Bio


Bruno C. Medeiros, MD is associate professor of medicine and director of the inpatient hematology service. He is also director of Cancer Center ITA services at Stanford Comprehensive Cancer Center. Dr. Medeiros graduated from the Universidade Federal do Parana with a medical degree, in 1998. He completed his post-graduate training at the University of Colorado in Denver and the Princess Margaret Hospital in Toronto (Acute leukemia fellowship). Dr. Medeiros’ clinical interests include management of advanced hematologic malignancies, including AML, ALL, MDS and CML. His clinical research interest focuses on the development of novel therapeutic regimens for patients with acute leukemia, with special interest in the development of novel therapeutic strategies for patients with acute myeloid leukemia. He is the leader in several institutional investigator initiated clinical trials, active investigator in collaborative multi-institutional clinical studies and an active member of the SWOG acute leukemia panel. Dr. Medeiros has authored more than 120 peer-reviewed manuscripts. Dr. Medeiros has served as the track leader for ASCO meeting Leukemia, Myelodysplasia and Transplantation scientific review subcommittee, he functions as the Associate Editor of the Leukemia Panel for Cancer.Net, he is a member of the editorial board for Leukemia Research and serves as a reviewer for several specialized journals, such as Blood, Leukemia, Haematologica and Cancer, among others.

Clinical Focus


  • Cancer > Hematology
  • Hematology
  • Acute leukemia

Academic Appointments


Administrative Appointments


  • Panel Member Multiple Myeloma Committee, National Comprehensive Cancer Network (2007 - 2011)
  • Acute Leukemia Panel Member, Southwest Oncology Group (SWOG) (2007 - 2016)
  • Panel member adult oncology committee, National comprehensive cancer network (2010 - 2016)
  • Director, Director of Infusion Services (ITA) (2015 - 2016)
  • Director, Stanford Hospital Hematology Inpatient service (2011 - 2016)

Professional Education


  • Fellowship:University of Colorado Health Science Center (2005) CO
  • Fellowship, Acute leukemia, Princess Margaret Hospital - University of Toronto (2006)
  • Board Certification: Hematology, American Board of Internal Medicine (2006)
  • Residency:University of Colorado Health Science Center (2002) CO
  • Internship:University of Connecticut Health Center (2000) CT
  • Medical Education:University Federal Do Parana (1998) Brazil

Current Research and Scholarly Interests


My clinical activities combine the development of novel therapeutic modalities, translational research activities and epidemiological study of acute leukemia. My special focus is on the development of better, patient tailored therapies for young and elderly patients with acute leukemia.

2016-17 Courses


All Publications


  • relapsed or refractory acute myeloid leukemia. Blood Stein, E. M., DiNardo, C. D., Pollyea, D. A., Fathi, A. T., Roboz, G. J., Altman, J. K., Stone, R. M., DeAngelo, D. J., Levine, R. L., Flinn, I. W., Kantarjian, H. M., Collins, R., Patel, M. R., Frankel, A. E., Stein, A., Sekeres, M. A., Swords, R. T., Medeiros, B. C., Willekens, C., Vyas, P., Tosolini, A., Xu, Q., Knight, R. D., Yen, K. E., Agresta, S., de Botton, S., Tallman, M. S. 2017

    Abstract

    Recurrent mutations in isocitrate dehydrogenase 2 (IDH2) occur in ~12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, leading to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human, phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant-IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients (N=239) and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML (n=176), from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50-650 mg daily. Enasidenib 100 mg daily was selected for the expansion phase based on pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3-4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (IDH-DS; 7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission was 19.7 months. Continuous daily enasidenib treatment was generally well-tolerated and induced hematologic responses in patients who had failed prior AML therapy. Inducing differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib.

    View details for DOI 10.1182/blood-2017-04-779405

    View details for PubMedID 28588020

  • Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. The New England journal of medicine Stone, R. M., Mandrekar, S. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., Thiede, C., Prior, T. W., Döhner, K., Marcucci, G., Lo-Coco, F., Klisovic, R. B., Wei, A., Sierra, J., Sanz, M. A., Brandwein, J. M., de Witte, T., Niederwieser, D., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Krauter, J., Schlenk, R. F., Ganser, A., Serve, H., Ehninger, G., Amadori, S., Larson, R. A., Döhner, H. 2017

    Abstract

    Background Patients with acute myeloid leukemia (AML) and a FLT3 mutation have poor outcomes. We conducted a phase 3 trial to determine whether the addition of midostaurin - an oral multitargeted kinase inhibitor that is active in patients with a FLT3 mutation - to standard chemotherapy would prolong overall survival in this population. Methods We screened 3277 patients, 18 to 59 years of age, who had newly diagnosed AML for FLT3 mutations. Patients were randomly assigned to receive standard chemotherapy (induction therapy with daunorubicin and cytarabine and consolidation therapy with high-dose cytarabine) plus either midostaurin or placebo; those who were in remission after consolidation therapy entered a maintenance phase in which they received either midostaurin or placebo. Randomization was stratified according to subtype of FLT3 mutation: point mutation in the tyrosine kinase domain (TKD) or internal tandem duplication (ITD) mutation with either a high ratio (>0.7) or a low ratio (0.05 to 0.7) of mutant to wild-type alleles (ITD [high] and ITD [low], respectively). Allogeneic transplantation was allowed. The primary end point was overall survival. Results A total of 717 patients underwent randomization; 360 were assigned to the midostaurin group, and 357 to the placebo group. The FLT3 subtype was ITD (high) in 214 patients, ITD (low) in 341 patients, and TKD in 162 patients. The treatment groups were well balanced with respect to age, race, FLT3 subtype, cytogenetic risk, and blood counts but not with respect to sex (51.7% in the midostaurin group vs. 59.4% in the placebo group were women, P=0.04). Overall survival was significantly longer in the midostaurin group than in the placebo group (hazard ratio for death, 0.78; one-sided P=0.009), as was event-free survival (hazard ratio for event or death, 0.78; one-sided P=0.002). In both the primary analysis and an analysis in which data for patients who underwent transplantation were censored, the benefit of midostaurin was consistent across all FLT3 subtypes. The rate of severe adverse events was similar in the two groups. Conclusions The addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy significantly prolonged overall and event-free survival among patients with AML and a FLT3 mutation. (Funded by the National Cancer Institute and Novartis; ClinicalTrials.gov number, NCT00651261 .).

    View details for DOI 10.1056/NEJMoa1614359

    View details for PubMedID 28644114

  • Novel Therapeutics in Acute Myeloid Leukemia. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Meeting DiNardo, C. D., Stone, R. M., Medeiros, B. C. 2017; 37: 495-503

    Abstract

    In this review, we focus on three key areas in acute myeloid leukemia (AML) developmental therapeutics: FLT3 inhibitors, IDH inhibitors, and drugs that may be particularly beneficial in secondary AML.

    View details for DOI 10.14694/EDBK_175401

    View details for PubMedID 28561688

  • Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia Medeiros, B. C., Fathi, A. T., Dinardo, C. D., Pollyea, D. A., Chan, S. M., SWORDS, R. 2016

    Abstract

    Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation, and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (TCA, also called the 'citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of α-KG to the (R) enantiomer of 2-hydroxyglutarate ([R]-2-HG), which is associated with DNA and histone hypermethylation, altered gene expression, and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated, and when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment, or in relapsed or refractory, AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH.Leukemia accepted article preview online, 10 October 2016. doi:10.1038/leu.2016.275.

    View details for DOI 10.1038/leu.2016.275

    View details for PubMedID 27721426

  • Improved outcome in acute myeloid leukemia patients enrolled in clinical trials: A national population-based cohort study of Danish intensive chemotherapy patients. Oncotarget Østgård, L. S., Nørgaard, M., Sengeløv, H., Medeiros, B. C., Kjeldsen, L., Overgaard, U. M., Severinsen, M. T., Marcher, C. W., Jensen, M. K., Nørgaard, J. M. 2016

    Abstract

    Clinical trials are critical to improve AML treatment. It remains, however, unclear if clinical trial participation per se affects prognosis and to what extent the patients selected for trials differ from those of patients receiving intensive therapy off-trial.We conducted a population-based cohort study of newly diagnosed Danish AML patients treated with intensive chemotherapy between 2000-2013. We estimated accrual rates and compared characteristics, complete remission (CR) rates, and relative risks (RRs) of death at 90-day, 1-year, and 3-years in clinical trial patients to patients treated off-trial.Of 867 patients, 58.3% (n = 504) were included in a clinical trial. Accrual rates were similar across age groups (p = 0.55). Patients with poor performance status, comorbidity, therapy-related and secondary AML were less likely to be enrolled in trials. CR rates were 80.2% in trial-patients versus 68.6% in patients treated off- trial. Also, trial-patients had superior survival at 1-year; 72%, vs. 54% (adjusted RR of death 1.28(CI = 1.06-1.54)), and at 3 years; 45% vs. 29% (adjusted RR 1.14(CI = 1.03-1.26)) compared to patients treated off-trial.Despite high accrual rates, patients enrolled in clinical trials had a favorable prognostic profile and a better survival than patients treated off-trial. In conclusion, all trial results should be extrapolated with caution and population-based studies of "real world patients" have a prominent role in examining the prognosis of AML.

    View details for DOI 10.18632/oncotarget.12495

    View details for PubMedID 27732947

  • Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2015

    Abstract

    Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age.In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs.Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61).Our results support that de novo AML, sAML, and tAML are biologically and prognostically distinct subtypes of AML. Patients with non-MDS-sAML have dismal outcomes, independent of age and cytogenetics. Previous myeloid disorder, age, and cytogenetics are crucial determinants of outcomes and should be integrated in treatment recommendations for these patients.

    View details for DOI 10.1200/JCO.2014.60.0890

    View details for PubMedID 26304885

  • Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proceedings of the National Academy of Sciences of the United States of America Corces-Zimmerman, M. R., Hong, W., Weissman, I. L., Medeiros, B. C., Majeti, R. 2014; 111 (7): 2548-2553

    Abstract

    Cancer is widely characterized by the sequential acquisition of genetic lesions in a single lineage of cells. Our previous studies have shown that, in acute myeloid leukemia (AML), mutation acquisition occurs in functionally normal hematopoietic stem cells (HSCs). These preleukemic HSCs harbor some, but not all, of the mutations found in the leukemic cells. We report here the identification of patterns of mutation acquisition in human AML. Our findings support a model in which mutations in "landscaping" genes, involved in global chromatin changes such as DNA methylation, histone modification, and chromatin looping, occur early in the evolution of AML, whereas mutations in "proliferative" genes occur late. Additionally, we analyze the persistence of preleukemic mutations in patients in remission and find CD34+ progenitor cells and various mature cells that harbor preleukemic mutations. These findings indicate that preleukemic HSCs can survive induction chemotherapy, identifying these cells as a reservoir for the reevolution of relapsed disease. Finally, through the study of several cases of relapsed AML, we demonstrate various evolutionary patterns for the generation of relapsed disease and show that some of these patterns are consistent with involvement of preleukemic HSCs. These findings provide key insights into the monitoring of minimal residual disease and the identification of therapeutic targets in human AML.

    View details for DOI 10.1073/pnas.1324297111

    View details for PubMedID 24550281

  • 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

  • Cytarabine Dose for Acute Myeloid Leukemia NEW ENGLAND JOURNAL OF MEDICINE Medeiros, B. C., Othus, M., Appelbaum, F. R. 2011; 364 (22): 2167-2168

    View details for Web of Science ID 000291200700028

    View details for PubMedID 21631340

  • Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience BLOOD Medeiros, B. C., Othus, M., Fang, M., Roulston, D., Appelbaum, F. R. 2010; 116 (13): 2224-2228

    Abstract

    Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.

