vaccine in Mantle Cell Lymphoma (MCL): Results in Safety and Efficacy from Planned Interim Analysis Chu, M. P., Brody, J., Kohrt, H. E., Frank, M. J., Khodadoust, M., Reddy, S., Advani, R. H., Gupta, N. K., Laport, G., Maeda, L. S., Meyer, E., Miklos, D. B., Negrin, R., Rezvani, A. R., Weng, W., Sheehan, K., Faham, M., Czerwinski, D. K., Okada, A., Levy, R. AMER SOC HEMATOLOGY. 2015
  • Dose-Adjusted EPOCH-Rituximab Therapy in Primary Mediastinal B-Cell Lymphoma NEW ENGLAND JOURNAL OF MEDICINE Dunleavy, K., Pittaluga, S., Maeda, L. S., Advani, R., Chen, C. C., Hessler, J., Steinberg, S. M., Grant, C., Wright, G., Varma, G., Staudt, L. M., Jaffe, E. S., Wilson, W. H. 2013; 368 (15): 1408-1416

    Abstract

    Primary mediastinal B-cell lymphoma is a distinct subtype of diffuse large-B-cell lymphoma that is closely related to nodular sclerosing Hodgkin's lymphoma. Patients are usually young and present with large mediastinal masses. There is no standard treatment, but the inadequacy of immunochemotherapy alone has resulted in routine consolidation with mediastinal radiotherapy, which has potentially serious late effects. We aimed to develop a strategy that improves the rate of cure and obviates the need for radiotherapy.We conducted a single-group, phase 2, prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) and filgrastim without radiotherapy in 51 patients with untreated primary mediastinal B-cell lymphoma. We used results from a retrospective study of DA-EPOCH-R from another center to independently verify the outcomes.The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.Therapy with DA-EPOCH-R obviated the need for radiotherapy in patients with primary mediastinal B-cell lymphoma. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00001337.).

    View details for DOI 10.1056/NEJMoa1214561

    View details for Web of Science ID 000317333600008

    View details for PubMedID 23574119

  • A retrospective study evaluating the efficacy and safety of bendamustine in the treatment of mantle cell lymphoma LEUKEMIA & LYMPHOMA Warsch, S., Hosein, P. J., Maeda, L. S., Alizadeh, A. A., Lossos, I. S. 2012; 53 (7): 1299-1305

    Abstract

    Bendamustine is approved in the United States for relapsed indolent lymphoma. However, it has not been widely studied in mantle cell lymphoma (MCL). We retrospectively reviewed the records of all patients with MCL who were treated with bendamustine at three centers. The primary endpoint was overall response rate (ORR). Thirty patients with MCL received bendamustine, 25 for relapsed disease. After a median follow-up of 12 months, there were 15 complete responses (CRs) with an ORR of 83% (95% confidence interval [CI] 70-97%). Factors significantly associated with longer survival were achieving a CR and classical (versus blastic) variant of MCL. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in 23%, 3% and 20%, respectively. There was one case of progressive multifocal leukoencephalopathy 10 months after therapy completion. Bendamustine in combination with rituximab demonstrated a high response rate in this study of patients with predominantly relapsed MCL.

    View details for DOI 10.3109/10428194.2011.649476

    View details for Web of Science ID 000305480100011

    View details for PubMedID 22185662

  • Clinical Outcome Prediction by MicroRNAs in Human Cancer: A Systematic Review JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Nair, V. S., Maeda, L. S., Ioannidis, J. P. 2012; 104 (7): 528-540

    Abstract

    MicroRNA (miR) expression may have prognostic value for many types of cancers. However, the miR literature comprises many small studies. We systematically reviewed and synthesized the evidence.Using MEDLINE (last update December 2010), we identified English language studies that examined associations between miRs and cancer prognosis using tumor specimens for more than 10 patients during classifier development. We included studies that assessed a major clinical outcome (nodal disease, disease progression, response to therapy, metastasis, recurrence, or overall survival) in an agnostic fashion using either polymerase chain reaction or hybridized oligonucleotide microarrays.Forty-six articles presenting results on 43 studies pertaining to 20 different types of malignancy were eligible for inclusion in this review. The median study size was 65 patients (interquartile range [IQR] = 34-129), the median number of miRs assayed was 328 (IQR = 250-470), and overall survival or recurrence were the most commonly measured outcomes (30 and 19 studies, respectively). External validation was performed in 21 studies, 20 of which reported at least one nominally statistically significant result for a miR classifier. The median hazard ratio for poor outcome in externally validated studies was 2.52 (IQR = 2.26-5.40). For all classifier miRs in studies that evaluated overall survival across diverse malignancies, the miRs most frequently associated with poor outcome after accounting for differences in miR assessment due to platform type were let-7 (decreased expression in patients with cancer) and miR 21 (increased expression).MiR classifiers show promising prognostic associations with major cancer outcomes and specific miRs are consistently identified across diverse studies and platforms. These types of classifiers require careful external validation in large groups of cancer patients that have adequate protection from bias. -

