Bruno Medeiros

All Publications

• Functional genomic landscape of acute myeloid leukaemia. Nature Tyner, J. W., Tognon, C. E., Bottomly, D., Wilmot, B., Kurtz, S. E., Savage, S. L., Long, N., Schultz, A. R., Traer, E., Abel, M., Agarwal, A., Blucher, A., Borate, U., Bryant, J., Burke, R., Carlos, A., Carpenter, R., Carroll, J., Chang, B. H., Coblentz, C., d'Almeida, A., Cook, R., Danilov, A., Dao, K. T., Degnin, M., Devine, D., Dibb, J., Edwards, D. K., Eide, C. A., English, I., Glover, J., Henson, R., Ho, H., Jemal, A., Johnson, K., Johnson, R., Junio, B., Kaempf, A., Leonard, J., Lin, C., Liu, S. Q., Lo, P., Loriaux, M. M., Luty, S., Macey, T., MacManiman, J., Martinez, J., Mori, M., Nelson, D., Nichols, C., Peters, J., Ramsdill, J., Rofelty, A., Schuff, R., Searles, R., Segerdell, E., Smith, R. L., Spurgeon, S. E., Sweeney, T., Thapa, A., Visser, C., Wagner, J., Watanabe-Smith, K., Werth, K., Wolf, J., White, L., Yates, A., Zhang, H., Cogle, C. R., Collins, R. H., Connolly, D. C., Deininger, M. W., Drusbosky, L., Hourigan, C. S., Jordan, C. T., Kropf, P., Lin, T. L., Martinez, M. E., Medeiros, B. C., Pallapati, R. R., Pollyea, D. A., Swords, R. T., Watts, J. M., Weir, S. J., Wiest, D. L., Winters, R. M., McWeeney, S. K., Druker, B. J. 2018

  Abstract

  The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

  View details for PubMedID 30333627

• CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Lancet, J. E., Uy, G. L., Cortes, J. E., Newell, L. F., Lin, T. L., Ritchie, E. K., Stuart, R. K., Strickland, S. A., Hogge, D. n., Solomon, S. R., Stone, R. M., Bixby, D. L., Kolitz, J. E., Schiller, G. J., Wieduwilt, M. J., Ryan, D. H., Hoering, A. n., Banerjee, K. n., Chiarella, M. n., Louie, A. C., Medeiros, B. C. 2018: JCO2017776112

  Abstract

  Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

  View details for PubMedID 30024784

• 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

• 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

• 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. n., Geyer, S. n., Bloomfield, C. D., Thiede, C. n., Prior, T. W., Döhner, K. n., Marcucci, G. n., Lo-Coco, F. n., Klisovic, R. B., Wei, A. n., Sierra, J. n., Sanz, M. A., Brandwein, J. M., de Witte, T. n., Niederwieser, D. n., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Krauter, J. n., Schlenk, R. F., Ganser, A. n., Serve, H. n., Ehninger, G. n., Amadori, S. n., Larson, R. A., Döhner, H. n. 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 PubMedID 28644114

• 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. n., Sengeløv, H. n., Medeiros, B. C., Kjeldsen, L. n., 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 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 Granfeldt Østgård, L. S., Medeiros, B. C., Sengeløv, H. n., Nørgaard, M. n., Andersen, M. K., Dufva, I. H., Friis, L. S., Kjeldsen, E. n., Marcher, C. W., Preiss, B. n., Severinsen, M. n., Nørgaard, J. M. 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 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

• A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML. Leukemia Garcia-Manero, G., Podoltsev, N. A., Othus, M., Pagel, J. M., Radich, J. P., Fang, M., Rizzieri, D. A., Marcucci, G., Strickland, S. A., Litzow, M. R., Savoie, M. L., Medeiros, B. C., Sekeres, M. A., Lin, T. L., Uy, G. L., Powell, B. L., Kolitz, J. E., Larson, R. A., Stone, R. M., Claxton, D., Essell, J., Luger, S. M., Mohan, S. R., Moseley, A., Appelbaum, F. R., Erba, H. P. 2023

  Abstract

  Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.).

  View details for DOI 10.1038/s41375-023-02073-x

  View details for PubMedID 37935977

  View details for PubMedCentralID 3545649

• Novel Data Analytics Identify Predictors of Quality-of-Life Trajectories in Patients with AML or High-Risk Myeloid Neoplasms Gauthier, J., Furtuna, B., Mangiavacchi, J., Gholami, S., Ferres, J., Dodhia, R., Fathi, A. T., Brunner, A. M., Gerds, A. T., Sekeres, M. A., Medeiros, B. C., Wang, E. S., Shami, P. J., Adekola, K., Luger, S. M., Baer, M. R., Rizzieri, D. A., Wildes, T., Koprivnikar, J. L., Smith, J., Garrison, M. A., Kojouri, K., Appelbaum, F. R., Percival, M. M., Lee, S. J., Sorror, M. L. AMER SOC HEMATOLOGY. 2022: 5254-5257

  View details for DOI 10.1182/blood-2022-165437

  View details for Web of Science ID 000893223205124

• An 8-year pragmatic observation evaluation of the benefits of allogeneic HCT in older and medically infirm AML patients. Blood Sorror, M. L., Gooley, T. A., Storer, B. E., Gerds, A. T., Sekeres, M. A., Medeiros, B. C., Wang, E. S., Shami, P. J., Adekola, K. U., Luger, S. M., Baer, M. R., Rizzieri, D. A., Wildes, T., Koprivnikar, J., Smith, J., Garrison, M., Kojouri, K., Schuler, T. A., Leisenring, W. M., Onstad, L., Becker, P. S., Lee, S. J., Sandmaier, B. M., Appelbaum, F. R., Estey, E. 2022

  Abstract

  We designed a prospective, observational study enrolling patients presenting for treatment of AML at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), function and geriatric health, in 6 groups: 1) the entire cohort, 2) ≥65 years old, 3) high comorbidity burden, 4) intermediate cytogenetic-risk, 5) adverse cytogenetic-risk, and 6) first complete remission with or without measurable residual disease. Patient health and preferences were assessed eight times across 2 years. Time-dependent regression models were used. Among 692 evaluable patients, 46% received HCT with 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality in the entire group and most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity-burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in all groups. While function, social life, performance status, and depressive symptoms were better for those selected for HCT compared to those who were not, these health advantages were lost after receiving HCT. Recipients and non-recipients of HCT similarly ranked and expected cure as main goal of therapy, while physicians expected more cure for the formers. Accounting for health impairments negate survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is due mostly to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT.

  View details for DOI 10.1182/blood.2022016916

  View details for PubMedID 36260765

• Genomic landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the CALGB 10603/RATIFY trial. Leukemia Jahn, N., Jahn, E., Saadati, M., Bullinger, L., Larson, R. A., Ottone, T., Amadori, S., Prior, T. W., Brandwein, J. M., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Ehninger, G., Heuser, M., Ganser, A., Pallaud, C., Gathmann, I., Krzykalla, J., Benner, A., Bloomfield, C. D., Thiede, C., Stone, R. M., Döhner, H., Döhner, K. 2022

  Abstract

  The aim of this study was to characterize the mutational landscape of patients with FLT3-mutated acute myeloid leukemia (AML) treated within the randomized CALGB 10603/RATIFY trial evaluating intensive chemotherapy plus the multi-kinase inhibitor midostaurin versus placebo. We performed sequencing of 262 genes in 475 patients: mutations occurring concurrently with the FLT3-mutation were most frequent in NPM1 (61%), DNMT3A (39%), WT1 (21%), TET2 (12%), NRAS (11%), RUNX1 (11%), PTPN11 (10%), and ASXL1 (8%) genes. To assess effects of clinical and genetic features and their possible interactions, we fitted random survival forests and interpreted the resulting variable importance. Highest prognostic impact was found for WT1 and NPM1 mutations, followed by white blood cell count, FLT3 mutation type (internal tandem duplications vs. tyrosine kinase domain mutations), treatment (midostaurin vs. placebo), ASXL1 mutation, and ECOG performance status. When evaluating two-fold variable combinations the most striking effects were found for WT1:NPM1 (with NPM1 mutation abrogating the negative effect of WT1 mutation), and for WT1:treatment (with midostaurin exerting a beneficial effect in WT1-mutated AML). This targeted gene sequencing study provides important, novel insights into the genomic background of FLT3-mutated AML including the prognostic impact of co-mutations, specific gene-gene interactions, and possible treatment effects of midostaurin.

  View details for DOI 10.1038/s41375-022-01650-w

  View details for PubMedID 35922444

• Factors associated with risk and prognosis of intensive care unit admission in patients with acute leukemia: a Danish nationwide cohort study. Leukemia & lymphoma Maeng, C. V., Christiansen, C. F., Liu, K. D., Kamper, P., Christensen, S., Medeiros, B. C., Ostgard, L. S. 2022: 1-11

  Abstract

  Identifying risk factors for intensive care unit (ICU) admission in acute leukemia (AL) patients may guide decision-making and improve prognosis. We included all adult AL patients receiving high-intensive chemotherapy in Denmark from 2005 to 2016. We examined risk factors [crude and adjusted (a) relative risks (RRs) with 95% confidence intervals (CI)] and calculated RRs of death after 1-, 3-, and 5-years in ICU-admitted patients compared with matched cohorts. In 1417 AML and 306 ALL patients, the 1-year risk of ICU admission was 28.1% for AML and 26.4% for ALL patients, with the majority related to the first course of chemotherapy. Performance status >1 was associated with increased risk. The 1-year mortality was higher in ICU-admitted patients (AML: 69.7 vs. 35.0% [aRR 2.74;CI = 2.17-3.47]; ALL 65.0 vs. 20.0% [aRR 3.04;CI = 1.54-6.02]). The excess mortality decreased with time. In this study, performance status was associated with increased risk of ICU admission and identifies high-risk patients. ICU admission was associated with high mortality, especially within the first year.

  View details for DOI 10.1080/10428194.2022.2074984

  View details for PubMedID 35583300

• Epidemiology of invasive fungal diseases in adults with newly diagnosed acute myeloid leukemia. Leukemia & lymphoma Miranti, E., Ho, D. Y., Enriquez, K., Subramanian, A. K., Medeiros, B. C., Epstein, D. J. 2022: 1-7

  Abstract

  Invasive fungal diseases (IFDs) are common in patients with acute myeloid leukemia (AML), but no recent data on incidence without antifungal prophylaxis are available. We evaluated the incidence of IFDs in patients with AML undergoing induction chemotherapy at Stanford University Hospital from 2012 to 2017, for up to 12weeks after induction. We also analyzed factors associated with IFD development. Thirty-six of 240 patients (13%) developed at least one proven or probable IFD. Seventy-eight percent of the proven or probable IFDs were due to Candida or Aspergillus species. Infection due to Fusarium and Mucorales was uncommon. Absolute neutrophil count (ANC) of <500L/L at the start of induction was associated with an increased risk of IFD. One hundred and eighty-seven patients (78%) were started on systemic antifungal drugs, even without microbiologic evidence of an IFD. IFDs remain frequent in AML patients undergoing induction chemotherapy without antifungal prophylaxis.

  View details for DOI 10.1080/10428194.2022.2060504

  View details for PubMedID 35410569

• Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome. Blood advances Gerds, A. T., Scott, B. L., Greenberg, P. L., Lin, T. L., Pollyea, D. A., Verma, A. K., Dail, M., Feng, Y., Green, C., Ma, C., Medeiros, B. C., Yan, M., Yousefi, K., Donnellan, W. B. 1800

  Abstract

  We present here primary results from the phase Ib GO29754 study (NCT02508870) evaluating the safety and tolerability of atezolizumab, a PD-L1 inhibitor, alone and in combination with azacitidine, a hypomethylating agent (HMA), in patients with relapsed/refractory (R/R) or HMA-naive myelodysplastic syndrome (MDS). R/R MDS patients received atezolizumab for 12 months (Cohort A), or atezolizumab plus azacitidine for six cycles followed by atezolizumab as maintenance for eight cycles (Cohort B). HMA-naive MDS patients received atezolizumab plus azacitidine until loss of clinical benefit (Cohort C). Safety, activity, and exploratory endpoints were investigated. Forty-six patients were enrolled and received treatment (11 in Cohort A, 14 in Cohort B, 21 in Cohort C). All patients experienced ≥1 adverse event (AE) on study, and all patients discontinued atezolizumab. In Cohort A, seven patients (63.6%) died, and no patients responded. In Cohort B, eight patients (57.1%) discontinued azacitidine, 11 patients (78.6%) died, and two patients (14.3%) responded. In Cohort C, all 21 patients discontinued azacitidine, 13 patients died (61.9%), and 13 patients (61.9%) responded. The study was terminated by the sponsor prior to completing recruitment due to the unexpected high early death rate in Cohort C (6/13 deaths [46.2%] were due to AEs and occurred within the first four treatment cycles.). The high death rate and poor efficacy observed in this study do not support a favorable risk-benefit profile for atezolizumab as a single agent or in combination with azacitidine in R/R or HMA-naive MDS.

  View details for DOI 10.1182/bloodadvances.2021005240

  View details for PubMedID 34932793

• Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia. Blood Sorror, M. L., Storer, B. E., Fathi, A. T., Brunner, A., Gerds, A. T., Sekeres, M. A., Mukherjee, S., Medeiros, B. C., Wang, E. S., Vachhani, P., Shami, P. J., Peña, E., Elsawy, M., Adekola, K., Luger, S., Baer, M. R., Rizzieri, D., Wildes, T. M., Koprivnikar, J., Smith, J., Garrison, M., Kojouri, K., Leisenring, W., Onstad, L., Nyland, J. E., Becker, P. S., McCune, J. S., Lee, S. J., Sandmaier, B. M., Appelbaum, F. R., Estey, E. H. 2021; 138 (5): 387-400

  Abstract

  Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

  View details for DOI 10.1182/blood.2020008812

  View details for PubMedID 34351368

• Molecular landscape and prognostic impact of FLT3-ITD insertion site in acute myeloid leukemia: RATIFY study results. Leukemia Rucker, F. G., Du, L., Luck, T. J., Benner, A., Krzykalla, J., Gathmann, I., Voso, M. T., Amadori, S., Prior, T. W., Brandwein, J. M., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Savoie, L., Sierra, J., Pallaud, C., Sanz, M. A., Jansen, J. H., Niederwieser, D., Fischer, T., Ehninger, G., Heuser, M., Ganser, A., Bullinger, L., Larson, R. A., Bloomfield, C. D., Stone, R. M., Dohner, H., Thiede, C., Dohner, K. 2021

  Abstract

  In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3-ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3-ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n=251, 55%), JMD and TKD1 (JMD/TKD1; n=117, 26%), and TKD1sole (n=84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P=0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P=0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3-ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin.