    View details for DOI 10.1182/blood-2010-02-270330

    View details for Web of Science ID 000282369700008

    View details for PubMedID 20562328

  • Identification of Interleukin-1 by Functional Screening as a Key Mediator of Cellular Expansion and Disease Progression in Acute Myeloid Leukemia CELL REPORTS Carey, A., Edwards, D. K., Eide, C. A., Newell, L., Traer, E., Medeiros, B. C., Pollyea, D. A., Deininger, M. W., Collins, R. H., Tyner, J. W., Druker, B. J., Bagby, G. C., McWeeney, S. K., Agarwal, A. 2017; 18 (13): 3204-3218

    Abstract

    Secreted proteins in the bone marrow microenvironment play critical roles in acute myeloid leukemia (AML). Through an ex vivo functional screen of 94 cytokines, we identified that the pro-inflammatory cytokine interleukin-1 (IL-1) elicited profound expansion of myeloid progenitors in ∼67% of AML patients while suppressing the growth of normal progenitors. Levels of IL-1β and IL-1 receptors were increased in AML patients, and silencing of the IL-1 receptor led to significant suppression of clonogenicity and in vivo disease progression. IL-1 promoted AML cell growth by enhancing p38MAPK phosphorylation and promoting secretion of various other growth factors and inflammatory cytokines. Treatment with p38MAPK inhibitors reversed these effects and recovered normal CD34(+) cells from IL-1-mediated growth suppression. These results highlight the importance of ex vivo functional screening to identify common and actionable extrinsic pathways in genetically heterogeneous malignancies and provide impetus for clinical development of IL-1/IL1R1/p38MAPK pathway-targeted therapies in AML.

    View details for DOI 10.1016/j.celrep.2017.03.018

    View details for Web of Science ID 000398230600016

    View details for PubMedID 28355571

  • Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes. Blood cancer journal Swords, R. T., Watts, J., Erba, H. P., Altman, J. K., Maris, M., ANWER, F., Hua, Z., Stein, H., Faessel, H., Sedarati, F., Dezube, B. J., Giles, F. J., Medeiros, B. C., DeAngelo, D. J. 2017; 7 (2)

    View details for DOI 10.1038/bcj.2017.1

    View details for PubMedID 28157218

  • Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes. Blood cancer journal Swords, R. T., Watts, J., Erba, H. P., Altman, J. K., Maris, M., ANWER, F., Hua, Z., Stein, H., Faessel, H., Sedarati, F., Dezube, B. J., Giles, F. J., Medeiros, B. C., DeAngelo, D. J. 2017; 7 (2)

    View details for DOI 10.1038/bcj.2017.1

    View details for PubMedID 28157218

  • Localized skin-limited blastic plasmacytoid dendritic cell neoplasm: A subset with possible durable remission without transplantation. JAAD case reports Amitay-Laish, I., Sundram, U., Hoppe, R. T., Hodak, E., Medeiros, B. C., Kim, Y. H. 2017; 3 (4): 310–15

    View details for DOI 10.1016/j.jdcr.2017.03.015

    View details for PubMedID 28752118

    View details for PubMedCentralID PMC5517837

  • Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies. Proceedings of the National Academy of Sciences of the United States of America Kurtz, S. E., Eide, C. A., Kaempf, A., Khanna, V., Savage, S. L., Rofelty, A., English, I., Ho, H., Pandya, R., Bolosky, W. J., Poon, H., Deininger, M. W., Collins, R., Swords, R. T., Watts, J., Pollyea, D. A., Medeiros, B. C., Traer, E., Tognon, C. E., Mori, M., Druker, B. J., Tyner, J. W. 2017

    Abstract

    Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

    View details for DOI 10.1073/pnas.1703094114

    View details for PubMedID 28784769

  • Unpaired extracellular cysteine mutations of CSF3R mediate gain or loss of function. Cancer research Zhang, H., Means, S., Schultz, A. R., Watanabe-Smith, K., Medeiros, B. C., Bottomly, D., Wilmot, B., McWeeney, S. K., Kükenshöner, T., Hantschel, O., Tyner, J. W. 2017

    Abstract

    Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g. T618I), functionally defective mutations in the extracellular domain of the granulocyte colony-stimulating factor receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here we describe the first activating mutation in the fibronectin like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain and loss of function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients.

    View details for DOI 10.1158/0008-5472.CAN-17-1052

    View details for PubMedID 28652245

  • A study of disseminated intravascular coagulation in acute leukemia reveals markedly elevated D-dimer levels are a sensitive indicator of acute promyelocytic leukemia. International journal of laboratory hematology Shahmarvand, N., Oak, J. S., Cascio, M. J., Alcasid, M., Goodman, E., Medeiros, B. C., Arber, D. A., Zehnder, J. L., Ohgami, R. S. 2017

    Abstract

    While the presence of disseminated intravascular coagulation (DIC) has been implicated in worse clinical outcome in acute leukemia, the relationship between different subtypes of acute leukemia and the clinicopathologic features of DIC has not been systematically well studied.In this study, we retrospectively reviewed 149 cases of newly diagnosed acute leukemia and assessed the utility of evaluating red blood cell morphologic features, and coagulation parameters in determining the presence of DIC as well as differentiating subtypes of acute leukemia.Review of our cohort demonstrates a novel finding, that elevated D-dimer concentrations ≥19 000 ng/mL fibrinogen equivalent units (FEU) are a sensitive diagnostic indicator of acute promyelocytic leukemia (APL) with moderate specificity, sensitivity 96%, specificity 92% in acute leukemia subtyping. Similar to other studies, APL showed an increased incidence of DIC (P < 0.01) compared to other subtypes of acute leukemia. Surprisingly, the presence of schistocytes on the peripheral blood smear was not a statistically significant indicator of DIC, sensitivity of 36% and specificity of 89%. Finally, the presence of DIC was not a significant indicator of poorer prognosis amongst all patients with AML.Overall we identify elevated D-dimer concentrations ≥19 000 ng/mL FEU are a sensitive indicator of acute promyelocytic leukemia (APL), with a sensitivity of 96% and specificity of 92% in the subtyping of acute leukemias, and that the presence of schistocytes in peripheral blood smears is not a diagnostically sensitive screening test for DIC with a sensitivity of 36%.

    View details for DOI 10.1111/ijlh.12636

    View details for PubMedID 28422420

  • Long non-coding RNAs: another brick in the wall of normal karyotype acute myeloid leukemia? Haematologica Medeiros, B. C. 2017; 102 (8): 1301–3

    View details for DOI 10.3324/haematol.2017.171744

    View details for PubMedID 28760807

  • NCCN Guidelines Insights: Older Adult Oncology, Version 2.2016. Journal of the National Comprehensive Cancer Network VanderWalde, N., Jagsi, R., Dotan, E., Baumgartner, J., Browner, I. S., Burhenn, P., Cohen, H. J., Edil, B. H., Edwards, B., Extermann, M., Ganti, A. K., Gross, C., Hubbard, J., Keating, N. L., Korc-Grodzicki, B., McKoy, J. M., Medeiros, B. C., Mrozek, E., O'Connor, T., Rugo, H. S., Rupper, R. W., Shepard, D., Silliman, R. A., Stirewalt, D. L., Tew, W. P., Walter, L. C., Wildes, T., Bergman, M. A., Sundar, H., Hurria, A. 2016; 14 (11): 1357-1370

    Abstract

    Cancer is the leading cause of death in older adults aged 60 to 79 years. Older patients with good performance status are able to tolerate commonly used treatment modalities as well as younger patients, particularly when adequate supportive care is provided. For older patients who are able to tolerate curative treatment, options include surgery, radiation therapy (RT), chemotherapy, and targeted therapies. RT can be highly effective and well tolerated in carefully selected patients, and advanced age alone should not preclude the use of RT in older patients with cancer. Judicious application of advanced RT techniques that facilitate normal tissue sparing and reduce RT doses to organs at risk are important for all patients, and may help to assuage concerns about the risks of RT in older adults. These NCCN Guidelines Insights focus on the recent updates to the 2016 NCCN Guidelines for Older Adult Oncology specific to the use of RT in the management of older adults with cancer.

    View details for PubMedID 27799507

  • NCCN Guidelines (R) Insights Older Adult Oncology, Version 2.2016 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK VanderWalde, N., Jagsi, R., Dotan, E., Baumgartner, J., Browner, I. S., Burhenn, P., Cohen, H. J., Edil, B. H., Edwards, B., Extermann, M., Ganti, A. K., Gross, C., Hubbard, J., Keating, N. L., Korc-Grodzicki, B., McKoy, J. M., Medeiros, B. C., Mrozek, E., O'Connor, T., Rugo, H. S., Rupper, R. W., Shepard, D., Silliman, R. A., Stirewalt, D. L., Tew, W. P., Walter, L. C., Wildes, T., Bergman, M. A., Sundar, H., Hurria, A. 2016; 14 (11): 1357-1370
  • Autophagy mediates proteolysis of NPM1 and HEXIM1 and sensitivity to BET inhibition in AML cells. Oncotarget Huang, M., Garcia, J. S., Thomas, D., Zhu, L., Nguyen, L. X., Chan, S. M., Majeti, R., Medeiros, B. C., Mitchell, B. S. 2016

    Abstract

    The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1. The Brd4 inhibitors JQ1 and I-BET-151 also inhibit autophagy and increase NPM1 and HEXIM1 expression. We conclude that the degradation of NPM1 and HEXIM1 through autophagy in certain AML subsets contributes to the activation of the BET pathway in these cells.

    View details for DOI 10.18632/oncotarget.12493

    View details for PubMedID 27732946

  • 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

  • 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

  • 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
  • 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

  • Novel germ line DDX41 mutations define families with a lower age of MDS/AML onset and lymphoid malignancies BLOOD Lewinsohn, M., Brown, A. L., Weinel, L. M., Phung, C., Rafidi, G., Lee, M. K., Schreiber, A. W., Feng, J., Babic, M., Chong, C., Lee, Y., Yong, A., Suthers, G. K., Poplawski, N., Altree, M., Phillips, K., Jaensch, L., Fine, M., D'Andrea, R. J., Lewis, I. D., Medeiros, B. C., Pollyea, D. A., King, M., Walsh, T., Keel, S., Shimamura, A., Godley, L. A., Hahn, C. N., Churpek, J. E., Scott, H. S. 2016; 127 (8): 1017-1023

    Abstract

    Recently our group and others have identified DDX41 mutations both as germline and acquired somatic mutations in families with multiple cases of late onset myelodysplastic syndrome and/or acute myeloid leukemia (MDS/AML), suggesting that DDX41 acts as a tumor suppressor. To determine if novel DDX41 mutations could be identified in families with additional types of hematologic malignancies, our groups screened two cohorts of families with a diverse range of hematologic malignancy subtypes. Among 289 families, we identified nine with DDX41 mutations (3%). As previously observed, MDS/AML were the most common malignancies, often of the erythroblastic subtype, and one family displayed early onset follicular lymphoma. Five novel mutations were identified, including missense mutations within important functional domains, and start-loss and splicing mutations predicted to result in truncated proteins. We also show that most asymptomatic mutation carriers have normal blood counts until malignancy develops. This study expands both the mutation and phenotypic spectra observed in families with germline DDX41 mutations. With an increasing number of both inherited and acquired mutations in this gene being identified, further study of how DDX41 disruption leads to hematologic malignancies is critical.