    View details for DOI 10.1093/jnci/djs027

    View details for PubMedID 22395642

  • STAGE I-IIIA NON-BULKY HODGKIN'S LYMPHOMA. IS FURTHER DISTINCTION BASED ON PROGNOSTIC FACTORS USEFUL? THE STANFORD EXPERIENCE INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Advani, R. H., Hoppe, R. T., Maeda, L. S., Baer, D. M., Mason, J., Rosenberg, S. A., Horning, S. J. 2011; 81 (5): 1374-1379

    Abstract

    In the United States, early-stage Hodgkin's lymphoma (HL) is defined as asymptomatic stage I/II non-bulky disease. European groups stratify patients to more intense treatment by considering additional unfavorable factors, such as age, number of nodal sites, sedimentation rate, extranodal disease, and elements of the international prognostic score for advanced HL. We sought to determine the prognostic significance of these factors in patients with early-stage disease treated at Stanford University Medical Center.This study was a retrospective analysis of 101 patients treated with abbreviated Stanford V chemotherapy (8 weeks) and 30-Gy (n=84 patients) or 20-Gy (n=17 patients) radiotherapy to involved sites. Outcomes were assessed after applying European risk factors.At a median follow-up of 8.5 years, freedom from progression (FFP) and overall survival (OS) rates were 94% and 97%, respectively. From 33% to 60% of our patients were unfavorable per European criteria (i.e., German Hodgkin Study Group [GHSG], n=55%; European Organization for Research and Treatment of Cancer, n=33%; and Groupe d'Etudes des Lymphomes de l'Adulte, n=61%). Differences in FFP rates between favorable and unfavorable patients were significant only for GHSG criteria (p=0.02) with there were no differences in OS rates for any criteria. Five of 6 patients who relapsed were successfully salvaged.The majority of our patients deemed unfavorable had an excellent outcome despite undergoing a significantly abbreviated regimen. Application of factors used by the GHSG defined a less favorable subset for FFP but with no impact on OS. As therapy for early-stage disease moves to further reductions in therapy, these factors take on added importance in the interpretation of current trial results and design of future studies.

    View details for DOI 10.1016/j.ijrobp.2010.07.041

    View details for PubMedID 20934280

  • Current concepts and controversies in the management of early stage Hodgkin lymphoma LEUKEMIA & LYMPHOMA Maeda, L. S., Lee, M., Advani, R. H. 2011; 52 (6): 962-971

    Abstract

    Over the past three decades, due to the recognition of late effects related to high-dose extended field radiotherapy and heavy alkylator chemotherapy, combined modality therapy with abbreviated chemotherapy and limited field radiotherapy has emerged as the standard of care for early stage Hodgkin lymphoma, with cure rates in excess of 80%. Currently, however, controversy remains over identifying the most appropriate criteria to risk-stratify patients with early stage disease, so that those with a favorable prognosis receive limited treatment without compromising cure rates and those with unfavorable risk receive more intensified therapy. The optimal risk stratification system remains unclear, with variable definitions of favorable and unfavorable disease used by research groups in North America and Europe. Thus, comparison of clinical trial results has been challenging, and additional controversies persist regarding optimal chemotherapy regimens, duration of therapy, and the role of radiotherapy. Investigations are ongoing to assess the potential of functional imaging and biomarkers as tools for risk stratification. The collective goal is to further refine current stratification strategies to allow for an individualized, risk-adapted treatment approach that minimizes long-term late effects without compromising high cure rates.