  View details for DOI 10.1038/s41375-021-01323-0

  View details for PubMedID 34316017

• Event free survival in adults with relapsed ALL who underwent front-line therapy with CALGB 10403. Raychaudhuri, S., Yurkiewicz, I., Mannis, G. N., Medeiros, B. C., Coutre, S. E., Muffly, L. S., Liedtke, M. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1200/JCO.2021.39.15_suppl.e19005

  View details for Web of Science ID 000708120304096

• Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial. Leukemia Larson, R. A., Mandrekar, S. J., Huebner, L. J., Sanford, B. L., Laumann, K., Geyer, S., Bloomfield, C. D., Thiede, C., Prior, T. W., Dohner, K., Marcucci, G., Voso, M. T., Klisovic, R. B., Galinsky, I., Wei, A. H., 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., Gathmann, I., Dohner, H., Stone, R. M. 2021

  Abstract

  The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR=0.71 (95% CI, 0.54-0.93); p=0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.

  View details for DOI 10.1038/s41375-021-01179-4

  View details for PubMedID 33654204

• Plasma Microbial Cell-free DNA Next Generation Sequencing in the Diagnosis and Management of Febrile Neutropenia. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Benamu, E. n., Gajurel, K. n., Anderson, J. N., Lieb, T. n., Gomez, C. A., Seng, H. n., Aquino, R. n., Hollemon, D. n., Hong, D. K., Blauwkamp, T. A., Kertesz, M. n., Blair, L. n., Bollyky, P. L., Medeiros, B. C., Coutre, S. n., Zompi, S. n., Montoya, J. G., Deresinski, S. n. 2021

  Abstract

  Standard testing fails to identify a pathogen in most patients with febrile neutropenia (FN). We evaluated the ability of the Karius microbial cell-free DNA (mcfDNA) sequencing Test (KT) to identify infectious etiologies of FN and its impact on antimicrobial management.This prospective study (ClinicalTrials.gov; NCT02912117) enrolled and analyzed 55 patients with FN. Up to 5 blood samples were collected per subject within 24h of fever onset (T1) and every 2-3 days. KT results were compared to blood culture (BC) and standard microbiological testing (SMT) results.Positive agreement was defined as KT identification of ≥1 isolate also detected by BC. At T1, positive and negative agreement were 90% (9/10) and 31% (14/45) respectively; 61% of KT detections were polymicrobial. Clinical adjudication by 3 independent infectious diseases specialists categorized Karius results as: unlikely to cause FN (N=0); Definite (N=12): KT identified ≥1 organism also found by SMT within 7 days; Probable (N=19): KT result was compatible with a clinical diagnosis; Possible (N=10): KT result was consistent with infection but not considered a common cause of FN. Definite, probable and possible cases were deemed true positives. Following adjudication, KT sensitivity and specificity were 85% (41/48) and 100% (14/14) respectively. Calculated time to diagnosis was generally shorter with KT (87%). Adjudicators determined real-time KT results could have allowed early optimization of antimicrobials in 47% of patients, by addition of antibacterials (20%) (mostly against anaerobes [12.7%]), antivirals (14.5%) and/or antifungals (3.6%); and antimicrobial narrowing in 27.3% of cases.KT shows promise in the diagnosis and treatment optimization of FN.

  View details for DOI 10.1093/cid/ciab324

  View details for PubMedID 33870413

• Multi-Site 11-Year Experience of Less-Intensive versus Intensive Therapies in Acute Myeloid Leukemia. Blood Sorror, M. L., Storer, B. E., Fathi, A. T., Brunner, A. M., Gerds, A. T., Sekeres, M. A., Mukherjee, S. n., Medeiros, B. C., Wang, E. S., Vachhani, P. n., Shami, P. J., Peña, E. n., Elsaway, M. n., Adekola, K. U., Luger, S. n., Baer, M. R., Rizzieri, D. n., Wildes, T. n., Koprivnikar, J. n., Smith, J. n., Garrison, M. n., Kojouri, K. n., Leisenring, W. M., Onstad, L. n., Nyland, J. E., Becker, P. S., McCune, J. S., Lee, S. J., Sandmaier, B. M., Appelbaum, F. n., Estey, E. H. 2021

  Abstract

  Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia, assuming they are better than intensive induction. Using an AML-composite model (AML-CM) that assigns higher scores to older age, increased comorbidity-burdens and adverse cytogenetic-risks, we defined three distinct prognostic groups, and within each, compared outcomes after less-intensive versus intensive induction therapies in a multicenter retrospective cohort (n=1292) treated at six institutions from 2008-2012 and a prospective cohort (n=695) treated at thirteen institutions from 2013-2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physicians' perceptions of cure. In the retrospective cohort, recipients of less-intensive therapies were older, had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks for mortality in AML-CM scores of 4-6, 7-9, and ≥10. Results were independent from receipt of allogeneic transplants and similar in those aged 70-79 years old. In the Prospective cohort, the two groups were similar in baseline QOL, geriatric assessment, and patients' outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS and chances of cure, mortality risks and QOL were similar. Less-intensive recipients had lessened length of hospitalization (LOH). Our studies question the survival or QOL, except LOH, benefits from less-intensive therapies in patients with AML, including those aged 70-79 years or with high comorbidity-burden. A randomized trial in older/medically infirm patients is needed to better assess the value of less-intensive, intensive, or a combination of both therapies. ClinicalTrials.gov #NCT01929408.

  View details for DOI 10.1182/blood.2020008812

  View details for PubMedID 33910230

• Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial. Blood advances Voso, M. T., Larson, R. A., Jones, D., Marcucci, G., Prior, T., Krauter, J., Heuser, M., Lavorgna, S., Nomdedeu, J., Geyer, S. M., Walker, A., Wei, A. H., Sierra, J., Sanz, M. A., Brandwein, J. M., de Witte, T. M., Jansen, J. H., Niederwieser, D., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Schlenk, R. F., Ganser, A., Amadori, S., Cheng, Y., Chen, Y., Pallaud, C., Du, L., Piciocchi, A., Ehninger, G., Byrd, J., Thiede, C., Dohner, K., Stone, R. M., Dohner, H., Bloomfield, C. D., Lo-Coco, F. 2020; 4 (19): 4945–54

  Abstract

  The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.

  View details for DOI 10.1182/bloodadvances.2020002904

  View details for PubMedID 33049054

• Multicenter 11-Year Experience of Outcomes After Intensive Versus Less-Intensive Therapy for Patients with Acute Myeloid Leukemia: Focus on Older and Medically Infirm Patients Sorror, M., Storer, B., Fathi, A., Brunner, A., Gerds, A., Sekeres, M., Medeiros, B., Wang, E., Shami, P., Adekola, K., Luger, S., Baer, M., Rizzieri, D., Wildes, T., Koprivnikar, J., Garrison, M., Kojouri, K., Schuler, T., Leisinring, W., Onstad, L., Becker, P., McCune, J., Lee, S., Sandmaier, B., Appelbaum, F., Estey, E. CIG MEDIA GROUP, LP. 2020: S185

  View details for Web of Science ID 000564055100092

• Economic and Clinical Burden of Acute Myeloid Leukemia Episodes of Care in the United States: A Retrospective Analysis of a Commercial Payer Database. Journal of managed care & specialty pharmacy Pandya, B. J., Chen, C., Medeiros, B. C., McGuiness, C. B., Wilson, S. D., Walsh, E. H., Wade, R. L. 2020: 1–11

  Abstract

  BACKGROUND: In the United States, the incidence of acute myeloid leukemia (AML) has steadily increased over the last decade; in 2019, it was estimated that AML would affect 21,450 new patients and lead to 10,920 deaths. Detailed real-world cost estimates and comparisons of key AML treatment episodes, such as in high-intensity chemotherapy (HIC), low-intensity chemotherapy (LIC), hematopoietic stem cell transplantation (HSCT), and relapsed/refractory (R/R), are scarce in the commercially insured U.S.POPULATION: OBJECTIVE: To examine health resource utilization (HRU), clinical burden, and direct health care costs across various AML treatment episodes in a large sample of commercially insured U.S.PATIENTS: METHODS: A retrospective cohort analysis was conducted. Patients with newly diagnosed AML were followed to identify the key active treatment episodes across the course of their disease. Data were obtained from 2 sources: IQVIA's Real-World Data (RWD) Adjudicated Claims Database - U.S. (formerly known as PharMetrics Plus), which comprises adjudicated claims for more than 150 million unique enrollees across the United States, and IQVIA Charge Detail Master Hospital Database, which has detailed data regarding services received in an inpatient setting. Calculation of all-cause HRU was based on physician office visits, nonphysician office visits, emergency department visits, inpatient visits, and outpatient pharmacy utilization. Calculation of all-cause health care costs was based on total allowed costs and reported by the following cost components: physician office visits, nonphysician office visits, emergency department visits, inpatient visits, and outpatient pharmacy utilization. Symptom and toxicity events were estimated via proxies such as diagnosis codes, procedures, and treatments administered.RESULTS: The final study sample consisted of 1,542 HIC-induction (HIC-I), 591 HIC-consolidation (HIC-C), 628 LIC, 1,000 patients with HSCT, and 707 patients with R/R AML. Total mean episode costs were highest in R/R episodes ($439,104), followed by HSCT ($329,621), HIC-I ($198,657), HIC-C ($73,428), and LIC ($53,081) episodes. Across all treatment episodes, hospitalization was the largest contributor to cost with mean hospitalization costs ranging from $308,978 in the R/R setting to $49,580 for patients receiving LIC; of these, costs related to intensive care unit admission were a noteworthy contributor. In patients with R/R AML and HSCT, expenditures related to pharmacy utilization averaged $24,640 and $12,203, respectively, and expenditures related to physician office visits averaged $10,926 and $6,090, respectively; these expenditures were much lower across other episodes. Across all categories of symptom and toxicity events, cardiovascular events was the only category of event that was a significant predictor of higher cost across all episodes. Symptom and toxicity events commonly associated with AML were associated with significantly increased costs, especially in R/R episodes.CONCLUSIONS: This resource utilization and direct health care cost analysis highlights the substantial economic burden associated with key AML treatment episodes in the United States, specifically during HIC-I, HSCT, and R/R episodes.DISCLOSURES: This study was funded by Astellas Pharma. Astellas employees were involved in the study design, interpretation of data, writing of the manuscript, and the decision to submit the manuscript for publication. Pandya and Wilson are employees of Astellas Pharma U.S. Walsh was an employee of Astellas Pharma U.S. while the study was conducted. Chen, McGuiness, and Wade are employees of IQVIA, which received funding from Astellas Pharma U.S. Madeiros was employed at Stanford University while this study was conducted and received a consulting fee from Astellas for work on this study. Data discussed in this study were previously presented at the 59th Annual American Society for Hematology Meeting & Exposition, 2017; December 9-12, 2017; Atlanta, GA.

  View details for DOI 10.18553/jmcp.2020.19220

  View details for PubMedID 32281456

• Functional characterization of two rare BCR-FGFR1+ leukemias. Cold Spring Harbor molecular case studies Barnes, E. J., Leonard, J. n., Medeiros, B. n., Druker, B. J., Tognon, C. E. 2020

  Abstract

  8p11 myeloproliferative syndrome (EMS) represents a unique WHO-classified hematologic malignancy defined by translocations of the FGFR1 receptor. The syndrome is a myeloproliferative neoplasm characterized by eosinophilia and lymphadenopathy, with risk of progression to either AML (acute myeloid leukemia) or T or B-lymphoblastic lymphoma/leukemia. Within the EMS subtype, translocations between Breakpoint Cluster Region (BCR) and Fibroblast Growth Factor Receptor 1 (FGFR1) have been shown to produce a dominant fusion protein that is notoriously resistant to tyrosine kinase inhibitors (TKIs). Here, we report two cases of BCR-FGFR1+ EMS identified via RNA-seq and confirmed by FISH. Sanger sequencing revealed that both cases harbored the exact same breakpoint. In the first case, the patient presented with AML-like disease, and in the second, the patient progressed to B-ALL. Additionally, we observed that that primary leukemia cells from Case 1 demonstrated sensitivity to the tyrosine kinase inhibitors Ponatinib and Dovitinib that can target FGFR1 kinase activity, while primary cells from Case 2 were resistant to both drugs. Taken together these results suggest that some but not all BCR-FGFR1 fusion positive leukemias may respond to TKIs that target FGFR1 kinase activity.

  View details for DOI 10.1101/mcs.a004838

  View details for PubMedID 31980503

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

  Abstract

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

  View details for DOI 10.1080/10428194.2020.1775214

  View details for PubMedID 32543932

• Single-cell mutational profiling enhances the clinical evaluation of AML MRD. Blood advances Ediriwickrema, A. n., Aleshin, A. n., Reiter, J. G., Corces, M. R., Köhnke, T. n., Stafford, M. n., Liedtke, M. n., Medeiros, B. C., Majeti, R. n. 2020; 4 (5): 943–52

  Abstract

  Although most patients with acute myeloid leukemia (AML) achieve clinical remission with induction chemotherapy, relapse rates remain high. Next-generation sequencing enables minimal/measurable residual disease (MRD) detection; however, clinical significance is limited due to difficulty differentiating between pre-leukemic clonal hematopoiesis and frankly malignant clones. Here, we investigated AML MRD using targeted single-cell sequencing (SCS) at diagnosis, remission, and relapse (n = 10 relapsed, n = 4 nonrelapsed), with a total of 310 737 single cells sequenced. Sequence variants were identified in 80% and 75% of remission samples for patients with and without relapse, respectively. Pre-leukemic clonal hematopoiesis clones were detected in both cohorts, and clones with multiple cooccurring mutations were observed in 50% and 0% of samples. Similar clonal richness was observed at diagnosis in both cohorts; however, decreasing clonal diversity at remission was significantly associated with longer relapse-free survival. These results show the power of SCS in investigating AML MRD and clonal evolution.