    View details for DOI 10.1182/blood-2015-10-676098

    View details for Web of Science ID 000373397800012

    View details for PubMedID 26712909

  • Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies. Biology of blood and marrow transplantation Pasquini, M. C., Zhang, M., Medeiros, B. C., Armand, P., Hu, Z., Nishihori, T., AlJurf, M. D., Akpek, G., Cahn, J., Cairo, M. S., Cerny, J., Copelan, E. A., Deol, A., Freytes, C. O., Gale, R. P., Ganguly, S., George, B., Gupta, V., Hale, G. A., Kamble, R. T., Klumpp, T. R., Lazarus, H. M., Luger, S. M., Liesveld, J. L., Litzow, M. R., Marks, D. I., Martino, R., Norkin, M., Olsson, R. F., Oran, B., Pawarode, A., Pulsipher, M. A., Ramanathan, M., Reshef, R., Saad, A. A., Saber, W., Savani, B. N., Schouten, H. C., Ringdén, O., Tallman, M. S., Uy, G. L., Wood, W. A., Wirk, B., Pérez, W. S., Batiwalla, M., Weisdorf, D. J. 2016; 22 (2): 248-257

    Abstract

    The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed.

    View details for DOI 10.1016/j.bbmt.2015.08.024

    View details for PubMedID 26327629

    View details for PubMedCentralID PMC4716890

  • Predictors of early death and survival among children, adolescents and young adults with acute myeloid leukaemia in California, 1988-2011: a population-based study. British journal of haematology 2016

    Abstract

    A better understanding of factors associated with early death and survival among children, adolescents and young adults with acute myeloid leukaemia (AML) may guide health policy aimed at improving outcomes in these patients. We examined trends in early death and survival among 3935 patients aged 0-39 years with de novo AML in California during 1988-2011 and investigated the associations between sociodemographic and selected clinical factors and outcomes. Early death declined from 9·7% in 1988-1995 to 7·1% in 2004-2011 (P = 0·062), and survival improved substantially over time. However, 5-year survival was still only 50% (95% confidence interval 47-53%) even in the most recent treatment period (2004-2011). Overall, the main factors associated with poor outcomes were older age at diagnosis, treatment at hospitals not affiliated with National Cancer Institute-designated cancer centres, and black race/ethnicity. For patients diagnosed during 1996-2011, survival was lower among those who lacked health insurance compared to those with public or private insurance. We conclude that mortality after AML remained strikingly high in California and increased with age. Possible strategies to improve outcomes include wider insurance coverage and treatment at specialized cancer centres.

    View details for DOI 10.1111/bjh.13944

    View details for PubMedID 26847024

  • Identification of Doxorubicin as an Inhibitor of the IRE1a-XBP1 Axis of the Unfolded Protein Response. Scientific reports Jiang, D., Lynch, C., Medeiros, B. C., Liedtke, M., Bam, R., Tam, A. B., Yang, Z., Alagappan, M., Abidi, P., Le, Q., Giaccia, A. J., Denko, N. C., Niwa, M., Koong, A. C. 2016; 6: 33353-?

    Abstract

    Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in multiple types of human cancers, including multiple myeloma (MM). Through an in silico drug discovery approach based on protein-compound virtual docking, we identified the anthracycline antibiotic doxorubicin as an in vitro and in vivo inhibitor of XBP1 activation, a previously unknown activity for this widely utilized cancer chemotherapeutic drug. Through a series of mechanistic and phenotypic studies, we showed that this novel activity of doxorubicin was not due to inhibition of topoisomerase II (Topo II). Consistent with its inhibitory activity on the IRE1α-XBP1 branch of the UPR, doxorubicin displayed more potent cytotoxicity against MM cell lines than other cancer cell lines that have lower basal IRE1α-XBP1 activity. In addition, doxorubicin significantly inhibited XBP1 activation in CD138(+) tumor cells isolated from MM patients. Our findings suggest that the UPR-modulating activity of doxorubicin may be utilized clinically to target IRE1α-XBP1-dependent tumors such as MM.

    View details for DOI 10.1038/srep33353

    View details for PubMedID 27634301

  • Why do subjects on clinical trials discontinue therapy? Do we really know? Leukemia research Medeiros, B. C., Gale, R. P. 2016; 51: 19–21

    View details for DOI 10.1016/j.leukres.2016.10.006

    View details for PubMedID 27776289

  • Management of invasive Aspergillosis in acute myelogenous leukemia. Clinical advances in hematology & oncology : H&O Medeiros, B. C. 2016; 14 (7): 502–4

    View details for PubMedID 27379944

  • Individualizing Therapeutic Strategies in Acute Myeloid Leukemia: Moving Beyond the 'One-Size-Fits-All' Approach. Oncology (Williston Park, N.Y.) Jonas, B. A., Medeiros, B. C. 2016; 30 (4)

    View details for PubMedID 27085331

  • Mass Cytometric Functional Profiling of Acute Myeloid Leukemia Defines Cell-Cycle and Immunophenotypic Properties That Correlate with Known Responses to Therapy. Cancer discovery Behbehani, G. K., Samusik, N., Bjornson, Z. B., Fantl, W. J., Medeiros, B. C., Nolan, G. P. 2015; 5 (9): 988-1003

    Abstract

    Acute myeloid leukemia (AML) is characterized by a high relapse rate that has been attributed to the quiescence of leukemia stem cells (LSCs), which renders them resistant to chemotherapy. However, this hypothesis is largely supported by indirect evidence and fails to explain the large differences in relapse rates across AML subtypes. To address this, bone marrow aspirates from 41 AML patients and five healthy donors were analyzed by high-dimensional mass cytometry. All patients displayed immunophenotypic and intracellular signaling abnormalities within CD34+CD38low populations and several karyotype and genotype-specific surface marker patterns were identified. The immunophenotypic stem and early progenitor cell populations from patients with clinically favorable core-binding factor AML demonstrated a five-fold higher fraction of cells in S-phase compared to other AML samples. Conversely, LSCs in less clinically favorable FLT3-ITD AML exhibited dramatic reductions in S-phase fraction. Mass cytometry also allowed direct observation of the in vivo effects of cytotoxic chemotherapy.

    View details for DOI 10.1158/2159-8290.CD-15-0298

    View details for PubMedID 26091827

  • Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States ANNALS OF HEMATOLOGY Medeiros, B. C., Satram-Hoang, S., Hurst, D., Hoang, K. Q., Momin, F., Reyes, C. 2015; 94 (7): 1127-1138

    Abstract

    Over half of patients diagnosed with acute myeloid leukemia (AML) are 65 years or older. We examined patient characteristics, treatment patterns, and survival among elderly patients in routine clinical practice. We utilized a retrospective cohort analysis of first primary AML patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 and December 31, 2009, >66 years, and continuously enrolled in Medicare Part A and B in the year prior to diagnosis. Kaplan-Meier curves and Cox proportional hazards regression assessed overall survival by treatment. There were 3327 (40 %) patients who received chemotherapy within 3 months of diagnosis. Treated patients were more likely younger, male, and married, and less likely to have secondary AML and poor performance indicators and comorbidity score compared to untreated patients. In multivariate survival analysis, treated patients exhibited a significant 33 % lower risk of death compared to untreated patients. Significant survival benefits were noted with receipt of intensive and hypomethylating agent (HMA) therapies compared to no therapy. A survival benefit with allogeneic hematopoietic stem cell transplantation was seen in younger Medicare patients. This real-world study showed that about 60 % of elderly AML patients remain untreated following diagnosis. Use of anti-leukemic therapy was associated with a significant survival benefit in this elderly cohort.

    View details for DOI 10.1007/s00277-015-2351-x

    View details for Web of Science ID 000354470600007

    View details for PubMedID 25791241

  • Improvements in the early death rate among 9380 patients with acute myeloid leukemia after initial therapy: A SEER database analysis CANCER Percival, M. M., Tao, L., Medeiros, B. C., Clarke, C. A. 2015; 121 (12): 2004-2012

    Abstract

    Acute myeloid leukemia (AML) is treated with conventional induction chemotherapy shortly after diagnosis for the majority of patients aged ≤65 years. A recent report suggested a substantial decline in the early, or 1-month, mortality rate in patients treated on clinical trials over the past 2 decades. It is unknown whether a similar improvement has been observed in the general population.The authors examined the 1-month mortality rate in a large population-based series of 9380 patients with AML who were aged ≤65 years and were diagnosed and treated with chemotherapy between 1973 and 2010.A significant decline was observed in the 1-month mortality rate from 18.7% among patients diagnosed from 1973 through 1977 (95% confidence interval [95% CI], 16.4%-21.2%) to 5.8% for those diagnosed between 2008 and 2010 (95% CI, 4.5%-7.6%) (P <.001). The median overall survival improved significantly from 6 months (95% CI, 5 months-7 months) in 1973 to 1977 to 23 months (95% CI, 16 months-20 months) in 2008 to 2010 (P <.001). Although age and geographic variation were found to significantly influence the 1-month mortality for the period between 1973 and 1977, these differences in 1-month mortality were no longer significant among patients with AML who were treated more recently (2008-2010).Over the past 4 decades, early mortality has become uncommon in younger patients (aged ≤65 years) with newly diagnosed AML undergoing induction chemotherapy. It is encouraging that the improvements noted in 1-month mortality rate among a selective cohort of patients in clinical trials have also been observed in a population-based analysis. Cancer 2015. © 2015 American Cancer Society.

    View details for DOI 10.1002/cncr.29319

    View details for Web of Science ID 000355768300015

    View details for PubMedID 25739348

  • Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study BRITISH JOURNAL OF HAEMATOLOGY Swords, R. T., Erba, H. P., DeAngelo, D. J., Bixby, D. L., Altman, J. K., Maris, M., Hua, Z., Blakemore, S. J., Faessel, H., Sedarati, F., Dezube, B. J., Giles, F. J., Medeiros, B. C. 2015; 169 (4): 534-543

    Abstract

    This trial was conducted to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the first in class NEDD8-activating enzyme (NAE) inhibitor, pevonedistat, and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Pevonedistat was administered via a 60-min intravenous infusion on days 1, 3 and 5 (schedule A, n = 27), or days 1, 4, 8 and 11 (schedule B, n = 26) every 21-days. Dose escalation proceeded using a standard '3 + 3' design. Responses were assessed according to published guidelines. The MTD for schedules A and B were 59 and 83 mg/m(2) , respectively. On schedule A, hepatotoxicity was dose limiting. Multi-organ failure (MOF) was dose limiting on schedule B. The overall complete (CR) and partial (PR) response rate in patients treated at or below the MTD was 17% (4/23, 2 CRs, 2 PRs) for schedule A and 10% (2/19, 2 PRs) for schedule B. Pevonedistat plasma concentrations peaked after infusion followed by elimination in a biphasic pattern. Pharmacodynamic studies of biological correlates of NAE inhibition demonstrated target-specific activity of pevonedistat. In conclusion, administration of the first-in-class agent, pevonedistat, was feasible in patients with MDS and AML and modest clinical activity was observed.