    View details for DOI 10.3109/10428194.2011.557455

    View details for PubMedID 21463118

  • The emerging role for rituximab in the treatment of nodular lymphocyte predominant Hodgkin lymphoma CURRENT OPINION IN ONCOLOGY Maeda, L. S., Advani, R. H. 2009; 21 (5): 397-400

    Abstract

    Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subset of Hodgkin lymphoma that is distinct from classical Hodgkin lymphoma (cHL). The unique malignant 'popcorn' cells express the B-cell antigen CD20 and lack expression of the cHL markers CD15 and CD30. Traditionally, NLPHL has been included with cHL in clinical trials with excellent prognosis reported in several series. The reliable expression of CD20 has led to the evaluation of the chimeric monoclonal anti-CD20 antibody rituximab in several recent trials.Three series have reported the efficacy of 4 weekly doses of rituximab in all stages of NLPHL, both in the treatment-naive and relapsed settings. Emerging data also suggest that longer courses of antibody therapy may improve the duration of response.Rituximab appears to offer a nonchemotherapy-based effective treatment option, which is well tolerated. Ongoing studies are required to further define the optimal patient population who may benefit from rituximab and evaluate its role in maintenance as well as in combination with radiotherapy and chemotherapy.

    View details for DOI 10.1097/CCO.0b013e32832f3ca3

    View details for PubMedID 19606035

  • Impact of positive positron emission tomography on prediction of freedom from progression after Stanford V chemotherapy in Hodgkin's disease 9th International Conference on Malignant Lymphoma Advani, R., Maeda, L., Lavori, P., Quon, A., Hoppe, R., Breslin, S., Rosenberg, S. A., Horning, S. J. AMER SOC CLINICAL ONCOLOGY. 2007: 3902–7

    Abstract

    To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.

    View details for DOI 10.1200/JCO.2007.11.9867

    View details for PubMedID 17664458

  • Transcription arrest at an abasic site in the transcribed strand of template DNA CHEMICAL RESEARCH IN TOXICOLOGY Tornaletti, S., Maeda, L. S., Hanawalt, P. C. 2006; 19 (9): 1215-1220

    Abstract

    A dedicated excision repair pathway, termed transcription-coupled repair (TCR), targets the removal of DNA lesions from transcribed strands of expressed genes. Transcription arrest at the site of the lesion has been proposed as the first step for initiation of TCR. In support of this model, a strong correlation between arrest of transcription by a lesion in vitro and TCR of that lesion in vivo has been found in most cases analyzed. TCR has been reported for oxidative DNA damage; however, very little is known about how frequently occurring and spontaneous DNA damage, such as depurination and base deamination, affects progression of the transcription complex. We have previously determined that the oxidative lesion, thymine glycol, is a significant block to transcription by T7 RNA polymerase (T7 RNAP) but has no detectable effect on transcription by RNA polymerase II (RNAP II) in a reconstituted system with all of the required factors. Another oxidative lesion, 8-oxoguanine, only slightly blocked T7 RNAP and caused RNAP II to briefly pause at the lesion before bypassing it. Because an abasic site is an intermediate in the repair of oxidative damage, it was of interest to learn whether it arrested transcription. Using in vitro transcription assays and substrates containing a specifically positioned lesion, we found that an abasic site in the transcribed strand is a 60% block to transcription by T7 RNAP but nearly a complete block to transcription by mammalian RNAP II. An abasic site in the nontranscribed strand did not block either polymerase. Our results clearly indicate that an abasic site is a much stronger block to transcription than either a thymine glycol or an 8-oxoguanine. Because the predominant model for TCR postulates that only lesions that block RNAP will be subject to TCR, our findings suggest that the abasic site may be sufficient to initiate TCR in vivo.

    View details for DOI 10.1021/tx060103g

    View details for PubMedID 16978026

  • Transcriptional inhibition by an oxidized abasic site in DNA CHEMICAL RESEARCH IN TOXICOLOGY Wang, Y. L., Sheppard, T. L., Tornaletti, S., Maeda, L. S., Hanawalt, P. C. 2006; 19 (2): 234-241

    Abstract

    2-Deoxyribonolactone (dL) is an oxidized abasic site in DNA that can be induced by gamma-radiolysis, ultraviolet irradiation, and numerous antitumor drugs. Although this lesion is incised by AP endonucleases, suggesting a base-excision repair mechanism for dL removal, subsequent excision and repair synthesis by DNA polymerase beta is inhibited due to accumulation of a protein-DNA cross-link. This raises the possibility that additional repair pathways might be required to eliminate dL from the genome. Transcription-coupled repair (TCR) is a pathway of excision repair specific to DNA lesions present in transcribed strands of expressed genes. A current model proposes that transcription arrest at the site of DNA damage is required to initiate TCR. In support of this model, a strong correlation between transcription arrest by a lesion in vitro and TCR of the lesion in vivo has been found in most cases analyzed. To assess whether dL might be subject to TCR, we have studied the behavior of bacteriophage T3 and T7 RNA polymerases (T3RNAP, T7RNAP) and of mammalian RNA polymerase II (RNAPII) when they encounter a dL lesion or its "caged" precursor located either in the transcribed or in the nontranscribed strand of template DNA. DNA plasmids containing a specifically located dL downstream of the T3, T7 promoter or the Adenovirus major late promoter were constructed and used for in vitro transcription with purified proteins. We found that both dL and its caged precursor located in the transcribed strand represented a complete block to transcription by T3- and T7RNAP. Similarly, they caused more than 90% arrest when transcription was carried out with mammalian RNAPII. Furthermore, RNAPII complexes arrested at dL were subject to the transcript cleavage reaction mediated by elongation factor TFIIS, indicating that these complexes were stable. A dL in the nontranscribed strand did not block either polymerase.