  View details for DOI 10.1182/bloodadvances.2019001181

  View details for PubMedID 32150611

• Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia. JCO oncology practice Pagel, J. M., Othus, M. n., Garcia-Manero, G. n., Fang, M. n., Radich, J. P., Rizzieri, D. A., Marcucci, G. n., Strickland, S. A., Litzow, M. R., Savoie, M. L., Spellman, S. R., Confer, D. L., Chell, J. W., Brown, M. n., Medeiros, B. C., Sekeres, M. A., Lin, T. L., Uy, G. L., Powell, B. L., Bayer, R. L., Larson, R. A., Stone, R. M., Claxton, D. n., Essell, J. n., Luger, S. M., Mohan, S. R., Moseley, A. n., Erba, H. P., Appelbaum, F. R. 2020: JOP1900133

  Abstract

  Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT.We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1.Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 (P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months).Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

  View details for DOI 10.1200/JOP.19.00133

  View details for PubMedID 32048933

• Increased mitochondrial apoptotic priming with targeted therapy predicts clinical response to re-induction chemotherapy. American journal of hematology Garcia, J. S., Bhatt, S., Fell, G., Sperling, A. S., Burgess, M., Keshishian, H., Yilma, B., Brunner, A., Neuberg, D., Carr, S. A., Ebert, B. L., Ballen, K., Stone, R. M., DeAngelo, D. J., Medeiros, B. C., Letai, A. 2019

  Abstract

  Most patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) do not benefit from current re-induction or approved targeted therapies. In the absence of targetable genetic mutations, there is minimal guidance on optimal treatment selection particularly in the R/R setting highlighting an unmet need for clinically useful functional biomarkers. Blood and bone marrow samples from patients treated on two clinical trials testing the combination of lenalidomide (LEN) and MEC (mitoxantrone, etoposide, and cytarabine) chemotherapy in R/R AML patients were available to test the clinical utility of the mitochondrial apoptotic BH3 and dynamic BH3 profiling (DBP) assays in predicting response, as there was no clear genetic biomarker identifying responders. To test whether LEN-induced mitochondrial priming predicted clinical response to LEN-MEC therapy, we performed DBP on patient myeloblasts and found that short-term ex vivo treatment with lenalidomide discriminated clinical responders from non-responders based on drug-induced change in priming (delta priming). Using paired patient samples collected before and after clinical LEN treatment (prior to MEC dosing), we confirmed LEN-induced increased apoptotic priming in vivo, suggesting LEN enhanced vulnerability of myeloblasts to cytotoxic MEC chemotherapy. This is the first study demonstrating the potential role of DBP in predicting clinical response to a combination regimen. Our findings demonstrate that functional properties of relapsed AML can identify active therapies. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ajh.25692

  View details for PubMedID 31804723

• Longer distance to specialized treatment centers does not adversely affect treatment intensity or outcomes in adult acute myeloid leukemia patients. A Danish national population-based cohort study. Clinical epidemiology Tøstesen, M., Nørgaard, M., Nørgaard, J. M., Medeiros, B. C., Marcher, C. W., Overgaard, U. M., Severinsen, M. T., Schoellkopf, C., Østgård, L. S. 2019; 11: 769-780

  Abstract

  Treatment of acute myeloid leukemia (AML) is widely centralized. Longer distances to a specialized treatment center may affect patients' access to curative-intended treatment. Especially during outpatient treatment, distance may also affect survival.The authors conducted a national population-based cohort study including all AML patients diagnosed in Denmark between 2000 and 2014. We investigated effects of distance (<10 kilometers [km; reference], 10-25, 25-50, 50-100, >100) to the nearest specialized treatment facility on the probability of receiving intensive chemotherapy, HSCT, and achieving a complete remission (CR) using logistic regression analysis (odds ratios; ORs). For overall survival, we used Cox proportional hazards regression (hazard ratios [HRs]) and adjusted (a) for relevant baseline characteristics.Of 2,992 patients (median age=68.5 years), 53% received intensive chemotherapy and 12% received low-dose chemotherapy outpatient regimens. The median distance to a specialized treatment center was 40 km (interquartile range=10-77 km). No impact of distance to specialized treatment centers was seen on the probability of receiving intensive chemotherapy (10-25 km, aOR=1.1 (CI=0.7-1.7), 25-50 km, aOR=1.1 (CI=0.7-1.7), 50-100 km, aOR=1.3 (CI=0.9-1.9), and >100 km, aOR=1.4 [CI=0.9-2.2]). Overall survival in patients regardless of therapy (<10 km, aOR=1.0 vs >100 km, aOR=1.0 [CI=0.9-1.2]), in intensive therapy patients, or in patients' choice of post-remission was not affected by distance to specialized treatment center. Distance to a transplant center also did not affect the probability of HSCT or survival post-HSCT.In Denmark, distance to a specialized treatment facility offering remission-induction chemotherapy and HSCT does not negatively affect access to curative-indented therapy, treatment-response, or survival in AML patients.

  View details for DOI 10.2147/CLEP.S210456

  View details for PubMedID 31695504

  View details for PubMedCentralID PMC6718163

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

  Abstract

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

  View details for DOI 10.1182/blood.2019000611

  View details for PubMedID 31366621

• Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Chan, S. M., Daver, N. G., Jonas, B. A., Pollyea, D. A. 2019; 94 (7): 803–11

  View details for DOI 10.1002/ajh.25484

  View details for Web of Science ID 000470918600015

• Economic and Clinical Burden of Relapsed and/or Refractory Active Treatment Episodes in Patients with Acute Myeloid Leukemia (AML) in the USA: A Retrospective Analysis of a Commercial Payer Database. Advances in therapy Pandya, B. J., Chen, C., Medeiros, B. C., McGuiness, C. B., Wilson, S., Horvath Walsh, L. E., Wade, R. L. 2019

  Abstract

  This retrospective study estimated healthcare resource use (HRU), symptoms and toxicities (SxTox), and costs in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML), stratified by hematopoietic stem cell transplantation (HSCT) status. Claims data were used to identify adult patients with AML diagnoses from 1 January 2008 to 31 March 2016 in the USA. Patients were considered R/R if they had an AML relapse ICD-9 code (205.02) or a line of therapy consistent with R/R disease. The final R/R sample (N=707) included 476 patients with and 231 patients without HSCT. The mean total episode cost (from relapse date to death or end of study period) for all patients was $439,104 (with HSCT $524,595 and without HSCT $263,310). Inpatient visits accounted for the greatest cost component (mean $308,978) followed by intensive care unit stays (mean $221,537), non-clinician (e.g., lab tests) visits (mean $30,909), and outpatient pharmacy utilization (mean $24,640). Patients with HSCT appeared to have longer episodes of care compared with patients without HSCT (16.8 vs 11.1months), perhaps reflecting longer survival for HSCT patients. Mean number of visits within each category and their associated costs appeared to be higher in patients with HSCT compared with patients without HSCT. Patients with HSCT appeared to experience more SxTox compared with patients without HSCT across all categories. Results of the current study suggest that there is a substantial HRU and cost burden on R/R AML patients in the USA receiving active treatments. More effective therapies with improved tolerability would meet this tremendous unmet need in the R/R AML population.Funding: Astellas Pharma, Inc.

  View details for DOI 10.1007/s12325-019-01003-7

  View details for PubMedID 31222713

• Real-World Impact of Physician and Patient Discordance on Health-Related Quality of Life in US Patients with Acute Myeloid Leukemia. Oncology and therapy Horvath Walsh, L. E., Rider, A., Piercy, J., Pike, J., Wilson, S., Pandya, B. J., Medeiros, B. C. 2019; 7 (1): 67-81

  Abstract

  There is limited understanding concerning the health-related quality of life (HRQoL) in acute myeloid leukemia (AML) patients. Due to an overlap of symptoms, it can be difficult to separate disease versus treatment-related effects. Study objectives were to understand the impact of factors that might influence patients' HRQoL, assess the degree of concordance in symptom reporting by patients and physicians, and assess the impact of any discordance on HRQoL in AML patients.Physicians in the USA captured demographics, current AML treatment and symptoms for 82 AML patients who completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), 5-Dimension EuroQol Questionnaire (EQ-5D-3L) and Cancer Treatment Satisfaction Questionnaire (CTSQ). Effect size (ES) and clinically meaningful differences between AML subgroups were assessed, as was the impact of disagreement between patients and physicians regarding symptom recognition.Clinically meaningful lower overall FACT-Leu scores were observed for: relapsed/refractory versus non-relapsed/refractory AML patients (92.5 vs. 103.7; P = 0.09; ES = 0.439), hypomethylating agent (HMA) monotherapy versus other therapies in patients with low treatment intensity (89.9 vs. 112.9; P = 0.0021; ES = 0.971) and presence/absence of FLT3-ITD mutation (85.5 vs. 100; P = 0.148; ES = 0.816). Differences in health state were also clinically meaningful between patients with/without FLT3-ITD; EQ-5D-Visual Analog Scale (VAS) (47.6 vs. 63.7; P = 0.0428; ES = 0.816). Patients were more likely than physicians to report bruising (κ = 0.1292), fatigue (κ = 0.0836), bleeding (κ = 0.0177), weight loss (κ = 0.0821) and appetite loss (κ = - 0.0246). FACT-Leu was associated with patient-physician discordance on bleeding (difference - 14.12; P = 0.046), weight loss (- 21.22; P = 0.001) and appetite loss (- 12.58; P = 0.027).HRQoL is generally low for AML patients, especially for particular subgroups. Discordance in symptom reporting between patients and physicians was common and associated with further negative impacts on HRQoL. There may be many reasons for this but better communication between physicians and patients may lead to shared objectives and improvement in patients' HRQoL.Astellas Pharma, Inc.

  View details for DOI 10.1007/s40487-019-0094-x

  View details for PubMedID 32700197

• Real-World Impact of Physician and Patient Discordance on Health-Related Quality of Life in US Patients with Acute Myeloid Leukemia ONCOLOGY AND THERAPY Walsh, L., Rider, A., Piercy, J., Pike, J., Wilson, S., Pandya, B. J., Medeiros, B. C. 2019; 7 (1): 67–81

  View details for DOI 10.1007/s40487-019-0094-x

  View details for Web of Science ID 000468873200003

• Addressing the room for improvement in management of acute promyelocytic leukemia EUROPEAN JOURNAL OF HAEMATOLOGY Norgaard, J. M., Friis, L. S., Kristensen, J. S., Severinsen, M. T., Molle, I., Marcher, C. W., Moller, P., Schoellkopf, C., Nielsen, O. J., Preiss, B. S., Andersen, M. K., Kjeldsen, E., Medeiros, B. C., Ostgard, L. G., Danish Acute Leukemia Grp 2019; 102 (6): 479–85

  View details for DOI 10.1111/ejh.13229

  View details for Web of Science ID 000470930900005

• Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial BRITISH JOURNAL OF HAEMATOLOGY Bixby, D., Noppeney, R., Lin, T. L., Cortes, J., Krauter, J., Yee, K., Medeiros, B. C., Kraemer, A., Assouline, S., Fiedler, W., Dimier, N., Simmons, B. P., Riehl, T., Colburn, D. 2019; 185 (3): 595–98

  View details for DOI 10.1111/bjh.15571

  View details for Web of Science ID 000465109900026

• Optimizing survival outcomes with post-remission therapy in acute myeloid leukemia. American journal of hematology Medeiros, B. C., Chan, S. M., Daver, N. G., Jonas, B. A., Pollyea, D. A. 2019

  Abstract

  Optimization of post-remission therapies to maintain complete remission and prevent relapse is a major challenge in treating patients with acute myeloid leukemia (AML). Monitoring patients for measurable residual disease (MRD) is helpful to identify those at risk for relapse. Hypomethylating agents are being investigated as post-remission therapy, and identification of recurrent genetic alterations that drive disease progression has enabled the design of new, personalized approaches to therapy for patients with AML. Emerging data suggest that targeted post-remission therapy, alone or in combination with chemotherapy, may improve outcomes, and results of ongoing clinical trials will further define potential clinical benefits. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30945331

• Treatment patterns in patients with acute myeloid leukemia in the United States: a cross-sectional, real-world survey CURRENT MEDICAL RESEARCH AND OPINION Medeiros, B. C., Pandya, B. J., Hadfield, A., Pike, J., Wilson, S., Mueller, C., Bui, C. N., Flanders, S. C., Rider, A., Walsh, L. 2019; 35 (5): 927–35

  View details for DOI 10.1080/03007995.2019.1578152

  View details for Web of Science ID 000461973000001

• Addressing the Room for Improvement in Management of Acute Promyelocytic Leukemia. European journal of haematology Norgaard, J. M., Friis, L. S., Kristensen, J. S., Severinsen, M. T., Molle, I., Marcher, C. W., Moller, P., Schoellkopf, C., Nielsen, O. J., Preiss, B. S., Andersen, M. K., Kjeldsen, E., Medeiros, B. C., Ostgard, L. S., Danish Acute Leukemia Group 2019

  Abstract

  Acute promyelocytic leukemia (APL) is highly curable. To achieve high cure rates, targeted therapy with retinoic acid (ATRA) must be started promptly at time of suspected diagnosis. Early death rates (EDRs, ≤30 days from diagnosis) differ markedly in patients treated on clinical trials compared to the general population.OBJECTIVES AND METHODS: We used the comprehensive Danish National Acute Leukemia Registry (DNLR) to investigate the incidence, treatment, EDR, and long-term clinical outcome in APL between 2000 and 2014.RESULTS: Twenty-two of 41 deaths occurring in 122 APL patients were EDs which were primarily caused by intracranial hemorrhage, disseminated intravascular coagulation (DIC), sepsis, and multiorgan failure. The overall EDR was 18.0%, whereas clinical trial participants had an EDR of 6.7%. Fifteen patients recruited to the NCRI AML17 APL trial from 2010 to 2013 were younger and had decreased mortality (HR 0.18, CI 0.04 - 0.86, p=0.02) compared to contemporarily treated patients (n = 15) not recruited to a clinical trial. Performance status, leukemia origin, and Sanz-score were independent prognostic variables.CONCLUSIONS: The very low EDR for on-trial patients is not observed in the general cohort of APL patients. Diagnostic awareness emerges as the greatest clinical challenge in management of APL. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30887583

• Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study Sorror, M. L., Storer, B. E., Gerds, A. T., Medeiros, B. C., Shami, P. J., Galvin, J. P., Adekola, K. U., Luger, S. M., Baer, M. R., Rizzieri, D. A., Wildes, T. M., Wang, E. S., Faderl, S., Koprivnikar, J. L., Sekeres, M. A., Mukherjee, S., Smith, J., Garrison, M., Kojouri, K., Nyland, J. E., Moore, R. R., Fleuret, S. L., Lynch, Y., Becker, P. S., Percival, M. M., Sandmaier, B. M., Appelbaum, F. R., Estey, E. H. ELSEVIER SCIENCE INC. 2019

  View details for Web of Science ID 000540655500157

• The relationship between clinical trial accrual volume and outcomes in acute myeloid leukemia: A SWOG/ECOG-ACRIN study (S0106 and E1900) LEUKEMIA RESEARCH Medeiros, B. C., Othus, M., Tallman, M. S., Sun, Z., Fernandez, H. F., Rowe, J. M., Lazarus, H. M., Appelbaum, F. R., Luger, S. M., Litzow, M. R., Erba, H. P. 2019; 78: 29–33

  View details for DOI 10.1016/j.leukres.2019.01.007

  View details for Web of Science ID 000458160400006

• Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study BLOOD ADVANCES Garcia-Manero, G., Abaza, Y., Takahashi, K., Medeiros, B. C., Arellano, M., Khaled, S. K., Patnaik, M., Odenike, O., Sayar, H., Tummala, M., Patel, P., Maness-Harris, L., Stuart, R., Traer, E., Karamlou, K., Yacoub, A., Ghalie, R., Giorgino, R., Atallah, E. 2019; 3 (4): 508–18

  View details for DOI 10.1182/bloodadvances.2018027409

  View details for Web of Science ID 000459729800003

• Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study. Blood advances Garcia-Manero, G., Abaza, Y., Takahashi, K., Medeiros, B. C., Arellano, M., Khaled, S. K., Patnaik, M., Odenike, O., Sayar, H., Tummala, M., Patel, P., Maness-Harris, L., Stuart, R., Traer, E., Karamlou, K., Yacoub, A., Ghalie, R., Giorgino, R., Atallah, E. 2019; 3 (4): 508–18

  Abstract

  Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.