    View details for DOI 10.1111/bjh.13323

    View details for Web of Science ID 000353961600007

    View details for PubMedID 25733005

  • G-CSF Priming, clofarabine, and high dose cytarabine (GCLAC) for upfront treatment of acute myeloid leukemia, advanced myelodysplastic syndrome or advanced myeloproliferative neoplasm AMERICAN JOURNAL OF HEMATOLOGY Becker, P. S., Medeiros, B. C., Stein, A. S., Othus, M., Appelbaum, F. R., Forman, S. J., Scott, B. L., Hendrie, P. C., Gardner, K. M., Pagel, J. M., Walter, R. B., Parks, C., Wood, B. L., Abkowitz, J. L., Estey, E. H. 2015; 90 (4): 295-300

    Abstract

    Prior study of the combination of clofarabine and high dose cytarabine with granulocyte colony-stimulating factor (G-CSF) priming (GCLAC) in relapsed or refractory acute myeloid leukemia resulted in a 46% rate of complete remission despite unfavorable risk cytogenetics. A multivariate analysis demonstrated that the remission rate and survival with GCLAC were superior to FLAG (fludarabine, cytarabine, G-CSF) in the relapsed setting. We therefore initiated a study of the GCLAC regimen in the upfront setting in a multicenter trial. The objectives were to evaluate the rates of complete remission (CR), overall and relapse-free survival (OS and RFS), and toxicity of GCLAC. Clofarabine was administered at 30 mg m(-2 ) day(-1) × 5 and cytarabine at 2 g m(-2 ) day(-1) × 5 after G-CSF priming in 50 newly-diagnosed patients ages 18-64 with AML or advanced myelodysplastic syndrome (MDS) or advanced myeloproliferative neoplasm (MPN). Responses were assessed in the different cytogenetic risk groups and in patients with antecedent hematologic disorder. The overall CR rate was 76% (95% confidence interval [CI] 64-88%) and the CR + CRp (CR with incomplete platelet count recovery) was 82% (95% CI 71-93%). The CR rate was 100% for patients with favorable, 84% for those with intermediate, and 62% for those with unfavorable risk cytogenetics. For patients with an antecedent hematologic disorder (AHD), the CR rate was 65%, compared to 85% for those without an AHD. The 60 day mortality was 2%. Thus, front line GCLAC is a well-tolerated, effective induction regimen for AML and advanced myelodysplastic or myeloproliferative disorders. Am. J. Hematol., 2015. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajh.23927

    View details for Web of Science ID 000351680800013

    View details for PubMedID 25545153

  • Cytogenetic heterogeneity negatively impacts outcomes in patients with acute myeloid leukemia. Haematologica Medeiros, B. C., Othus, M., Fang, M., Appelbaum, F. R., Erba, H. P. 2015; 100 (3): 331-335

    Abstract

    Clonal heterogeneity is a hallmark of malignant transformation. In acute myeloid leukemia, acquired cytogenetic abnormalities are important independent predictors of initial response to therapy, remission duration, and overall survival. It remains poorly defined, however, whether the presence of multiple cytogenetically characterized clones affects outcomes in acute myeloid leukemia. The aim of this study was to assess the prognostic impact of cytogenetic clonal heterogeneity in acute myeloid leukemia. This analysis included 1403 newly diagnosed acute myeloid leukemia patients fit for intensive chemotherapy between the ages of 15 and 88 years enrolled on SWOG protocols. The presence of multiple cytogenetic clones was found in 164 (24%) patients with abnormal karyotype. The proportion of patients with clonal heterogeneity increased with age, being present in 20% of patients younger than 40 years, but in 30% of those over age 70 (p=0.03). Clonal heterogeneity was significantly more common in association with unfavorable karyotype. Clonal heterogeneity was associated with decreased response rates and inferior event-free, relapse-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariable analysis. Subgroup analysis showed that clonal heterogeneity adds prognostic information particularly in the unfavorable karyotype group. Our results confirm the negative prognostic impact of clonal heterogeneity in acute myeloid leukemia patients with abnormal karyotype. (ClinicalTrials.gov Identifiers: NCT014343329; NCT01338974; NCT00899171; NCT1059734; NCT01059734; NCT00899743; NCT0143329, NCT00023777; NCT00085709; NCT01360125; NCT00004217).

    View details for DOI 10.3324/haematol.2014.117267

    View details for PubMedID 25527568

  • Increased plasma d-2-hydroxyglutarate in isocitrate dehydrogenase 2-mutated blastic plasmacytoid dendritic cell neoplasm. Human pathology Rakheja, D., Fuda, F., Vandergriff, T., Boriack, R., Medeiros, B. C., Frankel, A. E., Chen, W. 2015; 46 (2): 322-326

    Abstract

    Blastic plasmacytoid dendritic cell neoplasm is an exceedingly rare hematologic malignancy derived from the precursors of plasmacytoid dendritic cells. Mutations in isocitrate dehydrogenase (IDH) 1 and 2 genes have been discovered in a range of neoplasms including glioma, acute myeloid leukemia, chondrosarcoma, and intrahepatic cholangiocarcinoma. Mutant IDH acquires neomorphic enzymatic activity to generate the oncometabolite d-2-hydroxyglutarate (d-2HG). Here, we describe the first case of an IDH2 R140Q-mutated blastic plasmacytoid dendritic cell neoplasm in a patient with markedly elevated plasma d-2HG. This finding expands the spectrum of neoplasms with increased d-2HG in association with IDH mutation. The roles of IDH mutation and d-2HG in disease pathogenesis and assessment of clinical response are discussed.

    View details for DOI 10.1016/j.humpath.2014.10.013

    View details for PubMedID 25481493

  • Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia NATURE MEDICINE Chan, S. M., Thomas, D., Corces-Zimmerman, M. R., Xavy, S., Rastogi, S., Hong, W., Zhao, F., Medeiros, B. C., Tyvoll, D. A., Majeti, R. 2015; 21 (2): 90-96

    View details for DOI 10.1038/nm.3788

    View details for Web of Science ID 000348974800021

  • Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nature medicine Chan, S. M., Thomas, D., Corces-Zimmerman, M. R., Xavy, S., Rastogi, S., Hong, W., Zhao, F., Medeiros, B. C., Tyvoll, D. A., Majeti, R. 2015; 21 (2): 178-184

    Abstract

    Mutant isocitrate dehydrogenase (IDH) 1 and 2 proteins alter the epigenetic landscape in acute myeloid leukemia (AML) cells through production of the oncometabolite (R)-2-hydroxyglutarate (2-HG). Here we performed a large-scale RNA interference (RNAi) screen to identify genes that are synthetic lethal to the IDH1(R132H) mutation in AML and identified the anti-apoptotic gene BCL-2. IDH1- and IDH2-mutant primary human AML cells were more sensitive than IDH1/2 wild-type cells to ABT-199, a highly specific BCL-2 inhibitor that is currently in clinical trials for hematologic malignancies, both ex vivo and in xenotransplant models. This sensitization effect was induced by (R)-2-HG-mediated inhibition of the activity of cytochrome c oxidase (COX) in the mitochondrial electron transport chain (ETC); suppression of COX activity lowered the mitochondrial threshold to trigger apoptosis upon BCL-2 inhibition. Our findings indicate that IDH1/2 mutation status may identify patients that are likely to respond to pharmacologic BCL-2 inhibition and form the rational basis for combining agents that disrupt ETC activity with ABT-199 in future clinical studies.

    View details for DOI 10.1038/nm.3788

    View details for PubMedID 25599133

    View details for PubMedCentralID PMC4406275

  • Allogeneic hematopoietic cell transplant for normal karyotype AML: indirect evidence of selection for adverse molecular profile. Bone marrow transplantation 2015

    View details for DOI 10.1038/bmt.2015.62

    View details for PubMedID 25893457

  • Chemotherapy options for previously untreated acute myeloid leukemia EXPERT OPINION ON PHARMACOTHERAPY Lynch, R. C., Medeiros, B. C. 2015; 16 (14): 2149-2162

    Abstract

    Intensive chemotherapy with cytarabine and an anthracycline for untreated acute myeloid leukemia (AML) has remained largely unchanged over the past 40 years, despite many large trials examining the choice and dosing of these agents.We will review the major published clinical trials for untreated AML that have established the dosing choice and schedule for intensive therapy, as well as trials for patients not eligible for more intensive therapy. We will also discuss treatment considerations for subgroups of patients.While one or two cycles of anthracycline and cytarabine-based combination regimens remain the standard of care for younger and older patients with AML deemed fit to receive induction chemotherapy, controversy remains regarding the optimal selection and dosing schedule for anthracyclines. Low-intensity regimens, such as low-dose cytarabine and hypomethylating agents, can achieve a complete response even with adverse risk features, and can be used in a fit subset of older patients not eligible for clinical trial or transplant. Incorporation of new targeted agents, such as tyrosine kinase and small-molecule inhibitors, combined with better selection of drugs for unique patient cohorts, will likely be necessary to substantially improve outcomes in AML.

    View details for DOI 10.1517/14656566.2015.1076795

    View details for Web of Science ID 000361325200005

    View details for PubMedID 26364895

  • Monosomal karyotype acute myeloid leukemia: tread lightly. Acta haematologica Garcia, J. S., Medeiros, B. C. 2015; 133 (4): 324-326

    View details for DOI 10.1159/000368213

    View details for PubMedID 25503314

  • Disparities in early death and survival in children, adolescents and young adults with acute promyelocytic leukemia in California. Cancer 2015

    Abstract

    Findings from clinical trials and population-based studies have differed with regard to whether mortality within 30 days of diagnosis (early death) of acute promyelocytic leukemia (APL) has decreased in the era of all-trans retinoic acid and anthracycline-based chemotherapy.Using data from the California Cancer Registry, the authors investigated 7-day and 30-day mortality and survival in 772 patients who were aged birth to 39 years when they were diagnosed with APL during 1988 to 2011. Logistic regression and Cox proportional models were used to examine the association of early death and survival, respectively, with sociodemographic and clinical factors.The overall 30-day mortality decreased significantly over time, from 26% (1988-1995) to 14% (2004-2011) (P =.004). On multivariable analysis, the odds of 30-day mortality were 3 times as high during 1988 through 1995 than 2004 through 2011 (P =.001). However, 7-day mortality did not improve over time (P =.229). When patients who died within 7 days of diagnosis were excluded, the 30-day mortality during 1996 to 2011 was 3% to 8%, which is similar to levels reported in clinical trials. Higher early death and lower survival were associated with a lack of health insurance (1996-2011) (early death odds ratio, 2.67; P =.031) and Hispanic race/ethnicity (early death odds ratio, 2.13; P =.014). Early death was not found to be associated with age, sex, socioeconomic status, or hospital type. Black patients also experienced worse survival.The findings of the current study revealed a decreased 30-day mortality during the all-trans retinoic acid era, but 7-day mortality remained high. Efforts to achieve equal outcomes in young patients with APL should focus on improving access to effective treatment, mainly among uninsured patients and those of Hispanic and black race/ethnicity. Cancer 2015. © 2015 American Cancer Society.

    View details for DOI 10.1002/cncr.29631

    View details for PubMedID 26264598

  • Chemotherapy dose in obese AML patients: To cap or not to cap? LEUKEMIA RESEARCH Percival, M. M., Medeiros, B. C. 2015; 39 (1): 30-32
  • Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia. Leukemia 2015

    Abstract

    High levels of miR-155 are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is in part controlled by NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8 activating enzyme (NAE) presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. Since high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.Leukemia accepted article preview online, 14 May 2015. doi:10.1038/leu.2015.106.