    View details for DOI 10.1021/tx050292n

    View details for Web of Science ID 000235584800006

    View details for PubMedID 16485899

  • Effect of 8-oxoguanine on transcription elongation by T7 RNA polymerase and mammalian RNA polymerase II DNA REPAIR Silvia, T. A., Maeda, L. S., Kolodner, R. D., Hanawalt, P. C. 2004; 3 (5): 483-494

    Abstract

    8-Oxoguanine (8-oxoG) is a major oxidative lesion produced in DNA by normal cellular metabolism or after exposure to exogenous sources such as ionizing radiation. Persistence of this lesion in DNA causes G to T transversions, with deleterious consequences for the cell. As a result, several repair processes have evolved to remove this lesion from the genome. It has been reported that 8-oxoG is subject to transcription-coupled repair (TCR), a process dedicated to removal of lesions from transcribed strands of expressed genes. A current model assumes that RNA polymerase arrest at the site of the lesion is required for initiation of TCR. As a first step to understand how TCR of 8-oxoG occurs, we have studied the effect of 8-oxoG on transcription elongation by T7 RNA polymerase (T7 RNAP) and rat liver RNA polymerase II (RNAPII). We have utilized an in vitro transcription system with purified RNA polymerase and initiation factors, and substrates containing a single 8-oxoG in the transcribed or in the non-transcribed strand downstream of the T7 promoter or the Adenovirus major late promoter. We found that 8-oxoG only slightly inhibited T7 RNAP transcription, with a readthrough frequency of up to 95%. Similarly, this lesion only transiently blocked transcription by RNAPII. However, changes in nucleotide concentration affected the extent of RNAPII blockage at the 8-oxoG. When this lesion was positioned in the non-transcribed strand, complete lesion bypass was observed with either polymerase. Binding of the Saccharomyces cerevisiae MSH2-MSH6 complex to 8-oxoG containing substrates did not increase the frequency of RNAPII arrest at the site of the lesion, suggesting that this complex was displaced by the elongating polymerase. These results are discussed in the context of possible models for TCR.

    View details for DOI 10.1016/j.dnarep.2004.01.003

    View details for Web of Science ID 000221156400005

    View details for PubMedID 15084310

  • Effect of thymine glycol on transcription elongation by T7 RNA polymerase and mammalian RNA polymerase II JOURNAL OF BIOLOGICAL CHEMISTRY Tornaletti, S., Maeda, L. S., Lloyd, D. R., Reines, D., Hanawalt, P. C. 2001; 276 (48): 45367-45371

    Abstract

    Thymine glycols are formed in DNA by exposure to ionizing radiation or oxidative stress. Although these lesions are repaired by the base excision repair pathway, they have been shown also to be subject to transcription-coupled repair. A current model for transcription-coupled repair proposes that RNA polymerase II arrested at a DNA lesion provides a signal for recruitment of the repair enzymes to the lesion site. Here we report the effect of thymine glycol on transcription elongation by T7 RNA polymerase and RNA polymerase II from rat liver. DNA substrates containing a single thymine glycol located either in the transcribed or nontranscribed strand were used to carry out in vitro transcription. We found that thymine glycol in the transcribed strand blocked transcription elongation by T7 RNA polymerase approximately 50% of the time but did not block RNA polymerase II. Thymine glycol in the nontranscribed strand did not affect transcription by either polymerase. These results suggest that arrest of RNA polymerase elongation by thymine glycol is not necessary for transcription-coupled repair of this lesion. Additional factors that recognize and bind thymine glycol in DNA may be required to ensure RNA polymerase arrest and the initiation of transcription-coupled repair in vivo.

    View details for Web of Science ID 000172406700132

    View details for PubMedID 11571287

    View details for PubMedCentralID PMC3373304