  View details for PubMedID 30760466

• Treatment patterns in patients with acute myeloid leukemia in the United States: a cross-sectional, real-world survey. Current medical research and opinion Medeiros, B. C., Pandya, B. J., Hadfield, A., Pike, J., Wilson, S., Mueller, C., Bui, C. N., Flanders, S. C., Rider, A., Horvath, L. E. 2019: 1

  Abstract

  OBJECTIVE: The aim of this analysis was to examine treatment patterns in patients with acute myeloid leukemia (AML) in routine clinical practice in the United States, including factors influencing the choice of front-line treatment intensity and the effect of age and treatment line.METHODS: We used data from the Adelphi AML Disease Specific Programme, a real-world, cross-sectional survey conducted in 2015. Physicians completed patient record forms providing patients' demographic and clinical characteristics.RESULTS: In total, 61 academic, non-academic, and office-based hematologists and hematology/oncology specialists provided data on 457 patients with AML; 284 had ≥20% blasts (World Health Organization-defined AML) and were included in the analysis. In the front-line setting, 60% of patients received high-intensity therapy, most commonly cytarabine plus anthracycline; the most common low-intensity treatments were hypomethylating agents. Primary drivers for selecting high-intensity versus low-intensity treatment were age, performance status, and comorbidities; 67%, 64%, and 61% of physicians stated they would prescribe high-intensity treatment to patients aged <65 years, with good performance status, or no comorbidities, respectively. In practice, patients aged <60 years were more likely to receive high-intensity induction treatment (high vs low intensity by age p<.0001). In a selected cohort of relapsed/refractory patients, 69% of patients received high-intensity therapy (78% of patients aged <60 years and 57% of patients aged ≥60 years).CONCLUSIONS: Most patients in this analysis of real-world survey data received well-established, front-line induction therapies. Treatment intensity was determined by age, comorbidities, and performance status, as recommended by guidelines.

  View details for PubMedID 30712406

• The relationship between clinical trial accrual volume and outcomes in acute myeloid leukemia: A SWOG/ECOG-ACRIN study (S0106 and E1900). Leukemia research Medeiros, B. C., Othus, M., Tallman, M. S., Sun, Z., Fernandez, H. F., Rowe, J. M., Lazarus, H. M., Appelbaum, F. R., Luger, S. M., Litzow, M. R., Erba, H. P. 2019; 78: 29–33

  Abstract

  PURPOSE: To study whether institutional clinical trial accrual volume affects clinical outcomes of younger (age less than 61 years) patients with acute myeloid leukemia.PATIENTS AND METHODS: We investigated the impact of clinical trial accrual on response rates, early mortality and survival in patients with AML enrolled between 2002 and 2009 into two parallel cooperative group clinical trials SWOG S0106/ECOG-ACRIN E1900. Institutions were classified as low- (LAIs) (≤ 9 enrolled patients) or high-accruing institutions (HAIs) (≥10 enrolled patients). Fisher's exact text and logistic regression analysis were used to analyze the response and early mortality rates. The effect of accrual volume on survival was analyzed by log-rank tests and Cox regression models.RESULTS: A total of 1252 patients from 152 institutions were included in the final analyses. The median clinical trial registrations in HAIs was 19 patients (range, 10 to 92) versus 3 (range, 1 to 9) patients in LAIs. In multivariate analyses, HAIs, as a quantitative covariate, was associated with improved complete remission rates (odds ratio (OR) 1.08, p=0.0051), but no improvement median overall survival (HR 0.97, p=0.065) or median event-free (hazard ratio (HR) 0.97, p=0.05). Early mortality rates were similar between cohorts and academic affiliation had no impact on response rates or survival.CONCLUSION: Clinical trial accrual volume, had an independent, albeit modest, impact on complete remission rates, but not on overall survival and event-free in younger patients with AML.

  View details for PubMedID 30673620

• Acute myeloid leukemia immunopeptidome reveals HLA presentation of mutated nucleophosmin. PloS one Narayan, R. n., Olsson, N. n., Wagar, L. E., Medeiros, B. C., Meyer, E. n., Czerwinski, D. n., Khodadoust, M. S., Zhang, L. n., Schultz, L. n., Davis, M. M., Elias, J. E., Levy, R. n. 2019; 14 (7): e0219547

  Abstract

  Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.

  View details for DOI 10.1371/journal.pone.0219547

  View details for PubMedID 31291378

• Longer distance to specialized treatment centers does not adversely affect treatment intensity or outcomes in adult acute myeloid leukemia patients. A Danish national population-based cohort study CLINICAL EPIDEMIOLOGY Tostesen, M., Norgaard, M., Norgaard, J., Medeiros, B. C., Marcher, C., Overgaard, U., Severinsen, M., Schoellkopf, C., Ostgard, L. 2019; 11: 769–80

  View details for DOI 10.2147/CLEP.S210456

  View details for Web of Science ID 000483068200001

• Impact of NPM1/FLT3-ITD genotypes defined by the2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood Döhner, K. n., Thiede, C. n., Jahn, N. n., Panina, E. n., Gambietz, A. n., Larson, R. A., Prior, T. W., Marcucci, G. n., Jones, D. n., Krauter, J. n., Heuser, M. n., Voso, M. T., Ottone, T. n., Nomdedeu, J. F., Mandrekar, S. J., Klisovic, R. n., Wei, A. H., Sierra, J. n., Sanz, M. A., Brandwein, J. n., de Witte, T. M., Jansen, J. H., Niederwieser, D. n., Appelbaum, F. n., Medeiros, B. C., Tallman, M. S., Schlenk, R. F., Ganser, A. n., Serve, H. n., Ehninger, G. n., Amadori, S. n., Gathmann, I. n., Benner, A. n., Pallaud, C. n., Stone, R. M., Döhner, H. n., Bloomfield, C. D. 2019

  Abstract

  Patients with AML harboring FLT3 internal tandem duplications (ITD) have poor outcomes, in particular AML with a high ({greater than or equal to}0.5) mutant-to-wildtype allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined four distinct FLT3-ITD genotypes based on the ITD-AR and the NPM1 mutational status. In this retrospective, exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial evaluating the addition of midostaurin to standard chemotherapy. The four NPM1/FLT3-ITD genotypes significantly differed with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after one or two induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly between ELN risk groups with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate- and adverse-risk groups, respectively (P<0.001). Multivariate Cox model for OS using allogeneic hematopoietic-cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

  View details for DOI 10.1182/blood.2019002697

  View details for PubMedID 31826241

• Safety and efficacy of oral panobinostat plus chemotherapy in patients aged 65 years or younger with high-risk acute myeloid leukemia. Leukemia research DeAngelo, D. J., Walker, A. R., Schlenk, R. F., Sierra, J. n., Medeiros, B. C., Ocio, E. M., Röllig, C. n., Strickland, S. A., Thol, F. n., Valera, S. Z., Dasgupta, K. n., Berkowitz, N. n., Stuart, R. K. 2019; 85: 106197

  Abstract

  The role of histone deacetylase inhibitors in the treatment of acute myeloid leukemia (AML) is not well characterized. The current study evaluated the safety and efficacy of panobinostat in combination with idarubicin and cytarabine in newly diagnosed patients aged ≤65 years with primary or secondary high-risk AML based on cytogenetic classification. Treatment included fixed dose idarubicin (12 mg/m2/d, IV; day 1-3) and cytarabine (100 mg/m2/d, continuous IV infusion; day 1-7) and escalating oral doses of panobinostat at 15 mg, 20 mg, and 25 mg, thrice weekly starting at week 2 of a 28-day cycle. Forty-six patients were enrolled (primary AML [n = 36], secondary AML [n = 10]). The median age was 55 years. The most common all-grade AEs were diarrhea (54.3%), nausea (39.1%), vomiting, and decreased appetite (each, 21.7%), stomatitis (19.6%), and fatigue (17.4%). The overall response rate was 60.9%, 43.5% achieved a complete remission (CR), and 17.4% achieved CR with incomplete count recovery. The event-free survival at 1-year was 78.3%. Panobinostat in combination with idarubicin and cytarabine demonstrated tolerable safety and efficacy in younger patients with high-risk AML. The recommended phase 2 dose of panobinostat in this combination was 20 mg. ClinicalTrials.gov registry no: NCT01242774, and European Trial Registry EudraCT no: 2009-016809-42.

  View details for DOI 10.1016/j.leukres.2019.106197

  View details for PubMedID 31541945

• Is there a standard of care for relapsed AML? BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Medeiros, B. C. 2018; 31 (4): 384–86

  View details for DOI 10.1016/j.beha.2018.09.006

  View details for Web of Science ID 000452941900010

• Is there a standard of care for relapsed AML? Best practice & research. Clinical haematology Medeiros, B. C. 2018; 31 (4): 384–86

  Abstract

  Despite advances in treatment for acute myeloid leukemia (AML), the prognosis for patients with relapsed disease is extremely poor. The median overall survival for patients with relapsed AML ranges from 4-6 months and long-term survival from the time of relapse ranges from 5%-20%. Much of the difficulty in establishing a standard of care for relapsed AML is that the disease is clinically and genomically diverse. Nevertheless, significant progress has been made over the past 12 months with the approval of several agents, and the expectation is that additional therapies will be available soon. A brief review follows on the progress made in establishing a standard of care for relapsed AML.

  View details for PubMedID 30466752

• Increase in Chemotherapy Use and Associated Survival Benefit Among Medicare-Aged Patients with Acute Myeloid Leukemia (AML) Medeiros, B. C., Satram-Hoang, S., Momin, F., Parisi, M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-111281

  View details for Web of Science ID 000454842802007

• PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis Gerds, A. T., Scott, B. L., Greenberg, P. L., Khaled, S. K., Lin, T. L., Pollyea, D. A., Verma, A., Dail, M., Green, C., Ma, C., Medeiros, B. C., Phuong, P., Wenger, M., Yan, M., Donnellan, W. B. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-118577

  View details for Web of Science ID 000454837601175

• Survival Differences Among Patients (pts) with Acute Myeloid Leukemia (AML) Treated with Allogeneic Hematopoietic Cell Transplantation (HCT) Versus Non-HCT Therapies: A Large Real-Time Multi-Center Prospective Longitudinal Observational Study Sorror, M. L., Storer, B. E., Gerds, A. T., Medeiros, B. C., Shami, P. J., Galvin, J. P., Adekola, K. U., Luger, S., Baer, M. R., Rizzieri, D. A., Wildes, T. M., Wang, E. S., Faderl, S., Koprivnikar, J. L., Sekeres, M. A., Mukherjee, S., Smith, J., Garrison, M., Kojouri, K., Nyland, J. E., Moore, R. R., Fleuret, S. L., Lynch, Y., Becker, P. S., Percival, M. M., Sandmaier, B. M., Appelbaum, F. R., Estey, E. H. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-113094

  View details for Web of Science ID 000454837600261

• Comprehensive Molecular Profiling of FLT3-Mutated Acute Myeloid Leukemia (AML) Patients Treated within the Ratify Trial (Alliance C10603) Jahn, N., Panina, E., Bullinger, L., Dolnik, A., Herzig, J., Blaette, T. J., Benner, A., Krzykalla, J., Gathmann, I., Larson, R. A., Lo-Coco, F., Amadori, S., Prior, T. W., Brandwein, J. M., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Tiecke, E., Pallaud, C., Ehninger, G., Heuser, M., Ganser, A., Stone, R. M., Thiede, C., Doehner, H., Bloomfield, C. D., Doehner, K. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-115842

  View details for Web of Science ID 000454837604205

• Real-World Treatment Patterns and Comparative Effectiveness Among a Population of Elderly Patients with Acute Myeloid Leukemia (AML) Medeiros, B. C., Satram-Hoang, S., Momin, F., Parisi, M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-111267

  View details for Web of Science ID 000454837602213

• Prognostic Impact of Insertion Site in Acute Myeloid Leukemia (AML) with FLT3 Internal Tandem Duplication: Results from the Ratify Study (Alliance 10603) Ruecker, F. G., Du, L., Blaette, T. J., Benner, A., Krzykalla, J., Gathmann, I., Larson, R. A., Lo-Coco, F., Amadori, S., Prior, T. W., Brandwein, J. M., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Geddes, M., Sierra, J., Tiecke, E., Pallaud, C., Sanz, M. A., de Witte, T. M., Niederwieser, D., Ehninger, G., Heuser, M., Ganser, A., Bullinger, L., Bloomfield, C. D., Stone, R. M., Doehner, H., Thiede, C., Dohner, K. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-116149

  View details for Web of Science ID 000454837601144

• Longer Distance to a Specialized Treatment Center Does Not Adversely Affect Access to Treatment or Outcome in Acute Myeloid Leukemia: A National Population-Based Cohort Study Tostesen, M., Norgaard, J. M., Norgaard, M., Medeiros, B. C., Marcher, C., Overgaard, U., Schollkopf, C., Severinsen, M., Oestgaard, L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-110922