    View details for DOI 10.1038/leu.2015.106

    View details for PubMedID 25971362

  • 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
  • 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

  • Polypharmacy in AML: the tip of the iceberg. Leukemia research Patel, S., Medeiros, B. C. 2014; 38 (11): 1378-1379

    View details for DOI 10.1016/j.leukres.2014.09.009

    View details for PubMedID 25293516

  • Management considerations in older patients with AML: a 2014 perspective. [Rinsho ketsueki] The Japanese journal of clinical hematology Medeiros, B. C. 2014; 55 (10): 1803-1807

    View details for PubMedID 25297743

  • Activity of SL-401, a targeted therapy directed to interleukin-3 receptor, in blastic plasmacytoid dendritic cell neoplasm patients. Blood Frankel, A. E., Woo, J. H., Ahn, C., Pemmaraju, N., Medeiros, B. C., Carraway, H. E., Frankfurt, O., Forman, S. J., Yang, X. A., Konopleva, M., Garnache-Ottou, F., Angelot-Delettre, F., Brooks, C., Szarek, M., Rowinsky, E. 2014; 124 (3): 385-392

    Abstract

    This is the first prospective study of treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic malignancy derived from plasmacytoid dendritic cells that typically involves the skin and rapidly progresses to a leukemia phase. Despite being initially responsive to intensive combination chemotherapy, most patients relapse and succumb to their disease. Because BPDCN blasts overexpress the interleukin-3 receptor (IL3R), the activity of SL-401, diptheria toxin (DT)388IL3 composed of the catalytic and translocation domains of DT fused to IL3, was evaluated in BPDCN patients in a phase 1-2 study. Eleven patients were treated with a single course of SL-401 at 12.5 μg/kg intravenously over 15 minutes daily for up to 5 doses; 3 patients who had initial responses to SL-401 received a second course in relapse. The most common adverse events including fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia were transient. Seven of 9 evaluable (78%) BPDCN patients had major responses including 5 complete responses and 2 partial responses after a single course of SL-401. The median duration of responses was 5 months (range, 1-20+ months). Further studies of SL-401 in BPDCN including those involving multiple sequential courses, alternate schedules, and combinations with other therapeutics are warranted. This trial is registered at clinicaltrials.gov as #NCT00397579.

    View details for DOI 10.1182/blood-2014-04-566737

    View details for PubMedID 24859366

  • European LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation BLOOD CANCER JOURNAL Medeiros, B. C., Tian, L., Robenson, S., Laport, G. G., JOHNSTON, L. J., Shizuru, J. A., Miklos, D. B., Arai, S., Benjamin, J. E., Weng, W., Negrin, R. S., Lowsky, R. 2014; 4

    View details for DOI 10.1038/bcj.2014.35

    View details for Web of Science ID 000337229900010

    View details for PubMedID 24879117

  • Mcl-1 dependence predicts response to vorinostat and gemtuzumab ozogamicin in acute myeloid leukemia LEUKEMIA RESEARCH Pierceall, W. E., Lena, R. J., Medeiros, B. C., Blake, N., Doykan, C., Elashoff, M., Cardone, M. H., Walter, R. B. 2014; 38 (5): 564-568

    Abstract

    Older adults with acute myeloid leukemia (AML) are commonly considered for investigational therapies, which often only benefit subsets of patients. In this study, we assessed whether BH3 profiling of apoptotic functionality could predict outcomes following treatment with vorinostat (histone deacetylase inhibitor) and gemtuzumab ozogamicin (GO; CD33-targeted immunoconjugate). Flow cytometry of BH3 peptide priming with Noxa (anti-apoptotic protein Mcl-1 modulator) correlated with remission induction (p=.026; AUC=0.83 [CI: 0.65-1.00; p=.00042]: AUC=0.88 [CI:0.75-1.00] with age adjustment) and overall survival (p=.027 logistic regression; AUC=0.87 [0.64-1.00; p=.0017]). This Mcl-1-dependence suggests a pivotal role of Bcl-2 family protein-mediated apoptosis to vorinostat/GO in AML patients.

    View details for DOI 10.1016/j.leukres.2014.02.007

    View details for Web of Science ID 000334763300008

    View details for PubMedID 24636337

  • Unsuccessful diagnostic cytogenetic analysis is a poor prognostic feature in acute myeloid leukaemia BRITISH JOURNAL OF HAEMATOLOGY Medeiros, B. C., Othus, M., Estey, E. H., Fang, M., Appelbaum, F. R. 2014; 164 (2): 245-250

    Abstract

    Chromosome banding analysis is the gold standard method for the identification of recurrent cytogenetic abnormalities in acute myeloid leukaemia (AML). It allows stratification of AML patients into subgroups with distinct responses to therapy and survival. Unfortunately, a variety of issues hamper cytogenetic evaluation in c. 10% of cases [unsuccessful cytogenetics (UC)] and the outcome of these patients is poorly understood. To better define the significance of UC in patients with AML, we compared the baseline characteristics and the prognostic impact of 94 (6%) patients, whose standard metaphase analysis yielded unacceptable results, to the remaining 1403 AML patients with successful cytogenetic analysis treated on successive Southwestern Oncology Group protocols. The incidence of UC increased with age, with peak incidence in patients older than 60 years. These patients had a lower response rate to induction chemotherapy (complete remission rate of 43%) and dismal 5-year survival rates (16%), which was especially poor in patients older than 60 years (<5%). The complete remission and survival rates were similar to those seen in patients with unfavourable karyotype. The early death rate was not increased. These results suggest that UC increases with age and predict for poor outcomes, similar to the outcomes of patients with unfavourable karyotype.

    View details for DOI 10.1111/bjh.12625

    View details for Web of Science ID 000329178100011

    View details for PubMedID 24383844

  • Senior Adult Oncology, Version 2.2014 JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hurria, A., Wildes, T., Blair, S. L., Browner, I. S., Cohen, H. J., deShazo, M., Dotan, E., Edil, B. H., Extermann, M., Ganti, A. K., Holmes, H. M., Jagsi, R., Karlekar, M. B., Keating, N. L., Korc-Grodzicki, B., McKoy, J. M., Medeiros, B. C., Mrozek, E., O'Connor, T., Rugo, H. S., Rupper, R. W., Silliman, R. A., Stirewalt, D. L., Tew, W. P., Walter, L. C., Weir, A. B., Bergman, M. A., Sundar, H. 2014; 12 (1): 82-126

    View details for Web of Science ID 000330333200009

    View details for PubMedID 24453295

  • Facts about FCE (Fludarabine, Cytarabine, Etoposide) in Acute Myeloid Leukemia. Acta haematologica Medeiros, B. C. 2014; 131 (4): 200-201

    View details for DOI 10.1159/000355134

    View details for PubMedID 24296429

  • Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study HAEMATOLOGICA Walter, R. B., Medeiros, B. C., Gardner, K. M., Orlowski, K. F., Gallegos, L., Scott, B. L., Hendrie, P. C., Estey, E. H. 2014; 99 (1): 54-59

    Abstract

    Epigenetic therapeutics such as the histone deacetylase inhibitor, vorinostat, and the DNA methyltransferase I inhibitor, azacitidine, enhance gemtuzumab ozogamicin efficacy in vitro. We therefore investigated vorinostat/azacitidine/gemtuzumab ozogamicin in 52 adults aged 50 years or over with acute myeloid leukemia requiring therapy for first relapse (remission duration ≤ 12 months) or primary refractory disease in a phase I/II trial. Vorinostat and gemtuzumab ozogamicin were escalated step-wise during the phase I portion of the trial. Vorinostat (400 mg/day orally from Days 1-9), azacitidine (75 mg/m(2)/day intravenously or subcutaneously from Days 1-7), and gemtuzumab ozogamicin (3 mg/m(2)/day intravenously on Days 4 and 8) were identified as the maximum tolerated dose. Among the 43 patients treated at this dose, 10 achieved a complete remission and 8 achieved a complete remission with incomplete blood count recovery, for an overall response rate of 41.9% (exact 95% confidence interval (CI): 27.0-57.9%). Four of these 18 patients (2 with complete remission and 2 with complete remission with incomplete blood count recovery) had persistence of minimal residual disease by flow cytometry at the time of best response. Four patients died within 28 days of treatment initiation. Median overall survival for the 18 patients achieving complete remission/complete remission with incomplete blood count recovery was significantly longer than for those 21 patients who failed therapy but lived at least 29 days after treatment initiation (224.5 days (range 70-798) vs. 95 days (range 36-900); P=0.0023). These data indicate that vorinostat/azacitidine/gemtuzumab ozogamicin has activity in this difficult-to-treat acute myeloid leukemia patient subset. (ClinicalTrials.gov: identifier 00895934).

    View details for DOI 10.3324/haematol.2013.096545

    View details for Web of Science ID 000335890500014

    View details for PubMedID 24142996

  • Hematopoietic Stem Cell Transplantation for Hematologic Malignancies in Older Adults: Geriatric Principles in the Transplant Clinic JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Wildes, T. M., Stirewalt, D. L., Medeiros, B., Hurria, A. 2014; 12 (1): 128-136

    Abstract

    Hematopoietic cell transplantation (HCT) provides a life-prolonging or potentially curative treatment option for patients with hematologic malignancies. Given the high transplant-related morbidity, these treatment strategies were initially restricted to younger patients, but are increasingly being used in older adults. The incidence of most hematologic malignancies increases with age; with the aging of the population, the number of potential older candidates for HCT increases. Autologous HCT (auto-HCT) in older patients may confer a slightly increased risk of specific toxicities (such as cardiac toxicities and mucositis) and have modestly lower effectiveness (in the case of lymphoma). However, auto-HCT remains a feasible, safe, and effective therapy for selected older adults with multiple myeloma and lymphoma. Similarly, allogeneic transplant (allo-HCT) is a potential therapeutic option for selected older adults, although fewer data exist on allo-HCT in older patients. Based on currently available data, age alone is not the best predictor of toxicity and outcomes; rather, the comorbidities and functional status of the older patient are likely better predictors of toxicity than chronologic age in both the autologous and allogeneic setting. A comprehensive geriatric assessment (CGA) in older adults being considered for either an auto-HCT or allo-HCT may identify additional problems or geriatric syndromes, which may not be detected during the standard pretransplant evaluation. Further research is needed to establish the utility of CGA in predicting toxicity and to evaluate the quality of survival in older adults undergoing HCT.

    View details for Web of Science ID 000330333200010

    View details for PubMedID 24453296

  • Senior adult oncology, version 2.2014: clinical practice guidelines in oncology . Journal of the National Comprehensive Cancer Network Hurria, A., Wildes, T., Blair, S. L., Browner, I. S., Cohen, H. J., deShazo, M., Dotan, E., Edil, B. H., Extermann, M., Ganti, A. K., Holmes, H. M., Jagsi, R., Karlekar, M. B., Keating, N. L., Korc-Grodzicki, B., McKoy, J. M., Medeiros, B. C., Mrozek, E., O'Connor, T., Rugo, H. S., Rupper, R. W., Silliman, R. A., Stirewalt, D. L., Tew, W. P., Walter, L. C., Weir, A. B., Bergman, M. A., Sundar, H. 2014; 12 (1): 82-126

    Abstract

    Cancer is the leading cause of death in older adults aged 60 to 79 years. The biology of certain cancers and responsiveness to therapy changes with the patient's age. Advanced age alone should not preclude the use of effective treatment that could improve quality of life or extend meaningful survival. The challenge of managing older patients with cancer is to assess whether the expected benefits of treatment are superior to the risk in a population with decreased life expectancy and decreased tolerance to stress. These guidelines provide an approach to decision-making in older cancer patients based on comprehensive geriatric assessment and also include diseasespecific issues related to age in the management of some cancer types in older adults.