  View details for Web of Science ID 000454837601322

• Ratify (Alliance 10603): Prognostic Impact of FLT3 tyrosine Kinase Domain (TKD) and NPM1 Mutation Status in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Treated with Midostaurin or Placebo Plus Standard Chemotherapy Voso, M., Larson, R. A., Prior, T., Marcucci, G., Jones, D., Krauter, J., Heuser, M., Lavorgna, S., Nomdedeu, J., Geyer, S. M., Klisovic, R., Wei, A. H., Sierra, J., Sanz, M. A., Brandwein, J. M., de Witte, T. M., Jansen, J. H., Niederweiser, D., Appelbaum, F. R., Medeiros, B. C., Tallman, M. S., Schlenk, R. F., Ganser, A., Amadori, S., Cheng, Y., Gathmann, I., Tiecke, E., Thiede, C., Doehner, K., Doehner, H., Stone, R. M., Bloomfield, C. D., Lo-Coco, F. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-114318

  View details for Web of Science ID 000454837607274

• Limitations to Receiving Allogeneic Hematopoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia: A Large Multi-Center Prospective Longitudinal Observational Study Sorror, M. L., Storer, B. E., Gerds, A. T., Medeiros, B. C., Shami, P. J., Galvin, J. P., Adekola, K. U., Luger, S., Baer, M. R., Rizzieri, D. A., Wildes, T. M., Wang, E. S., Faderl, S., Koprivnikar, J. L., Sekeres, M. A., Mukherjee, S., Smith, J., Garrison, M., Kojouri, K., Nyland, J. E., Moore, R. R., Fleuret, S. L., Lynch, Y., Becker, P. S., Percival, M. M., Sandmaier, B. M., Appelbaum, F. R., Estey, E. H. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-112672

  View details for Web of Science ID 000454837604059

• Single-Cell Mutational Profiling of Clonal Evolution in De Novo AML during Therapy and Relapse Aleshin, A., Durruthy-Durruthy, R., Corces, M., Stafford, M., Liedtke, M., Medeiros, B. C., Eastburn, D. J., Majeti, R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-118089

  View details for Web of Science ID 000454837604140

• Dynamic BH3 Profiling Predicts for Clinical Response to Lenalidomide Plus Chemotherapy in Relapsed Acute Myeloid Leukemia Garcia, J. S., Bhatt, S., Fell, G., Blonquist, T. M., Taw, J., Iberri, D., Letai, A., Medeiros, B. C. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117428

  View details for Web of Science ID 000454842803094

• The Relationship between Age and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in a Cohort of Older Patients with Acute Myeloid Leukemia (AML) Medeiros, B. C., Satram-Hoang, S., Momin, F., Parisi, M. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-111274

  View details for Web of Science ID 000454842802004

• Single-Cell Mutational Profiling Describes the Molecular Heterogeneity of Clonal Evolution in MDS during Therapy and Relapse Aleshin, A., Durruthy-Durruthy, R., Medeiros, B. C., Eastburn, D. J., Greenberg, P. L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-120368

  View details for Web of Science ID 000454842806351

• Augmentation of the Acute Myeloid Leukemia-Composite Model (AML-CM) with Performance Status and Secondary Leukemia Elsayed, S., Storer, B. E., Medeiros, B. C., Asslan, M., Lynch, Y., Nyland, J. E., Becker, P. S., Percival, M. M., Estey, E. H., Sorror, M. L. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-117415

  View details for Web of Science ID 000454842803028

• NSAID consumption and risk of acute myeloid leukemia: a national population-based case-control study. Cancer management and research Østgård, L. S., Nørgaard, M., Pedersen, L., Østgård, R., Friis, L. S., Schöllkopf, C., Severinsen, M. T., Marcher, C. W., Medeiros, B. C., Jensen, M. K. 2018; 10: 5043-5051

  Abstract

  Most cases of acute leukemia arise without identifiable risk factors. Studies investigating the impact of autoimmune diseases and infections on leukemogenesis have revealed conflicting results. If inflammation increases the risk of acute myeloid leukemia (AML), nonsteroidal anti-inflammatory drug (NSAID) use may decrease the risk of leukemia.We conducted a case-control study of 3,053 patients with AML diagnosed between 2000 and 2013, who were registered in the Danish National Acute Leukemia Registry, and 30,530 population controls matched on sex and age. We identified prescriptions through the Danish National Health Service Prescription Database. We used conditional logistic regression analysis to compute ORs associating AML with NSAID use overall, in patients with inflammatory diseases, and for specific AML subtypes (de novo AML, AML related to previous hematological disease, ie, secondary AML [sAML], or therapy-related AML [tAML; exposed to previous cytotoxic therapy]).Overall, NSAID use was not associated with a lower risk of AML (OR 1.1, 95% CI=1.0-1.2), de novo AML (OR 1.0, 95% CI=0.9-1.1), and sAML/tAML (OR 1.3, 95% CI=1.1-1.5). In addition, in patients with known inflammatory diseases, NSAIDs did not affect AML risk (OR 0.9, 95% CI=0.5-1.6). Number of prescriptions, type of NSAID, age, or sex did not influence the results.In line with our recent findings that showed no association between autoimmune diseases and infections and de novo AML, NSAID use was not found to reduce the risk of AML.

  View details for DOI 10.2147/CMAR.S165498

  View details for PubMedID 30464604

  View details for PubMedCentralID PMC6214335

• Functional genomic landscape of acute myeloid leukaemia NATURE Tyner, J. W., Tognon, C. E., Bottomly, D., Wilmot, B., Kurtz, S. E., Savage, S. L., Long, N., Schultz, A., Traer, E., Abel, M., Agarwal, A., Blucher, A., Borate, U., Bryant, J., Burke, R., Carlos, A., Carpenter, R., Carroll, J., Chang, B. H., Coblentz, C., d'Almeida, A., Cook, R., Danilov, A., Dao, K. T., Degnin, M., Devine, D., Dibb, J., Edwards, D. K., Eide, C. A., English, I., Glover, J., Henson, R., Ho, H., Jemal, A., Johnson, K., Johnson, R., Junio, B., Kaempf, A., Leonard, J., Lin, C., Liu, S., Lo, P., Loriaux, M. M., Luty, S., Macey, T., MacManiman, J., Martinez, J., Mori, M., Nelson, D., Nichols, C., Peters, J., Ramsdill, J., Rofelty, A., Schuff, R., Searles, R., Segerdell, E., Smith, R. L., Spurgeon, S. E., Sweeney, T., Thapa, A., Visser, C., Wagner, J., Watanabe-Smith, K., Werth, K., Wolf, J., White, L., Yates, A., Zhang, H., Cogle, C. R., Collins, R. H., Connolly, D. C., Deininger, M. W., Drusbosky, L., Hourigan, C. S., Jordan, C. T., Kropf, P., Lin, T. L., Martinez, M. E., Medeiros, B. C., Pallapati, R. R., Pollyea, D. A., Swords, R. T., Watts, J. M., Weir, S. J., Wiest, D. L., Winters, R. M., McWeeney, S. K., Druker, B. J. 2018; 562 (7728): 526-+

  View details for DOI 10.1038/s41586-018-0623-z

  View details for Web of Science ID 000448277800046

• Chemotherapy based combinations in AML: Time to take a step back? LEUKEMIA RESEARCH Medeiros, B. C. 2018; 73: 39–40

  View details for DOI 10.1016/j.leukres.2018.08.018

  View details for Web of Science ID 000446480400008

• Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial. British journal of haematology Bixby, D., Noppeney, R., Lin, T. L., Cortes, J., Krauter, J., Yee, K., Medeiros, B. C., Kramer, A., Assouline, S., Fiedler, W., Dimier, N., Simmons, B. P., Riehl, T., Colburn, D. 2018

  View details for PubMedID 30203489

• CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia JOURNAL OF CLINICAL ONCOLOGY Lancet, J. E., Uy, G. L., Cortes, J. E., Newell, L. F., Lin, T. L., Ritchie, E. K., Stuart, R. K., Strickland, S. A., Hogge, D., Solomon, S. R., Stone, R. M., Bixby, D. L., Kolitz, J. E., Schiller, G. J., Wieduwilt, M. J., Ryan, D. H., Hoering, A., Banerjee, K., Chiarella, M., Louie, A. C., Medeiros, B. C. 2018; 36 (26): 2684-+

  View details for DOI 10.1200/JCO.2017.77.6112

  View details for Web of Science ID 000445669600004

• Chemotherapy based combinations in AML: Time to take a step back? Leukemia research Medeiros, B. C. 2018; 73: 39–40

  View details for PubMedID 30212655

• Non-zero-sum game of transfusions: EOL in leukemia BLOOD Medeiros, B. C. 2018; 132 (7): 676-+

  View details for PubMedID 30115633

• Recurrent drug sensitivity patterns in myelodysplastic syndrome patients are recapitulated by ex vivo drug response profiling Aleshin, A., Medeiros, B. C., Kamble, S., Heiser, D., Santaguida, M., Prashad, S., Greenberg, P. L. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-568

  View details for Web of Science ID 000468818902084

• Single-cell mutational profiling of clonal evolution in myelodysplastic syndromes (MDS) during therapy and disease progression Aleshin, A., Greenberg, P. L., Medeiros, B. C., Heiser, D., Santaguida, M., Prashad, S., Durruthy-Durruthy, R., Eastburn, D. J. AMER ASSOC CANCER RESEARCH. 2018

  View details for DOI 10.1158/1538-7445.AM2018-3004

  View details for Web of Science ID 000468819500368

• Associations between cohabitation status, treatment, and outcome in AML patients: a national population-based study BLOOD Ostgard, L., Norgaard, M., Medeiros, B. C., Severinsen, M., Friis, L., Marcher, C., Schoellkopf, C., Norgaard, J. 2018; 131 (24): 2730–33

  View details for PubMedID 29695517

• Epidemiology and impact of preceding or underlying disease in secondary acute myeloid leukemia HEMASPHERE Ostgard, L., Medeiros, B. C. 2018; 2: 153–55

  View details for Web of Science ID 000530680700059

• Outcomes by number of induction cycles with CPX-351 vs 7+3 chemotherapy in older adults with newly diagnosed, high-risk/secondary acute myeloid leukemia (sAML). Lin, T. L., Medeiros, B. C., Uy, G. L., Newell, L., Ritchie, E. K., Stuart, R. K., Strickland, S., Hogge, D., Solomon, S. R., Stone, R. M., Bixby, D. L., Kolitz, J. E., Schiller, G. J., Wieduwilt, M., Ryan, D. H., Ryan, R. J., Chiarella, M., Louie, A., Lancet, J. E., Cortes, J. E. AMER SOC CLINICAL ONCOLOGY. 2018

  View details for DOI 10.1200/JCO.2018.36.15_suppl.7040

  View details for Web of Science ID 000442916002538

• National Survey of Pathologists on the Application of Ancillary Testing in the Diagnosis of Acute Myeloid Leukemia Hasserjian, R., Altman, J., Denzen, E., Block, A., Klepin, H., Medeiros, B., Noe, A., Scales, W., Tallman, M., Wiley, K., Burns, L. NATURE PUBLISHING GROUP. 2018: 520

  View details for Web of Science ID 000429308603328

• National Survey of Pathologists on the Application of Ancillary Testing in the Diagnosis of Acute Myeloid Leukemia Hasserjian, R., Altman, J., Denzen, E., Block, A., Klepin, H., Medeiros, B., Noe, A., Scales, W., Tallman, M., Wiley, K., Burns, L. NATURE PUBLISHING GROUP. 2018: 520

  View details for Web of Science ID 000459341002328

• Subanalysis of Patients with Secondary Acute Myeloid Leukemia (sAML) with Refractory Anemia with Excess of Blasts in Transformation (RAEB-T) Enrolled in a Phase 3 Study of CPX-351 Versus Conventional 7+3 Cytarabine and Daunorubicin Lin, T. L., Uy, G. L., Wieduwilt, M. J., Newell, L. F., Stuart, R. K., Medeiros, B. C., Schiller, G. J., Rubenstein, S., Stock, W., Warlick, E., Foster, M., Bixby, D. L., Podoltsev, N., An, Q., Faderl, S., Louie, A. C., Lancet, J. E. ELSEVIER SCIENCE INC. 2018: S228–S229

  View details for Web of Science ID 000425476000315

• Cardiovascular, pulmonary, and metabolic toxicities complicating tyrosine kinase inhibitor therapy in chronic myeloid leukemia: Strategies for monitoring, detecting, and managing. Blood reviews Medeiros, B. C., Possick, J. n., Fradley, M. n. 2018

  Abstract

  Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, the incidence of which increases with age. Tyrosine kinase inhibitors (TKIs) are the mainstay of CML treatment, including imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Beyond matching patient disease profiles with TKI specificity, differences in the efficacy and toxicity profiles and a patient's comorbid risk factors should be considered when selecting the most appropriate agent. Our objectives are to review the incidence and severity of cardiovascular, metabolic, and pulmonary disorders associated with these TKIs, highlighting differences in adverse event profiles, suggested risk-mitigation strategies, and guidance for TKI selection in different settings. Patients receiving TKI agents for CML should be monitored for signs and symptoms of toxicity throughout therapy. Preemptive assessment, early toxicity recognition, and prompt management of cardiovascular, metabolic, and pulmonary toxicities can minimize treatment-limiting complications and improve outcomes in patients with CML.

  View details for PubMedID 29454474

• NSAID consumption and risk of acute myeloid leukemia: a national population-based case-control study CANCER MANAGEMENT AND RESEARCH Ostgard, L., Norgaard, M., Pedersen, L., Ostgard, R., Friis, L., Schollkopf, C., Severinsen, M., Marcher, C., Medeiros, B. C., Jensen, M. 2018; 10: 5043–51

  View details for DOI 10.2147/CMAR.S165498

  View details for Web of Science ID 000448625200002

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

  Abstract

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

  View details for PubMedID 29802551

• A Phase I/II Trial of the Combination of Azacitidine and Gemtuzumab Ozogamicin for Treatment of Relapsed Acute Myeloid Leukemia. Clinical lymphoma, myeloma & leukemia Medeiros, B. C., Tanaka, T. N., Balaian, L. n., Bashey, A. n., Guzdar, A. n., Li, H. n., Messer, K. n., Ball, E. D. 2018

  Abstract

  Treatment with hypomethylating agent therapy might enhance anti-CD33 monoclonal antibody-mediated cytotoxicity against acute myeloid leukemia (AML) blasts through epigenetic effects on Syk and SHP-1 expression.In the present phase I/II study, we treated patients with relapsed or refractory AML with azacitidine, followed by 2 doses of gemtuzumab ozogamicin (GO) at 6 mg/m2, the Food and Drug Administration-approved dose and schedule at study initiation. We sought to determine the maximum tolerated dose and clinical activity of this combination therapy. Secondarily, we aimed to determine whether baseline Syk and SHP-1 expression can be used as predictive biomarkers of treatment response.The established maximum tolerated dose was azacitidine 75 mg/m2daily for 6 consecutive days, followed by GO 6 mg/m2on days 7 and 21. Of the 50 evaluable patients, 12 (24%) obtained complete remission (CR) or CR with incomplete peripheral blood recovery (CRp). No dose-limiting toxicities were observed in phase I, and no patient developed hepatic sinusoidal obstructive syndrome. Although no significant correlation was found between Syk and SHP-1 expression and the clinical response to combination therapy, in vitro studies repeatedly demonstrated that azacitidine-treated AML cells had an increased response to GO treatment.Our study found that the combination of GO with azacitidine is relatively well tolerated, with response rates similar to those with GO monotherapy at higher doses. Differences in the GO drug schedule, dose level, and frequency might explain the discrepant response rates between our study and others, suggesting that the optimal GO dose remains unclear, especially when combined with hypomethylating agent therapy.