    View details for PubMedID 24453295

  • Qualitative analysis of practicing oncologists' attitudes and experiences regarding collection of patient-reported outcomes. Journal of oncology practice / American Society of Clinical Oncology Jagsi, R., Chiang, A., Polite, B. N., Medeiros, B. C., McNiff, K., Abernethy, A. P., Zon, R., Loehrer, P. J. 2013; 9 (6): e290-7

    Abstract

    There is growing interest in incorporating routine collection of patient-reported outcomes (PROs) into cancer care. Practicing oncologists are a stakeholder group whose views are not well characterized.We developed an interview guide after literature review and in-depth interviews with leaders in the field. We conducted 45-minute semistructured interviews with a diverse sample of medical oncologists identified through affiliation with the Quality Oncology Practice Initiative or a minority-based Community Clinical Oncology Program until thematic saturation. Multiple analysts independently reviewed and thematically coded verbatim transcripts.Seventeen interviews were conducted with oncologists from 15 states. Emergent themes included variable understanding and experience with PROs. There was enthusiasm for the potential of PROs to improve the efficiency and thoroughness of the patient encounter. Fundamental concerns included information overload, possibility of identifying problems without access to intervention, depersonalization of the physician-patient encounter, cost, and inefficiency. Barriers identified included the need for buy-in from other stakeholders in the practice, lack of appropriate referral resources, staffing needs, and technology concerns. Few identified patient compliance, data sharing/privacy, or medical liability as a major barrier to implementation.Practicing oncologists had variable understanding of the details of PROs but, when introduced to the concept, recognized utility in improving the efficiency and thoroughness of the patient encounter if implemented properly. The time is right to begin pilot testing such measures with community oncologists so they can lend their expertise to national discussions on which measures to use and how best to use them.

    View details for DOI 10.1200/JOP.2012.000823

    View details for PubMedID 23943890

  • A single-center experience of the nationwide daunorubicin shortage: substitution with doxorubicin in adult acute lymphoblastic leukemia. Leukemia & lymphoma Patel, S., Liedtke, M., Ngo, D., Medeiros, B. C. 2013; 54 (10): 2231-2235

    Abstract

    Due to a national shortage of daunorubicin we evaluated the effects of substituting doxorubicin 1:1 in the induction phase for adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). We identified 10 patients receiving doxorubicin instead of daunorubicin as part of their induction on Cancer and Leukemia Group B (CALGB) 9511 or CALGB10403 and retrospectively compared them to 83 patients who received treatment on the same protocols with daunorubicin. Response rates were similar, independent of anthracycline received, with either CALGB9511 or CALGB10403. In either regimen, doxorubicin resulted in longer absolute neutrophil count (ANC) recovery time and hospitalization. Doxorubicin as part of CALGB9511 resulted in greater than three-fold higher mucositis. Sepsis and death during induction were significantly more frequent in patients who received doxorubicin on CALGB10403. While remission rates were similar, the use of doxorubicin was associated with prolonged neutropenia, higher risk of mucositis, infection and sepsis, and prolonged hospitalization. Higher induction mortality observed with doxorubicin substitution in this analysis needs further study.

    View details for DOI 10.3109/10428194.2013.772606

    View details for PubMedID 23383599

  • 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

  • CD11b expression and MK+ AML: A sign of impending doom? LEUKEMIA RESEARCH Medeiros, B. C. 2013; 37 (2): 121-121
  • 2-Hydroxyglutarate in IDH mutant acute myeloid leukemia: predicting patient responses, minimal residual disease and correlations with methylcytosine and hydroxymethylcytosine levels LEUKEMIA & LYMPHOMA Pollyea, D. A., Kohrt, H. E., Zhang, B., Zehnder, J., Schenkein, D., Fantin, V., Straley, K., Vasanthakumar, A., Abdel-Wahab, O., Levine, R., Godley, L. A., Medeiros, B. C. 2013; 54 (2): 408-410

    View details for DOI 10.3109/10428194.2012.701009

    View details for Web of Science ID 000313285400034

    View details for PubMedID 22680765

  • CD19(-)CD45(low/-)CD38(high)/CD138(+) plasma cells enrich for human tumorigenic myeloma cells LEUKEMIA Kim, D., Park, C. Y., Medeiros, B. C., Weissman, I. L. 2012; 26 (12): 2530-2537

    Abstract

    Multiple myeloma is a hematological neoplasm characterized by the accumulation of clonal plasma cells in the bone marrow. Its frequent relapse following achievement of clinical remissions implicates the existence of therapy-resistant myeloma-initiating cells. To date, results on the identity of myeloma-initiating cells have differed. Here, we prospectively identified a myeloma-initiating population by fractionating and transplanting patient bone marrow cells into human bone-bearing immunocompromised mice. Xenotransplantation of fractionated CD138(+)/CD38(high) cells from 40% of patients (8/20) led to a repopulation of CD19(+)CD38(low) or CD138(+)CD38(+) B-lineage cells in human bone grafts; and these grafts were clonally derived from patient myeloma cells. Meanwhile, CD19(+)CD38(low) xenografts were detected in human bone-bearing mice transplanted with CD19(+)CD38(low/-) B cells from 8 of 22 samples but were not clonally related to patient myeloma cells. Further fractionation and xenotransplantation of CD138(+)CD38(high) cells demonstrated that (CD45(low/-) or CD19(-)) CD38(high)/CD138(+) plasma cells, but not (CD45(high) or CD19(+)) CD38(high)/CD138(+) plasmablasts enrich for myeloma-initiating cells. Quantitative reverse transcription-PCR of two serially transplantable xenografts, which were CD19(-)CD138(+), revealed that they were Pax5 (a B-cell-specific transactivator)-negative. These results suggest that CD19(-)CD45(low/-) fully differentiated plasma cells enrich for long-lived and tumor-initiating cells whereas B cells or plasmablasts do not.

    View details for DOI 10.1038/leu.2012.140

    View details for Web of Science ID 000312186000012

    View details for PubMedID 22733078

  • 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
  • Multicenter Phase 2 Trial of G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Becker, P. S., Medeiros, B. C., Stein, A. S., Appelbaum, F. R., Scott, B. L., Delaney, C., Othus, M., Hendrie, P. C., Gardner, K. M., Petersdorf, S., Pagel, J. M., Walter, R. B., Parks, C., Estey, E. H. 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
  • Hemophagocytic lymphohistiocytosis in pregnancy: a case report and review of treatment options HEMATOLOGY Dunn, T., Cho, M., Medeiros, B., Logan, A., Ungewickell, A., Liedtke, M. 2012; 17 (6): 325-328

    Abstract

    Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening inflammatory disorder characterized by uncontrolled proliferation and activation of histiocytes with phagocytosis of normal hematopoietic cells. A 41-year-old woman, 19 weeks pregnant with twins, and a history of Still's disease, presented with rash, fever, and headache. Laboratory studies revealed transaminitis, hyperbilirubinemia, and eventually severe neutropenia as well as elevations in ferritin, lactate dehydrogenase, and C-reactive protein. A bone marrow biopsy confirmed HLH. She declined standard HLH-treatment but responded well to high-dose corticosteroids. Her blood counts remained stable following corticosteroid taper, and she delivered healthy twin girls at 30-week gestation. Few cases of HLH during pregnancy have been reported. In some cases, the condition has proved fatal. Therefore recognizing signs and symptoms of HLH is essential to avoid treatment delay. In our case, high-dose corticosteroids alone were a safe and effective therapy for the mother and fetuses resulting in long-term disease control.

    View details for DOI 10.1179/1607845412Y.0000000007

    View details for Web of Science ID 000311490800004

    View details for PubMedID 23168071

  • Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma, Version 2.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Bensinger, W., Biermann, J. S., Cohen, A. D., Devine, S., Djulbegovic, B., Faber, E. A., Gasparetto, C., Hernandez-Ilizaliturri, F., Huff, C. A., Kassim, A., Krishnan, A. Y., Medeiros, B. C., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Tricot, G., Weber, D. M., Yahalom, J., Yunus, F., Kumar, R., Shead, D. A. 2012; 10 (10): 1211-1219
  • Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma, version 2.2013. Journal of the National Comprehensive Cancer Network Anderson, K. C., Alsina, M., Bensinger, W., Biermann, J. S., Cohen, A. D., Devine, S., Djulbegovic, B., Faber, E. A., Gasparetto, C., Hernandez-Ilizaliturri, F., Huff, C. A., Kassim, A., Krishnan, A. Y., Medeiros, B. C., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Tricot, G., Weber, D. M., Yahalom, J., Yunus, F., Kumar, R., Shead, D. A. 2012; 10 (10): 1211-1219

    Abstract

    These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenström's Macroglobulinemia/Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth international workshop on Waldenström's Macroglobulinemia, and a section on management of peripheral neuropathy in the accompanying discussion.

    View details for PubMedID 23054875

  • Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia AMERICAN JOURNAL OF HEMATOLOGY Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A., Bates, J., Sekeres, M. A., Coutre, S., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. 2012; 87 (10): 957-960

    Abstract

    We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ≥350 cells/μL at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/μL (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ≥350 cells/μL on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/μL (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/μL vs. ≥350 cells/μL, P ≤ .0004 for OS and EFS) along with WBC at diagnosis (≤6.0 or >30.0 K/μL vs. >6.0-30.0 K/μL, P ≤ 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.

    View details for DOI 10.1002/ajh.23279

    View details for Web of Science ID 000309065700081

    View details for PubMedID 22729847

  • Impact of body-mass index on the outcome of adult patients with acute myeloid leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Medeiros, B. C., Othus, M., Estey, E. H., Fang, M., Appelbaum, F. R. 2012; 97 (9): 1401-1404

    Abstract

    Obesity increases the risk of treatment-related complications and reduces survival in children with acute myeloid leukemia. Little is known about the impact of obesity on the outcome of adult patients with acute myeloid leukemia.We compared the baseline characteristics and effect on treatment and survival in 1,974 previously untreated adult patients with acute myeloid leukemia undergoing treatment, according to international classification of body-mass index.The median body-mass index was 26.7 (15.5-61) and 63% of patients were overweight/obese. After adjustment for other confounders, such as age, gender, performance status, karyotype, white blood cell, platelet and peripheral blast counts, obese patients had better complete remission rates (P=0.0046), lower rates of resistant disease (P=0.038) but similar rates of survival and severe adverse events.In the treatment of acute myeloid leukemia in adults, obesity was associated with increased response rates and no apparent increase in toxicity. Obesity should not, therefore, be a criterion for excluding patients from aggressive therapy.

    View details for DOI 10.3324/haematol.2011.056390

    View details for Web of Science ID 000308908300020

    View details for PubMedID 22315487

  • Novel agents in acute myeloid leukemia INTERNATIONAL JOURNAL OF HEMATOLOGY Ungewickell, A., Medeiros, B. C. 2012; 96 (2): 178-185

    Abstract

    Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, long-term survivors represent only 10-15 % of all AML patients older than 60 years of age and <10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

    View details for DOI 10.1007/s12185-012-1151-5

    View details for Web of Science ID 000307764900006

    View details for PubMedID 22907734

  • New treatment approaches for older adults with multiple myeloma JOURNAL OF GERIATRIC ONCOLOGY Wildes, T. M., Vij, R., Petersdorf, S. H., Medeiros, B. C., Hurria, A. 2012; 3 (3): 279-290
  • Blood consult: monosomal karyotype acute myeloid leukemia BLOOD Garcia, J. S., Medeiros, B. C., Appelbaum, F. R. 2012; 119 (24): 5659-5660

    View details for DOI 10.1182/blood-2012-01-405225

    View details for Web of Science ID 000307396500015

    View details for PubMedID 22498746

  • Impact of residual normal metaphases in core binding factor acute myeloid leukemia CANCER Medeiros, B. C., Othus, M., Fang, M., Appelbaum, F. R., Estey, E. H. 2012; 118 (9): 2420-2423

    Abstract

    Karyotype allows for stratification of outcomes in acute myeloid leukemia (AML) patients. Previous data suggested that the presence of residual normal cells improved the prognosis in patients with monosomy 7. The Southwest Oncology Group (SWOG) reported the impact of residual normal metaphases in AML patients with monosomal karyotype (MK) and found a similar relationship. We determined the influence of residual normal metaphases in patients with core binding factor (CBF) AML.The presence and total number of normal and abnormal metaphases were tallied for patients with CBF AML treated in 10 consecutive SWOG trials and used as a variable to determine the effect on complete remission, refractory disease, and overall survival (OS) rates.Among 113 CBF AML patients, median age of diagnosis was 45 years (range, 18-77 years), and median OS was 4 years (CI-2 years-not reached). Patients with inv(16) and no normal metaphases had improved OS compared with those with 1+ normal metaphases (P = .00005), whereas no difference was noted for patients with t(8;21). Multivariate analysis demonstrated that having cells with a normal karyotype had a negative impact on survival (HR, 2.11; 95% CI, 1.09-4.08; P = .026). This shorter survival was a consequence of a higher rate of refractory disease in older patients (OR, 1.03; 95% CI, 0.9998-1.06; P = .05) and in those with normal metaphases (HR, 1.26 95% CI, 1.04-1.51; P = .02).In patients with CBF AML, the presence of cells with normal metaphases and increasing age negatively affect the prognosis, especially in patients with inv(16).

    View details for DOI 10.1002/cncr.26557

    View details for Web of Science ID 000303044600011

    View details for PubMedID 21928314

  • Aggressive EBV-associated Lymphoproliferative Disorder: A Prodrome to Diffuse Large B-cell Lymphoma? APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Batra, R., Medeiros, B. C., Zehnder, J. L., Warnke, R. A., Natkunam, Y. 2012; 20 (3): 325-330

    Abstract

    A 19-year-old male patient presented with intermittent high fever and left cervical lymphadenopathy. The lymph node biopsy findings were interpreted as "Epstein-Barr virus (EBV)-associated lymphoproliferative disorder consistent with infectious mononucleosis." No molecular studies were performed at that time. The patient was followed without treatment. Five months later, the patient again presented with fever, lymphadenopathy, and splenomegaly. The lymph node biopsy showed features of a diffuse large B-cell lymphoma. Molecular studies on this lymph node biopsy showed a clonal EBV population, although polymerase chain reaction studies failed to reveal a clonal B-cell or T-cell population. A concurrent bone marrow biopsy showed features consistent with hemophagocytic syndrome. He had elevated ferritin, soluble interleukin-2 receptors and persistent EBV viremia. The patient responded to Rituxan for a short period with undetectable EBV levels. Subsequent right cervical lymph node, liver, and jejunal biopsies showed involvement by diffuse large B-cell lymphoma and the patient expired soon thereafter.

    View details for Web of Science ID 000303140100012

    View details for PubMedID 22505014

  • Phase II trial of vorinostat and gemtuzumab ozogamicin as induction and post-remission therapy in older adults with previously untreated acute myeloid leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Walter, R. B., Medeiros, B. C., Powell, B. L., Schiffer, C. A., Appelbaum, F. R., Estey, E. H. 2012; 97 (5): 739-742

    Abstract

    Histone deacetylase inhibitors such as vorinostat enhance gemtuzumab ozogamicin efficacy in vitro. We, therefore, investigated vorinostat+gemtuzumab ozogamicin for adults aged 60 years and over with untreated acute myeloid leukemia. We stratified patients into 2 groups (group 1: patients aged ≥ 70 years and performance status 2-3; group 2: aged 60-69 years with performance status 0-3 or aged ≥ 70 years and performance status 0-1). Responses were monitored separately in group 2 patients with normal or favorable cytogenetics (group 2A) and other cytogenetics (group 2B). Among 31 patients, 6 (19.4%) achieved complete remission, and one (3.2%) achieved complete remission with incomplete platelet recovery; these patients had a higher median overall survival than non-responders (553 vs. 131 days, P = 0.0026). Response rates were: group 1, one of 10 (10.0%); group 2A, 6 of 13 (46.2%); and group 2B, none of 8 (0%). These data indicate that vorinostat+gemtuzumab ozogamicin has activity that is mostly confined to patients with normal karyotype disease. ClinicalTrial.gov: NCT00673153.

    View details for DOI 10.3324/haematol.2011.055822

    View details for Web of Science ID 000304669000020

    View details for PubMedID 22133771

  • Unveiling the complexity of CK+ AML. Blood Medeiros, B. C. 2012; 119 (9): 1958-1959

    Abstract

    In acute myeloid leukemia (AML), cytogenetic abnormalities are present in more than half of patients and these chromosomal alterations are critical factors that determine response to chemotherapy and survival.

    View details for DOI 10.1182/blood-2012-01-401505

    View details for PubMedID 22383788

  • "It doesn't matter if you're black or white", does it? LEUKEMIA RESEARCH Medeiros, B. C. 2012; 36 (2): 127-127
  • Senior Adult Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Hurria, A., Browner, I. S., Cohen, H. J., Denlinger, C. S., deShazo, M., Extermann, M., Ganti, A. K., Holland, J. C., Holmes, H. M., Karlekar, M. B., Keating, N. L., Mckoy, J., Medeiros, B. C., Mrozek, E., O'Connor, T., Petersdorf, S. H., Rugo, H. S., Silliman, R. A., Tew, W. P., Walter, L. C., Weir, A. B., Wildes, T. 2012; 10 (2): 162-209

    View details for Web of Science ID 000300067400005

    View details for PubMedID 22308515

  • 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

  • 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

  • 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

  • Phase 2 Trial of G-CSF Priming, Clofarabine, and High Dose Cytarabine (GCLAC) for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML) or Advanced Myelodysplastic Syndrome or Advanced Myeloproliferative Neoplasm 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Becker, P. S., Medeiros, B. C., Appelbaum, F. R., Scott, B. L., Hendrie, P. C., Storer, B., Pierce, S., Petersdorf, S. H., Estey, E. H. AMER SOC HEMATOLOGY. 2011: 1545–45
  • Multiple Myeloma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Bensinger, W., Biermann, J. S., Chanan-Khan, A., Cohen, A. D., Devine, S., Djulbegovic, B., Faber, E. A., Gasparetto, C., Huff, C. A., Kassim, A., Medeiros, B. C., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Treon, S. P., Tricot, G., Weber, D. M., Yahalom, J., Yunus, F. 2011; 9 (10): 1146-1183

    View details for Web of Science ID 000295721800005

    View details for PubMedID 21975914

  • Unfavorable-risk cytogenetics in acute myeloid leukemia EXPERT REVIEW OF HEMATOLOGY Hong, W., Medeiros, B. C. 2011; 4 (2): 173-184

    Abstract

    Cytogenetic analysis at diagnosis is one of the most significant prognostic factors in acute myeloid leukemia (AML). AML patients with unfavorable-risk cytogenetic abnormalities account for 16-30% of younger adult patients and have poor response to standard treatment, with only 32-55% achieving a complete response. Overall survival is also extremely poor with only 5-12% patients alive at 5-10 years after diagnosis. Owing to the poor response in this subset of patients, risk-adapted treatment has been investigated. Allogeneic stem cell transplant has been shown to provide a survival benefit in patients with unfavorable-risk cytogenetic abnormalities in complement receptor 1. Other risk-adapted treatment strategies, such as reduced-intensity conditioning regimens prior to allogeneic stem cell transplant for older patients with AML, have also shown some survival benefit, without increasing treatment-related toxicities. Risk-stratification models that include cytogenetic abnormalities, as well as other molecular markers, are being developed to allow for individualized risk-adapted treatment for patients with AML. Prospective multicenter trials will be needed to validate these prognostic models.

    View details for DOI 10.1586/EHM.11.10

    View details for Web of Science ID 000290371000014

    View details for PubMedID 21495927

  • Acute myeloid leukaemia in the elderly: a review BRITISH JOURNAL OF HAEMATOLOGY Pollyea, D. A., Kohrt, H. E., Medeiros, B. C. 2011; 152 (5): 524-542

    Abstract

    The majority of patients with acute myeloid leukaemia (AML) are elderly. Advancements in supportive care and regimen intensification have resulted in improvements in clinical outcomes for younger AML patients, but analogous improvements in older patients have not been realized. While outcomes are compromised by increased comorbidities and susceptibility to toxicity from therapy, it is now recognized that elderly AML represents a biologically distinct disease that is more aggressive and less responsive to therapy. Some patients tolerate and benefit from intensive remission-induction approaches, while others are best managed with less aggressive strategies. The challenge is to differentiate these groups based on host-related and biological features, in order to maximize the therapeutic benefit and minimize toxicity. As more is understood about the complicated pathogenesis and molecular basis of AML, there are more opportunities to develop and test targeted therapies. Elderly patients, with their narrow therapeutic window, are well positioned to derive a benefit from these novel agents, and therefore, despite a difficult past, there are reasons to be optimistic about the future of elderly AML.

    View details for DOI 10.1111/j.1365-2141.2010.08470.x

    View details for Web of Science ID 000287315600003

    View details for PubMedID 21314823

  • Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer EXPERT OPINION ON THERAPEUTIC TARGETS Wang, M., Medeiros, B. C., Erba, H. P., DeAngelo, D. J., Giles, F. J., Swords, R. T. 2011; 15 (3): 253-264

    Abstract

    The NEDD8 (neural precursor cell-expressed developmentally downregulated 8) conjugation pathway regulates the post-translational modification of oncogenic proteins. This pathway has important potential for cancer therapeutics. Several proteins vital in cancer biology are regulated by protein neddylation. These observations led to the development of a small molecule inhibitor that disrupts protein neddylation and leads to cancer cell death and important activity in early phase clinical trials.This review provides an extensive coverage of cellular protein homeostasis with particular emphasis on the NEDD8 conjugation pathway. Insights into a new investigational drug that specifically disrupts the NEDD8 pathway are discussed. The clinical data for this agent are also updated.Neddylation controls key cellular pathways found to be dysregulated in many cancers. Protein neddylation is a relatively under-explored pathway for pharmacologic inhibition in cancer. Selective disruption of this pathway has demonstrated clinical activity in patients with myeloid neoplasms and is worth exploring further in combination with other anti-leukemia agents.

    View details for DOI 10.1517/14728222.2011.550877

    View details for Web of Science ID 000287203500003

    View details for PubMedID 21219242

  • Microfluidic purification and analysis of hematopoietic stem cells from bone marrow LAB ON A CHIP Schirhagl, R., Fuereder, I., Hall, E. W., Medeiros, B. C., Zare, R. N. 2011; 11 (18): 3130-3135

    Abstract

    Hematopoietic stem cells are larger in size than other cells present in bone marrow, with the exception of monocytes. This distinguishing characteristic can be used to separate them from a whole-marrow sample. A microfluidic device was fabricated using an integrated membrane that is porous at defined areas. This allows for simultaneous valving and filtering functionality, which is crucial for preventing irreversible clogging. This device, as well as a separation procedure, was optimized in this work to enrich hematopoietic progenitor cells from diluted bone marrow of leukemia patients without any additional sample preparation. An enrichment of up to 98% was achieved with this method and the process was scaled up to 17.2 μL min(-1) of processed sample. Additionally, stem cells were stained with specific antibodies for further analysis. Using a custom-made computer program, the filter was scanned to characterize and quantify cells based on fluorescence. The results were evaluated by comparing them against the results obtained from flow cytometry, confocal microscopy, and Coulter counting.