  View details for DOI 10.1016/j.clml.2018.02.017

  View details for PubMedID 29572158

• Autoimmune diseases, infections, use of antibiotics and the risk of acute myeloid leukaemia: a national population-based case-control study. British journal of haematology Østgård, L. S., Nørgaard, M. n., Pedersen, L. n., Østgård, R. D., Medeiros, B. C., Overgaard, U. M., Schöllkopf, C. n., Severinsen, M. n., Marcher, C. W., Jensen, M. K. 2018

  Abstract

  Previous studies reported increased risk of acute myeloid leukaemia (AML) in individuals with inflammatory conditions. However, it is unclear whether this association is explained by preceding cytotoxic therapy or haematological diseases. We conducted a nationwide case-control study that included 3053 AML patients, diagnosed in Denmark between 2000 and 2013, and 30 530 sex- and age-matched population controls. We retrieved information on autoimmune disease, infections, and use of antibiotics and computed odds ratios for AML (conditional logistic regression). Results were stratified by AML type, sex, and age. Autoimmune diseases were associated with an overall increased risk of AML {odds ratio [OR] 1·3 [95% confidence interval (CI) = 1·1-1·5]}. However, the risk was confined to patients with previous haematological disease or cytotoxic therapy exposure [secondary/therapy-related AML (sAML/tAML0) OR 2·0 (95% CI = 1·6-2·6)] and not de novo AML [OR 1·1 (95% CI = 0·9-1·3)]. Similarly, any prior infection requiring hospitalization was associated with a higher risk of AML [OR 1·3 (95% CI = 1·1-1·4)]. Again, this association was evident for sAML/tAML [OR 1·8 (95% CI = 1·5-2·2)], and not de novo AML [OR 1·1 (95% CI = 1·0-1·2)]. In conclusion, autoimmune diseases and infections were associated with an increased AML risk only in subjects with prior haematological disease and/or cytotoxic treatment. These observations suggest, that inflammation plays - if any - a minor role for the development of de novo AML.

  View details for PubMedID 29504124

• Interpretation of clinical endpoints in trials of acute myeloid leukemia. Leukemia research Medeiros, B. C. 2018; 68: 32–39

  Abstract

  Treatment regimens for acute myeloid leukemia (AML) have remained largely unchanged until recently. Molecular advances have opened the door to targeted therapies, many of which are in late-phase clinical trials. As new therapeutic opportunities arise, it is appropriate to review key aspects of clinical trial design, statistical interpretation of outcomes, and methods of data reporting. Complete remission and overall survival (OS) are common primary endpoints in early-phase AML clinical trials. OS and event-free survival are frequent primary endpoints in phase 3 trials. Clinical trials are designed to address the primary endpoint using prespecified α and power levels. Interpretation of additional endpoints (eg, secondary endpoints and subgroup analyses) must be viewed in light of a trial's statistical design. Furthermore, variations in reporting of endpoints must be considered in order to understand trial outcomes. Time-to-event endpoints are typically reported using Kaplan-Meier curves, which are visually informative. Statistical data derived from these curves can be complex, and a variety of factors may impact interpretation. The purpose of this review is to discuss the nuances of common AML trial endpoints and their data presentation to better inform evaluation and understanding of clinical trial data.

  View details for PubMedID 29524739

• Report of the relapsed/refractory cohort of SWOG S0919: A phase 2 study of idarubicin and cytarabine in combination with pravastatin for acute myelogenous leukemia (AML). Leukemia research Advani, A. S., Li, H. n., Michaelis, L. C., Medeiros, B. C., Liedtke, M. n., List, A. F., O'Dwyer, K. n., Othus, M. n., Erba, H. P., Appelbaum, F. R. 2018; 67: 17–20

  Abstract

  Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi <6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p = .062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.

  View details for PubMedID 29407182

• Overall Survival (OS) by Outpatient versus Inpatient Consolidation in a Phase 3 Study of CPX-351 versus 7+3 in Older Adults with Newly Diagnosed, High-Risk Acute Myeloid Leukemia (AML) Kolitz, J., Strickland, S., Cortes, J., Hogge, D., Lancet, J., Goldberg, S., Chung, K., Ryan, R., Chiarella, M., Louie, A., Stuart, R., Medeiros, B. CIG MEDIA GROUP, LP. 2017: S287

  View details for DOI 10.1016/j.clml.2017.07.073

  View details for Web of Science ID 000558818800063

• Overall Survival (OS) and Stem Cell Transplant (SCT) in Patients with FLT3 Mutations Treated with CPX-351 versus 7+3: Subgroup Analysis of a Phase 3 Study of Older Adults with Newly Diagnosed, High-Risk Acute Myeloid Leukemia (AML) Medeiros, B., Hogge, D., Newell, L., Bixby, D., Solomon, S., Strickland, S., Lin, T., Erba, H., Powell, B., Podoltsev, N., Ryan, R., Chiarella, M., Louie, A., Lancet, J. CIG MEDIA GROUP, LP. 2017: S286

  View details for DOI 10.1016/j.clml.2017.07.071

  View details for Web of Science ID 000558818800061

• Efficacy by consolidation administration site: Subgroup analysis of a phase III study of CPX-351 versus 7+3 in older adults with newly diagnosed, high-risk acute myeloid leukemia (AML). Kolitz, J. E., Strickland, S., Cortes, J. E., Hogge, D., Lancet, J. E., Goldberg, S. L., Chung, K. C., Ryan, R., Chiarella, M., Louie, A., Stuart, R. K., Medeiros, B. C. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.7036

  View details for Web of Science ID 000411931708066

• Correlation between mutation clearance and clinical response in elderly patients with acute myeloid leukemia (AML) treated with azacitidine and pracinostat. Takahashi, K., Abaza, Y., Atallah, E. L., Medeiros, B. C., Khal, S., Arellano, M., Patnaik, M., Ghalie, R., Garcia-Manero, G. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.7034

  View details for Web of Science ID 000411931708064

• Quality of life of acute myeloid leukemia patients in a real-world setting. Pandya, B. J., Hadfield, A., Medeiros, B. C., Wilson, S., Bui, C. N., Bailey, T., Flanders, S., Rider, A., Horvath, L. E. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.e18525

  View details for Web of Science ID 000411931708129

• Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study. Stein, E. M., Dinardo, C., Pollyea, D., Fathi, A., Roboz, G. J., Altman, J. K., Stone, R. M., Flinn, I., Kantarjian, H. M., Collins, R., Patel, M. R., Stein, A., Sekeres, M. A., Swords, R. T., Medeiros, B. C., Knight, R. D., Agresta, S. V., De Botton, S., Tallman, M. S. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.7004

  View details for Web of Science ID 000411931708034

• Real-world prescribing patterns in acute myeloid leukemia in the United States. Medeiros, B. C., Pandya, B. J., Hadfield, A., Wilson, S., Mueller, C., Bailey, T., Flanders, S., Horvath, L. E., Rider, A. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.e18524

  View details for Web of Science ID 000411931708128

• Overall survival (OS) and stem cell transplant (SCT) in patients with FLT3 mutations treated with CPX-351 versus 7+3: Subgroup analysis of a phase III study of older adults with newly diagnosed, high-risk acute myeloid leukemia (AML). Medeiros, B. C., Hogge, D., Newell, L. F., Bixby, D. L., Solomon, S. R., Strickland, S., Lin, T. L., Erba, H., Powell, B. L., Podoltsev, N., Ryan, R., Chiarella, M., Louie, A., Lancet, J. E. AMER SOC CLINICAL ONCOLOGY. 2017

  View details for DOI 10.1200/JCO.2017.35.15_suppl.e18507

  View details for Web of Science ID 000411931708112

• Novel Therapeutics in Acute Myeloid Leukemia. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting DiNardo, C. D., Stone, R. M., Medeiros, B. C. 2017: 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 10.1200/EDBK_175401

  View details for PubMedID 30372205

• 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 PubMedID 28355571

• Analysis of Transplantation Rate and Overall Treatment Efficacy by Age for Patients Aged 60 to 75 with Untreated Secondary Acute Myeloid Leukemia (AML) Given CPX-351 Liposome Injection Versus Conventional Cytarabine and Daunorubicin in a Phase III Trial Lancet, J., Uy, G. L., Cortes, J., Newell, L. F., Lin, T. L., Ritchie, E., Stuart, R., Strickland, S., Hogge, D., Solomon, S. R., Stone, R. M., Bixby, D. L., Kolitz, J. E., Schiller, G. J., Wieduwilt, M. J., Ryan, D. H., Hoering, A., Chiarella, M., Louie, A. C., Medeiros, B. C. ELSEVIER SCIENCE INC. 2017: S31–S32

  View details for Web of Science ID 000540635000019

• 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

  View details for PubMedCentralID PMC5386335

• Isocitrate dehydrogenase mutations in myeloid malignancies LEUKEMIA Medeiros, B. C., Fathi, A. T., Dinardo, C. D., Pollyea, D. A., Chan, S. M., SWORDS, R. 2017; 31 (2): 272-281

  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 Web of Science ID 000394058800002

• A Study of Disseminated Intravascular Coagulation in Acute Leukemia Reveals Markedly Elevated D-Dimer Levels Are a Sensitive Indicator of Acute Promyelocytic Leukemia Oak, J., Shahmarvand, N., Alcasid, M., Cascio, M., Goodman, E., Medeiros, B., Arber, D. A., Zehnder, J., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 367A

  View details for Web of Science ID 000393724401747

• A Study of Disseminated Intravascular Coagulation in Acute Leukemia Reveals Markedly Elevated D-Dimer Levels Are a Sensitive Indicator of Acute Promyelocytic Leukemia Oak, J., Shahmarvand, N., Alcasid, M., Cascio, M., Goodman, E., Medeiros, B., Arben, D. A., Zehnder, J., Ohgami, R. NATURE PUBLISHING GROUP. 2017: 367A

  View details for Web of Science ID 000394467302050

• 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. n., Oak, J. S., Cascio, M. J., Alcasid, M. n., Goodman, E. n., 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 PubMedID 28422420

• 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. n., Khanna, V. n., Savage, S. L., Rofelty, A. n., English, I. n., Ho, H. n., Pandya, R. n., Bolosky, W. J., Poon, H. n., Deininger, M. W., Collins, R. n., Swords, R. T., Watts, J. n., Pollyea, D. A., Medeiros, B. C., Traer, E. n., Tognon, C. E., Mori, M. n., 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 PubMedID 28784769

• 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 PubMedID 28760807

• Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial. Leukemia DeAngelo, D. J., George, T. I., Linder, A. n., Langford, C. n., Perkins, C. n., Ma, J. n., Westervelt, P. n., Merker, J. D., Berube, C. n., Coutre, S. n., Liedtke, M. n., Medeiros, B. n., Sternberg, D. n., Dutreix, C. n., Ruffie, P. A., Corless, C. n., Graubert, T. J., Gotlib, J. n. 2017

  Abstract

  Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.Leukemia advance online publication, 25 August 2017; doi:10.1038/leu.2017.234.

  View details for PubMedID 28744009

• Randomized study of continuous high-dose lenalidomide, sequential azacitidine and lenalidomide or azacitidine in persons ≥65 years with newly-diagnosed acute myeloid leukemia. Haematologica Medeiros, B. C., McCaul, K. n., Kambhampati, S. n., Pollyea, D. A., Kumar, R. n., Silverman, L. R., Kew, A. n., Saini, L. n., Beach, C. L., Vij, R. n., Wang, X. n., Zhong, J. n., Gale, R. P. 2017

  Abstract

  Therapy of acute myeloid leukemia in older persons is associated with poor outcomes because of intolerance to intensive therapy, resistant disease and co-morbidities. This multi-center, randomized, open-label, phase-2 trial compared safety and efficacy of three therapeutic strategies in persons ≥65 years with newly-diagnosed acute myeloid leukemia: (1) continuous high-dose lenalidomide (N=15); (2) sequential azacitidine and lenalidomide (N=39); and (3) azacitidine (N=34) only. The efficacy endpoint was 1-year survival. Median age was 76 years (range, 66-87 years). Thirteen subjects (15%) had prior myelodysplastic syndrome and 41 (47%), adverse cytogenetics. One-year survival was 21% (95% confidence interval, 0, 43%) with high-dose lenalidomide, 44% (28, 60%) with sequential azacitidine and lenalidomide, and 52% (35, 70%) with azacitidine only. Lenalidomide at a continuous high-dose schedule was poorly-tolerated resulting in a high rate of early-therapy discontinuations. Hazard of death in the 1(st) 4 months was greatest in subjects receiving continuous high-dose lenalidomide; hazards of death thereafter were similar. These data do not favor use of continuous high-dose lenalidomide or sequential lenalidomide and azacitidine over the conventional dose and schedule of azacitidine only in persons aged ≥65 years with newly-diagnosed acute myeloid leukemia. The study is registered at ClinicalTrials.gov (NCT01358734).