    View details for DOI 10.1039/c1lc20353c

    View details for Web of Science ID 000294263400013

    View details for PubMedID 21799976

  • 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
  • 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
  • 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

  • Plasma cell leukemia: concepts and management. Expert review of hematology Liedtke, M., Medeiros, B. C. 2010; 3 (5): 543-549

    Abstract

    Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia. Patients with PCL have a very poor prognosis with median survival measured in months. PCL can present de novo or following a prodrome of plasma cell myeloma. Patients with PCL tend to present with aggressive clinical features, such as extramedullary disease, bone marrow failure, advanced stage disease and expression of distinct immunophenotypic markers, such as lack of CD56 and presence of CD20. Historically, the treatment of PCL has primarily been palliative, with only a small minority of patients achieving a durable remission. The impact of newer agents, such as bortezomib and lenalidomide, in conjunction with autologous and allogeneic stem cell transplantation is uncertain, but emerging data suggest that use of these modalities may help improve the poor prognosis of patients with PCL.

    View details for DOI 10.1586/ehm.10.52

    View details for PubMedID 21083471

  • Plasma cell leukemia: concepts and management EXPERT REVIEW OF HEMATOLOGY Liedtke, M., Medeiros, B. C. 2010; 3 (5): 539-549

    View details for DOI 10.1586/EHM.10.52

    View details for Web of Science ID 000284746200008

  • 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 Web of Science ID 000280562800011

    View details for PubMedID 20658589

  • PHASE 2 TRIAL OF VORINOSTAT (SAHA) IN COMBINATION WITH GEMTUZUMAB OZOGAMICIN AS INDUCTION AND POST-REMISSION THERAPY IN OLDER PATIENTS WITH PREVIOUSLY UNTREATED ACUTE MYELOID LEUKEMIA (AML) 15th Annual Meeting of the European-Hematology-Association Walter, B., Medeiros, B., Nielsen-Stoeck, M., Harrington, E., Powell, B., Schiffer, C., Appelbaum, F., Estey, E. FERRATA STORTI FOUNDATION. 2010: 29–30
  • Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) LEUKEMIA RESEARCH Medeiros, B. C., Kohrt, H. E., Arber, D. A., Bangs, C. D., Cherry, A. M., Majeti, R., Kogel, K. E., Azar, C. A., Patel, S., Alizadeh, A. A. 2010; 34 (5): 594-597

    Abstract

    Immunophenotypic identification of myeloid specific antigens is an important diagnostic tool in the management of patients with acute myeloid leukemia (AML). These antigens allow determination of cell of origin and degree of differentiation of leukemia blasts. AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a relatively rare subtype of AML. The immunophenotypic characteristics of inv(3) AML patients are somewhat limited. We identified 14 new cases of hematological disorders with increased myeloid blasts carrying inv(3)(q21q26.2)/t(3;3)(q21;q26.2). Also, we identified another 13 cases previously published in the literature, where the immunophenotype of inv(3)(q21q26.2) was documented. As a group, patients with AML with inv(3)(q21q26.2) had high levels of early myeloid (CD13, CD33, CD117 and MPO) and uncommitted markers (CD34, HLA-DR and CD56) and a high rate of monosomy 7 in addition to the inv(3)(q21q26.2). Differential karyotype and expression of certain antigens were noted in patients with de novo AML with inv(3)(q21q26.2) vs. those with inv(3)(q21q26.2)-containing blasts.

    View details for DOI 10.1016/j.leukres.2009.08.029

    View details for Web of Science ID 000276945300009

    View details for PubMedID 19781775

  • 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
  • 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
  • Thalidomide-induced pneumonitis in a patient with plasma cell leukemia: No recurrence with subsequent lenalidomide therapy AMERICAN JOURNAL OF HEMATOLOGY Pretz, J., Medeiros, B. C. 2009; 84 (10): 698-699

    View details for DOI 10.1002/ajh.21495

    View details for Web of Science ID 000270744300022

    View details for PubMedID 19691102

  • NCCN clinical practice guidelines in oncology: multiple myeloma. Journal of the National Comprehensive Cancer Network Anderson, K. C., Alsina, M., Bensinger, W., Biermann, J. S., Chanan-Khan, A., Cohen, A. D., Devine, S., Djulbegovic, B., Gasparetto, C., Huff, C. A., Jagasia, M., Medeiros, B. C., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Tricot, G., Vose, J. M., Weber, D., Yahalom, J., Yunus, F. 2009; 7 (9): 908-942

    View details for PubMedID 19878637

  • Multiple Myeloma JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Anderson, K. C., Alsina, M., Bensinger, W., Biermann, S., Chanan-Khan, A., Cohen, A. D., Devine, S., Djulbegovic, B., Gasparetto, C., Huff, C. A., Jagasia, M., Medeiros, B. C., Meredith, R., Raje, N., Schriber, J., Singhal, S., Somlo, G., Stockerl-Goldstein, K., Tricot, G., Vose, J. M., Weber, D., Yahalom, J., Yunus, F. 2009; 7 (9): 908-942
  • 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
  • Deletion of IKZF1 and Prognosis in Acute Lymphoblastic Leukemia NEW ENGLAND JOURNAL OF MEDICINE Medeiros, B. C. 2009; 360 (17): 1787-1787

    View details for Web of Science ID 000265377800016

    View details for PubMedID 19387020

  • Role of CEBPA in Normal Karyotype Acute Myeloid Leukemia JOURNAL OF CLINICAL ONCOLOGY Medeiros, B. C. 2009; 27 (12): 2105-2105

    View details for DOI 10.1200/JCO.2008.21.5418

    View details for Web of Science ID 000266194700034

    View details for PubMedID 19273693

  • Comparing Apples and Oranges in Normal Karyotype Acute Myeloid Leukemia JOURNAL OF CLINICAL ONCOLOGY Medeiros, B. C. 2009; 27 (3): 474-474

    View details for DOI 10.1200/JCO.2008.19.3011

    View details for Web of Science ID 000262499100031

    View details for PubMedID 19075259

  • 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

  • Complete remission of primary plasma cell leukemia with bortezomib, doxorubicin, and dexamethasone: a case report. Cases journal Chan, S. M., George, T., Cherry, A. M., Medeiros, B. C. 2009; 2 (1): 121-?

    Abstract

    Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder considered to be a variant of multiple myeloma. It is an aggressive disease with a poor clinical response to standard chemotherapeutic agents.A novel regimen consisting of bortezomib, doxorubicin, and dexamethasone is currently under active evaluation for the treatment of multiple myeloma. We employed this combination as front-line chemoinduction therapy for a case of primary PCL.Complete remission was achieved with rapid normalization of hematologic parameters. The combination of bortezomib, doxorubicin and dexamethasone demonstrates promise in the treatment of PCL.

    View details for DOI 10.1186/1757-1626-2-121

    View details for PubMedID 19192311

  • Reversible high-output cardiac failure, an unusual marker of disease status in multiple myeloma LEUKEMIA & LYMPHOMA Kohrt, H., Logan, A., Temmins, C., Witteles, R., Liedtke, M., Medeiros, B. 2008; 49 (3): 581-585

    View details for DOI 10.1080/10428190701861702

    View details for Web of Science ID 000253513300029

    View details for PubMedID 18297538

  • Inv (11)(p15q21) in donor-derived Ph-negative cells in a patient with chronic myeloid leukemia in relapse successfully treated with imatinib mesylate post allogeneic stem cell transplantation AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Chun, K., Kamel-Reid, S., Lipton, J. 2007; 82 (8): 758-760

    Abstract

    Imatinib mesylate (IM) is the standard first-line treatment for patients with chronic myeloid leukemia (CML). Surprisingly, 2-15% of patients achieving a complete cytogenetic response develop cytogenetic abnormalities in Philadelphia (Ph)-negative cells. Following hematopoietic stem cell transplantation (HSCT), IM induces complete molecular responses (CMR) in approximately 70% patients with relapsed CML, and no IM-related cytogenetic abnormalities in Ph-negative donor-derived cells have been described after HSCT. We report a 56-year-old female who presented with a relapse from CML in September 2002. She had received a matched related HSCT for CML in chronic phase. Donor lymphocyte infusion was given 3 years post-HSCT for a relapse. Sustained CMR was achieved within 3 months of initiation of IM. In October 2005, routine evaluation demonstrated continuous CMR, full male donor engraftment and an inv (11) on donor cells. Evaluation of the donor demonstrated no dysplasia or cytogenetic abnormalities. This observation reinforces the possibility that IM therapy may be casually linked to the phenomenon of secondary cytogenetic changes in diploid cells.

    View details for DOI 10.1002/ajh.20882

    View details for Web of Science ID 000248749300016

    View details for PubMedID 17301975

  • Absence of FTL3 mutations in patients with JAK2(V617F) mutation negative essential thrombocythemia AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Zhang, T., Lipton, J. H., Kamel-Reid, S. 2007; 82 (4): 293-294

    Abstract

    A common point mutation in the JAK2 tyrosine kinase leads to constitutive hematopoietic growth factor receptor signaling and was recently described in many patients with myeloproliferative disorders (MPDs). However, this JAK2 mutation is present in only a subset (35-50%) of patients with essential thrombocythemia (ET). Thus, the proliferative signals responsible for MPDs in the absence of JAK2 mutations remain largely unknown. Despite intriguing pre-clinical data, where transgenic mice overexpressing FLT3-ITD developed a MPD resembling ET, none of the patient samples from ET patients who were JAK2(V617F)-negative demonstrated the presence of activating mutations in the FLT3 receptor.

    View details for DOI 10.1002/ajh.20765

    View details for Web of Science ID 000245464400008

    View details for PubMedID 17013813

  • Characteristics and outcomes of acute myelogenous leukemia patients with very late relapse (> 5 years) LEUKEMIA & LYMPHOMA Medeiros, B. C., Minden, M. D., Schuh, A. C., Schimmer, A. D., Yee, K., Lipton, J. H., Messner, H. A., Gupta, V., Chun, K., Xu, W., Das, P., Kamel-Reid, S., Brandwein, J. M. 2007; 48 (1): 65-71

    Abstract

    The clinical characteristics and outcome of 15 patients with acute myelogenous leukemia (AML) who experienced relapse at least 5 years after induction of complete remission (very late-relapse AML) are described. This subgroup represented 3% of all relapsed patients seen at this institution over the same time period. There were eight males in this cohort and the median age at diagnosis was 48 years (range 13 - 77 years). Nine patients had M4/M5 French - American - British (FAB) classification subtype and most had intermediate risk cytogenetics. The median duration of first complete remission (CR-1) was 9 years (range 5.2 - 11.5 years). Thirteen patients (86%) achieved CR-2 with reinduction therapy. The 5-year relapse-free survival and overall survival rates of this cohort were 59% and 51%, respectively. We conclude that very late-relapse AML is a rare event, and that reinduction in these patients is associated with very high CR rates and a potential cure fraction.

    View details for DOI 10.1080/10428190601043252

    View details for Web of Science ID 000244249900011

    View details for PubMedID 17325849

  • Transfusion-related acute lung injury (TRALI) following platelet transfusion in a patient receiving high-dose Interleukin-2 for treatment of metastatic renal cell carcinoma TRANSFUSION AND APHERESIS SCIENCE Medeiros, B. C., Kogel, K. E., Kane, M. A. 2003; 29 (1): 25-27

    Abstract

    Transfusion-related acute lung injury (TRALI) is an uncommon life-threatening complication of hemotherapy. It is hypothesized to be the result of two independent insults: the first related to the clinical status of the patient and the second to the infusion of biologic response modifiers within blood components. We present a case of TRALI in a patient who received high-dose Interleukin-2 (IL-2) as treatment for metastatic renal cell carcinoma, where IL-2 is speculated to have been the first insult and transfusion of platelet concentrate the second. This is the first reported case of TRALI complicating treatment with high-dose immunotherapy.

    View details for DOI 10.1016/S1473-0502(03)00094-6

    View details for Web of Science ID 000184768900007

    View details for PubMedID 12877889