  View details for PubMedID 29097499

• Effects of Education and Income on Treatment and Outcome in Patients With Acute Myeloid Leukemia in a Tax-Supported Health Care System: A National Population-Based Cohort Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Østgård, L. S., Nørgaard, M. n., Medeiros, B. C., Friis, L. S., Schoellkopf, C. n., Severinsen, M. T., Marcher, C. W., Nørgaard, J. M. 2017: JCO2017736728

  Abstract

  Purpose Previous US studies have shown that socioeconomic status (SES) affects survival in acute myeloid leukemia (AML). However, no large study has investigated the association between education or income and clinical characteristics, treatment, and outcome in AML. Methods To investigate the effects of education and income in a tax-supported health care system, we conducted a population-based study using individual-level SES and clinical data on all Danish patients with AML (2000 to 2014). We compared treatment intensity, allogeneic transplantation, and response rates by education and income level using logistic regression (odds ratios). We used Cox regression (hazard ratios [HRs]) to compare survival, adjusting for age, sex, SES, and clinical prognostic markers. Results Of 2,992 patients, 1,588 (53.1%) received intensive chemotherapy. Compared with low-education patients, highly educated patients more often received allogeneic transplantation (16.3% v 8.7%). In intensively treated patients younger than 60 years of age, increased mortality was observed in those with lower and medium education (1-year survival, 66.7%; adjusted HR, 1.47; 95% CI, 1.11 to 1.93; and 1-year survival, 67.6%; adjusted HR, 1.55; CI, 1.21 to 1.98, respectively) compared with higher education (1-year survival, 76.9%). Over the study period, 5-year survival improvements were limited to high-education patients (from 39% to 58%), increasing the survival gap between groups. In older patients, low-education patients received less intensive therapy (30% v 48%; adjusted odds ratio, 0.65; CI, 0.44 to 0.98) compared with high-education patients; however, remission rates and survival were not affected in those intensively treated. Income was not associated with therapy intensity, likelihood of complete remission, or survival (high income: adjusted HR, 1.0; medium income: adjusted HR, 0.96; 95% CI, 0.82 to 1.12; low income: adjusted HR, 1.06; CI, .88 to 1.27). Conclusion In a universal health care system, education level, but not income, affects transplantation rates and survival in younger patients with AML. Importantly, recent survival improvement has exclusively benefitted highly educated patients.

  View details for PubMedID 28892433

• Development and Validation of a Novel Acute Myeloid Leukemia-Composite Model to Estimate Risks of Mortality. JAMA oncology Sorror, M. L., Storer, B. E., Fathi, A. T., Gerds, A. T., Medeiros, B. C., Shami, P. n., Brunner, A. M., Sekeres, M. A., Mukherjee, S. n., Peña, E. n., Elsawy, M. n., Wardyn, S. n., Whitten, J. n., Moore, R. n., Becker, P. S., McCune, J. S., Appelbaum, F. R., Estey, E. H. 2017

  Abstract

  To our knowledge, this multicenter analysis is the first to test and validate (1) the prognostic impact of comorbidities on 1-year mortality after initial therapy of acute myeloid leukemia (AML) and (2) a novel, risk-stratifying composite model incorporating comorbidities, age, and cytogenetic and molecular risks.To accurately estimate risks of mortality by developing and validating a composite model that combines the most significant patient-specific and AML-specific features.This is a retrospective cohort study. A series of comorbidities, including those already incorporated into the hematopoietic cell transplantation-comorbidity index (HCT-CI), were evaluated. Patients were randomly divided into a training set (n = 733) and a validation set (n = 367). In the training set, covariates associated with 1-year overall mortality at a significance level of P < .10 constructed a multivariate Cox proportional hazards model in which the impact of each covariate was adjusted for that of all others. Then, the adjusted hazard ratios were used as weights. Performances of models were compared using C statistics for continuous outcomes and area under the curve (AUC) for binary outcomes.Initial therapy for AML.Death within 1 year after initial therapy for AML.A total of 1100 patients, ages 20 to 89 years, were treated for AML between January 1, 2008, and December 31, 2012, at 5 academic institutions specialized in treating AML; 605 (55%) were male, and 495 (45%) were female. In the validation set, the original HCT-CI had better C statistic and AUC estimates compared with the AML comorbidity index for prediction of 1-year mortality. Augmenting the original HCT-CI with 3 independently significant comorbidities, hypoalbuminemia, thrombocytopenia, and high lactate dehydrogenase level, yielded a better C statistic of 0.66 and AUC of 0.69 for 1-year mortality. A composite model comprising augmented HCT-CI, age, and cytogenetic/molecular risks had even better predictive estimates of 0.72 and 0.76, respectively.In this cohort study, comorbidities influenced 1-year survival of patients with AML, and comorbidities are best captured by an augmented HCT-CI. The augmented HCT-CI, age, and cytogenetic/molecular risks could be combined into an AML composite model that could guide treatment decision-making and trial design in AML. Studying physical, cognitive, and social health might further clarify the prognostic role of aging. Targeting comorbidities with interventions alongside specific AML therapy might improve survival.

  View details for PubMedID 28880971

• Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm. Haematologica Walter, R. B., Othus, M. n., Orlowski, K. F., McDaniel, E. N., Scott, B. L., Becker, P. S., Percival, M. M., Hendrie, P. C., Medeiros, B. C., Chiarella, M. T., Louie, A. C., Estey, E. H. 2017

  View details for PubMedID 29242304

• Impact of Allogeneic Stem Cell Transplantation in First Complete Remission in Acute Myeloid Leukemia: a National Population-Based Cohort Study. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Østgård, L. S., Lund, J. L., Nørgaard, J. M., Nørgaard, M. n., Medeiros, B. C., Nielsen, B. n., Nielsen, O. J., Overgaard, U. M., Kallenbach, M. n., Marcher, C. W., Riis, A. H., Sengeløv, H. n. 2017

  Abstract

  To examine the outcome of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared to chemotherapy alone in a population-based setting, we identified a cohort of acute myeloid leukemia (AML) patients aged 15-70 years diagnosed between 2000-2014 in Denmark. Using the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival between patients with non-favorable cytogenetic features receiving post-remission therapy with conventional chemotherapy-only versus those undergoing HSCT in CR1. To minimize immortal time bias, we performed Cox proportional hazards regression, included date of alloHSCT as a time-dependent covariate, and stratified results by age, (<60, ≥60 years) and cytogenetic risk group. Overall, 1031 patients achieved a CR1. Of these, 196 patients (19%) underwent HSCT. HSCT was associated with decreased relapse-rates (24% versus 49%), despite similar median-time to relapse (287 days versus 265 days). In all subgroups, the risk of relapse was lower, and both relapse-free and overall survival was superior among patients receiving HSCT (overall survival, adjusted mortality ratios (MRs): all patients: 0.54 (CI=0.42-0.71), patients<60 years, 0.58 (CI=0.42-0.81), patients≥60 years, 0.42 (CI=0.26-0.69), intermediate risk cytogenetics, 0.63 (CI=0.43-0.87), and adverse risk cytogenetics, 0.40 (CI=0.24-0.67)). In conclusion, in this population-based nation-wide cohort study, HSCT was associated with improved survival both in younger and older patients with intermediate and adverse cytogenetic risk.

  View details for PubMedID 29051022

• Localized skin-limited blastic plasmacytoid dendritic cell neoplasm: A subset with possible durable remission without transplantation. JAAD case reports Amitay-Laish, I. n., Sundram, U. n., Hoppe, R. T., Hodak, E. n., 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

• Unpaired extracellular cysteine mutations of CSF3R mediate gain or loss of function. Cancer research Zhang, H. n., Means, S. n., Schultz, A. R., Watanabe-Smith, K. n., Medeiros, B. C., Bottomly, D. n., Wilmot, B. n., McWeeney, S. K., Kükenshöner, T. n., Hantschel, O. n., 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 PubMedID 28652245

• Feasibility of Allogeneic Hematopoietic Cell Transplantation Among High-Risk AML Patients in First Complete Remission: Results of the Transplant Objective from the SWOG (S1203) Randomized Phase III Study of Induction Therapy Using Standard 7+3 Therapy or Idarubicin with High-Dose Cytarabine (IA) Versus IA Plus Vorinostat Pagel, J. M., Othus, M., Garcia-Manero, G., Fang, M., Radich, J. P., Rizzieri, D. A., Marcucci, G., Strickland, S. A., Litzow, M., Savoie, M., Spellman, S. R., Confer, D. L., Chell, J., Brown, M., Medeiros, B. C., Sekeres, M. A., Lin, T. L., Uy, G. L., Powell, B. L., Kolitz, J. E., Larson, R. A., Stone, R. M., Claxton, D. F., Essell, J., Luger, S., Mohan, S. R., Moseley, A., Erba, H. P., Appelbaum, F. R. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446807012

• Intensive Versus Non-Intensive Induction Therapy for Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) Using Two Different Novel Prognostic Models Sorror, M. L., Storer, B. E., Elsawy, M., Fathi, A. T., Brunner, A. M., Gerds, A. T., Sekeres, M. A., Mukherjee, S., Medeiros, B. C., Wang, E. S., Vachhani, P., Shami, P. J., Pena, E., Wardyn, S., Whitten, J., Moore, R., Becker, P. S., McCune, J., Lee, S. J., Sandmaier, B. M., Appelbaum, F. R., Estey, E. H. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446802103

• A Phase 2 Study of Pracinostat and Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML) Not Eligible for Induction Chemotherapy: Response and Long-Term Survival Benefit Manero, G., Atallah, E., Khaled, S. K., Arellano, M., Patnaik, M. M., Odenike, O., Sayar, H., Tummala, M., Patel, P. A., Ghalie, R. G., Medeiros, B. C. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446803016

• Survival Following Allogeneic Hematopoietic Cell Transplantation in Older High-Risk Acute Myeloid Leukemia Patients Initially Treated with CPX-351 Liposome Injection Versus Standard Cytarabine and Daunorubicin: Subgroup Analysis of a Large Phase III Trial Lancet, J. E., Hoering, A., Uy, G. L., Cortes, J. E., Newell, L. F., Lin, T. L., Ritchie, E. K., Stuart, R. K., Strickland, S. A., Hogge, D., Solomon, S. R., Stone, R. M., Bixby, D. L., Kolitz, J. E., Schiller, G. J., Wieduwilt, M. J., Ryan, D. H., Chiarella, M. T., Louie, A. C., Medeiros, B. C. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446802160

• SWOG S1203: A Randomized Phase III Study of Standard Cytarabine Plus Daunorubicin (7+3) Therapy Versus Idarubicin with High Dose Cytarabine (IA) with or without Vorinostat (IA plus V) in Younger Patients with Previously Untreated Acute Myeloid Leukemia (AML) Garcia-Manero, G., Othus, M., Pagel, J. M., Radich, J. P., Fang, M., Rizzieri, D. A., Marcucci, G., Strickland, S. A., Litzow, M., Savoie, M., Medeiros, B. C., Sekeres, M. A., Lin, T. L., Uy, G. L., Powell, B. L., Kolitz, J. E., Larson, R. A., Stone, R. M., Claxton, D. F., Essell, J., Luger, S., Mohan, S. R., Moseley, A., Appelbaum, F. R., Erba, H. P. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446802158

• Analysis of Efficacy By Age for Patients Aged 60-75 with Untreated Secondary Acute Myeloid Leukemia (AML) Treated with CPX-351 Liposome Injection Versus Conventional Cytarabine and Daunorubicin in a Phase III Trial Medeiros, B. C., Lancet, J. E., Cortes, J. E., Newell, L. F., Lin, T. L., Ritchie, E. K., Stuart, R. K., Strickland, S. A., Hogge, D., Solomon, S. R., Stone, R. M., Bixby, D. L., Kolitz, J. E., Schiller, G. J., Wieduwilt, M. J., Ryan, D. H., Hoering, A., Chiarella, M. T., Louie, A. C., Uy, G. L. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446802157

• 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

  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 Web of Science ID 000386880300007

• 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

• Optimizing infusion scheduling through lean methods and data science. Medeiros, B. C., Healy, D., Seshadri, S., Rosenthal, E., Martin, J., Giridharadas, M., Cassidy, H., DeMarco, S. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.e18240

  View details for Web of Science ID 000404711504097

• Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. Lancet, J. E., Uy, G. L., Cortes, J. E., Newell, L. F., Lin, T. L., Ritchie, E. K., Stuart, R. K., Strickland, S., Hogge, D., Solomon, S. R., Stone, R. M., Bixby, D. L., Kolitz, J. E., Schiller, G. J., Wieduwilt, M., Ryan, D. H., Hoering, A., Chiarella, M., Louie, A., Medeiros, B. C. AMER SOC CLINICAL ONCOLOGY. 2016

  View details for DOI 10.1200/JCO.2016.34.15_suppl.7000

  View details for Web of Science ID 000404711504136

• 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

  Abstract

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

  View details for DOI 10.3109/10428194.2015.1091930

  View details for Web of Science ID 000372499800017

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

  Abstract

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

  View details for DOI 10.3109/10428194.2015.1091930

  View details for PubMedID 26374199

• 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 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

• 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 Abrahão, R. n., Keogh, R. H., Lichtensztajn, D. Y., Marcos-Gragera, R. n., Medeiros, B. C., Coleman, M. P., Ribeiro, R. C., Keegan, T. H. 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 PubMedID 26847024

• Real-World Treatment Patterns and Outcomes among Elderly Acute Myeloid Leukemia Patients in the United States BIG DATA ON REAL-WORLD APPLICATIONS Satram-Hoang, S., Reyes, C., Hurst, D., Hoang, K. Q., Medeiros, B. C., Soto, S. V., Luna, J. M., Cano, A. 2016: 23–40

  View details for DOI 10.5772/63758

  View details for Web of Science ID 000432397700003

• 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

  View details for PubMedCentralID PMC5025885

• 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 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

• Impact of Comorbidities at Diagnosis of Acute Myeloid Leukemia on One-Year Mortality Sorror, M. L., Storer, B. E., Elsawy, M., Fathi, A. T., Brunner, A., Gerds, A. T., Sekeres, M. A., Mukherjee, S., Medeiros, B. C., Shami, P., Pena, E., Wardyn, S., Whitten, J., Frenkel, H., McCune, J., Lee, S. J., Estey, E. H. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019001278

• The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) Stone, R. M., Mandrekar, S., Sanford, B. L., Geyer, S., Bloomfield, C. D., Dohner, K., Thiede, C., 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., Dohner, H. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019000070

• Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial Stein, E. M., DiNardo, C., Altman, J. K., Collins, R., DeAngelo, D. J., Kantarjian, H. M., Sekeres, M. A., Fathi, A. T., Flinn, I. W., Frankel, A. E., Levine, R. L., Medeiros, B. C., Patel, M. R., Pollyea, D., Roboz, G. J., Stone, R. M., Swords, R. T., Tallman, M. S., Yen, K., Attar, E. C., Xu, Q., Tosolini, A., Mei, J. M., Thakurta, A., Knight, R. D., De Botton, S. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019001075

• Final Results from a Phase 2 Study of Pracinostat in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML) Garcia-Manero, G., Atallah, E., Khaled, S. K., Arellano, M., Patnaik, M. M., Butler, T. A., Ashby, C., Medeiros, B. C. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019001205

• Predictors of Early Death and Survival Among Children, Adolescents and Young Adults with Acute Myeloid Leukemia in California, 1988-2011: A Population-Based Study Abrahao, R., Keogh, R. H., Lichtensztajn, D. Y., Marcos-Gragera, R., Medeiros, B. C., Coleman, M. I., Ribeiro, R. C., Keegan, T. M. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019004123

• A Phase 1b Study of Panobinostat in Combination with Idarubicin and Ara-C in Patients with High-Risk Acute Myeloid Leukemia DeAngelo, D. J., Walker, A. R., Schlenk, R. F., Sierra, J., Medeiros, B. C., Ocio, E. M., Roellig, C., Strickland, S. A., Thol, F., Valera, S., Wegener, A., De, T., Mu, S., Binlich, F., Stuart, R. K. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368020102065

• 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

• 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

• 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

• 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

• Allogeneic hematopoietic cell transplant for normal karyotype AML: indirect evidence of selection for adverse molecular profile. Bone marrow transplantation Percival, M. M., Medeiros, B. C., Tian, L. n., Robeson, S. n., Laport, G. G., Johnston, L. J., Shizuru, J. A., Miklos, D. B., Arai, S. n., Weng, W. K., Negrin, R. S., Lowsky, R. n. 2015

  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 Abrahão, R. n., Ribeiro, R. C., Medeiros, B. C., Keogh, R. H., Keegan, T. H. 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 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

  View details for DOI 10.1016/j.leukres.2014.10.007

  View details for Web of Science ID 000346858200004

  View details for PubMedID 25499234

• Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia. Leukemia Khalife, J. n., Radomska, H. S., Santhanam, R. n., Huang, X. n., Neviani, P. n., Saultz, J. n., Wang, H. n., Wu, Y. Z., Alachkar, H. n., Anghelina, M. n., Dorrance, A. n., Curfman, J. n., Bloomfield, C. D., Medeiros, B. C., Perrotti, D. n., Lee, L. J., Lee, R. J., Caligiuri, M. A., Pichiorri, F. n., Croce, C. M., Garzon, R. n., Guzman, M. L., Mendler, J. H., Marcucci, G. n. 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 PubMedID 25971362

• Preclinical Activity of a New Proteasome Inhibitor, MLN9708, in Acute Myelogenous Leukemias Expressing NPM1 Mutated Protein Garcia, J. S., Huang, M., Medeiros, B. C., Mitchell, B. S. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242705110

• AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a Phase I Study in Patients with IDH2 Mutation Positive Advanced Hematologic Malignancies Stein, E. M., Altman, J. K., Collins, R., DeAngelo, D. J., Fathi, A. T., Flinn, I., Frankel, A., Levine, R. L., Medeiros, B. C., Patel, M., Pollyea, D. A., Roboz, G. J., Stone, R. M., Swords, R. T., Tallman, M. S., Agresta, S., Fan, B., Yang, H., Yen, K., de Botton, S. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233806164

• Isocitrate Dehydrogenase Mutations Induce BCL-2 Dependence in Acute Myeloid Leukemia through Inhibition of Cytochrome C Oxidase Function Chan, S. M., Thomas, D., Medeiros, B. C., Majeti, R. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233803063

• Big Data Analysis of Treatment Patterns and Outcomes Among Elderly Medicare Acute Myeloid Leukemia Patients Satram-Hoang, S., Reyes, C., Hoang, K. Q., Momin, F., Hurst, D., Medeiros, B. C. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233803127

• Improvements in the Early Death Rate in Younger Acute Myeloid Leukemia Patients Following Initial Therapy: A SEER Database Analysis Percival, M. M., Tao, L., Medeiros, B. C., Clarke, C. A. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349233804170

• Mass Cytometric Analysis of AML Stem and Early Progenitor Cells Reveals Karyotype and Genotype-Specific Cell Cycle Properties That Correlate with Known Responses to Chemotherapy Behbehani, G. K., Fantl, W. J., Medeiros, B. C., Nolan, G. P. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243504132

• Mass Cytometric Analysis of AML Stem and Early Progenitor Cells Reveals Karyotype and Genotype-Specific Immunophenotypes That May Represent Targets for Antibody-Directed Therapies Behbehani, G. K., Fantl, W. J., Medeiros, B. C., Nolan, G. P. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243504181

• Pevonedistat (MLN4924), an Investigational, First-in-Class NAE Inhibitor, in Combination with Azacitidine in Elderly Patients with Acute Myeloid Leukemia (AML) Considered Unfit for Conventional Chemotherapy: Updated Results from the Phase 1 C15009 Trial Swords, R. T., Savona, M. R., Maris, M. B., Erba, H. P., Berdeja, J. G., Foran, J. M., Hua, Z., Faessel, H. M., Dash, A. B., Sedarati, F., Dezube, B. J., Medeiros, B. C. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243505126

• Pracinostat in Combination with Azacitidine Produces a High Rate and Rapid Onset of Disease Remission in Patients with Previously Untreated Acute Myeloid Leukemia (AML) Garcia-Manero, G., Atallah, E., Odenike, O., Medeiros, B. C., Cortes, J. E., Esquibel, V., Cha, S., Khaled, S. K. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349243506106

• Comparative Effectiveness of Chemotherapy in an Elderly Acute Myeloid Leukemia Population in the United States Medeiros, B. C., Satram-Hoang, S., Hoang, K. Q., Momin, F., Hurst, D., Reyes, C. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242700202

• Real-World Outcomes Among Elderly Acute Myeloid Leukemia Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation Medeiros, B. C., Satram-Hoang, S., Hoang, K. Q., Momin, F., Hurst, D., Reyes, C. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242704082

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

  Abstract

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

  View details for DOI 10.1016/j.leukres.2014.09.018

  View details for Web of Science ID 000345614400011

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

  Abstract

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

  View details for DOI 10.1016/j.leukres.2014.09.018

  View details for PubMedID 25449689

• 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

• Mutations in UBA3 Confer Resistance to the NEDD8-Activating Enzyme Inhibitor MLN4924 in Human Leukemic Cells (vol 9, e93530, 2014) PLOS ONE Xu, G. W., Toth, J., da Silva, S. R., Paiva, S., Lukkarila, J. L., Medeiros, B. 2014; 9 (10)

  View details for DOI 10.1371/journal.pone.0112004

  View details for Web of Science ID 000343674800135

• 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

• 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

• 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 PubMedID 24879117

• Mutations in UBA3 Confer Resistance to the NEDD8-Activating Enzyme Inhibitor MLN4924 in Human Leukemic Cells PLOS ONE Xu, G. W., Toth, J. I., da Silva, S. R., Paiva, S., Lukkarila, J. L., Hurren, R., Maclean, N., Sukhai, M. A., Bhattacharjee, R. N., Goard, C. A., Gunning, P. T., dhe-Paganon, S., Petroski, M. D., Schimmer, A. D. 2014; 9 (4)

  Abstract

  The NEDD8-activating enzyme (NAE) initiates neddylation, the cascade of post-translational NEDD8 conjugation onto target proteins. MLN4924, a selective NAE inhibitor, has displayed preclinical anti-tumor activity in vitro and in vivo, and promising clinical activity has been reported in patients with refractory hematologic malignancies. Here, we sought to understand the mechanisms of resistance to MLN4924. K562 and U937 leukemia cells were exposed over a 6 month period to MLN4924 and populations of resistant cells (R-K562(MLN), R-U937(MLN)) were selected. R-K562(MLN) and R-U937(MLN) cells contain I310N and Y352H mutations in the NAE catalytic subunit UBA3, respectively. Biochemical analyses indicate that these mutations increase the enzyme's affinity for ATP while decreasing its affinity for NEDD8. These mutations effectively contribute to decreased MLN4924 potency in vitro while providing for sufficient NAE function for leukemia cell survival. Finally, R-K562(MLN) cells showed cross-resistance to other NAE-selective inhibitors, but remained sensitive to a pan-E1 (activating enzyme) inhibitor. Thus, our work provides insight into mechanisms of MLN4924 resistance to facilitate the development of more effective second-generation NAE inhibitors.

  View details for DOI 10.1371/journal.pone.0093530

  View details for Web of Science ID 000334101100099

  View details for PubMedID 24691136

  View details for PubMedCentralID PMC3972249

• 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

  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 Web of Science ID 000330333200009

  View details for PubMedID 24453295

• Consolidation therapy in acute myeloid leukemia CANCER CONSULT: EXPERTISE FOR CLINICAL PRACTICE Behbehani, G. K., Medeiros, B. C., Abutalib, S. A., Markman, M. 2014: 67–70

  View details for Web of Science ID 000351672800010

• 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

  View details for PubMedCentralID PMC4007917

• 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

• 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

• 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

• Qualitative Analysis of Practicing Oncologists' Attitudes and Experiences Regarding Collection of Patient-Reported Outcomes JOURNAL OF ONCOLOGY PRACTICE Jagsi, R., Chiang, A., Polite, B. N., Medeiros, B. C., McNiff, K., Abernethy, A. P., Zon, R., Loehrer, P. J. 2013; 9 (6): E290–E297

  View details for DOI 10.1200/JOP.2012.000823

  View details for Web of Science ID 000214657800003

• 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

  View details for DOI 10.1016/j.leukres.2012.10.013

  View details for Web of Science ID 000313636700001

  View details for PubMedID 23146558

• 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

• Qualitative analysis of practicing oncologists' attitudes and experiences regarding HIT-facilitated collection of patientreported outcomes Jagsi, R., Chiang, A. C., Medeiros, B. C., Polite, B. N., McNiff, K., Zon, R., Loehrer, P. J. AMER SOC CLINICAL ONCOLOGY. 2012

  View details for DOI 10.1200/jco.2012.30.34_suppl.56

  View details for Web of Science ID 000208943900056

• Amrubicin, a Novel Investigational Anthracycline, in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Results of a Phase 1 Dose-Escalation Study Dinner, S. N., Dunn, T. J., Medeiros, B. C., Coutre, S. E., Berube, C., Gotlib, J., Liedtke, M. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000314049603073

• Azacitidine Plus Lenalidomide for Untreated AML Patients Ineligible for Conventional Chemotherapy Pollyea, D. A., Zehnder, J. L., Coutre, S., Gotlib, J., Gallegos, L., Greenberg, P., Zhang, B., Liedtke, M., Levine, R. L., Medeiros, B. C. AMER SOC HEMATOLOGY. 2012

  View details for Web of Science ID 000313838906082

• 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

  View details for Web of Science ID 000313838906063

• 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

  View details for Web of Science ID 000314049604427

• 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

  View details for Web of Science ID 000313838903369

• 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

  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 Web of Science ID 000309901900005

• 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

  View details for PubMedCentralID PMC3436242

• 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

  Abstract

  The incidence of multiple myeloma (MM) increases with age, and with the aging of the population, the number of adults with MM is expected to double in the next 20 years. Novel agents, including the immunomodulatory agents thalidomide and lenalidomide, and the proteosome inhibitor bortezomib have dramatically changed the treatment of multiple myeloma in the past decade. The purpose of this review was to examine the recent clinical therapeutic trials in older adults with MM. A number of trials have evaluated the addition of novel agents to the traditional backbone of melphalan and prednisone. The combination of thalidomide with melphalan and prednisone has been evaluated in 7 randomized trials. The combination improves response rates and, in meta-analyses, survival, but at the expense of increased toxicity. Other combination regimens which include lenalidomide or bortezomib likewise are associated with higher response rates, but at the expense of greater toxicity. High dose dexamethasone is excessively toxic in older adults and should be avoided. The roles for high-dose therapy with autologous stem cell transplant or intermediate-dose melphalan with autologous stem cell transplant in older adults with MM in the era of modern therapy remain to be defined. In summary, there are a number of new therapeutic options for older adults with MM, allowing an individualized treatment strategy based on the patient's comorbidities and goals of care.

  View details for DOI 10.1016/j.jgo.2012.02.001

  View details for Web of Science ID 000305864400015

  View details for PubMedCentralID PMC3458649

• 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

  View details for PubMedCentralID PMC3490403

• 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

  View details for PubMedCentralID PMC3342977

• 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

  View details for DOI 10.1016/j.leukres.2011.10.028

  View details for Web of Science ID 000298658600003

  View details for PubMedID 22112975

• 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

• 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

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

  Abstract

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

  View details for DOI 10.3324/haematol.2011.046490

  View details for Web of Science ID 000299870500022

  View details for PubMedID 21993679

  View details for PubMedCentralID PMC3248942

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

  Abstract

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

  View details for DOI 10.3324/haematol.2011.045997

  View details for Web of Science ID 000299870500009

  View details for PubMedID 21993685

  View details for PubMedCentralID PMC3248928

• 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

  View details for Web of Science ID 000299597105346

• Absolute Lymphocyte Count At Day 28 Independently Predicts Event-Free and Overall Survival in Adults with Newly Diagnosed Acute Lymphocytic Leukemia Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A. A., Bates, J., Sekeres, M. A., Coutre, S. E., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. AMER SOC HEMATOLOGY. 2011: 1095

  View details for Web of Science ID 000299597103418

• Gemtuzumab Ozogamicin in Combination with Vorinostat and Azacitidine As Induction and Post-Remission Therapy in Older Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML): A Phase 1 Study Walter, R. B., Medeiros, B. C., Gardner, K. M., Estey, E. H. AMER SOC HEMATOLOGY. 2011: 670

  View details for Web of Science ID 000299597102136

• 2-Hydroxyglutarate in IDH mutant AML: Predicting Patient Responses, Minimal Residual Disease and Correlations with Methylcytosine and Hydroxymethylcytosine Levels Pollyea, D. A., Kohrt, H. E., Zhang, B., Zehnder, J. L., Schenkein, D. P., Fantin, V., Straley, K., Vasanthakumar, A., Abdel-Wahab, O., Levine, R. L., Godley, L., Medeiros, B. C. AMER SOC HEMATOLOGY. 2011: 1073–74

  View details for Web of Science ID 000299597103375

• 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

• Personalized medicine for acute myelogenous leukemia-At the entrance gate AMERICAN JOURNAL OF HEMATOLOGY Swords, R. T., Dezube, B. J., Medeiros, B. C. 2011; 86 (8): 631–32

  View details for DOI 10.1002/ajh.22060

  View details for Web of Science ID 000293508600001

  View details for PubMedID 21761430

• Cytarabine Dose for Acute Myeloid Leukemia NEW ENGLAND JOURNAL OF MEDICINE Mori, J., Tsubokura, M., Kami, M. 2011; 364 (22): 2166–67

  View details for Web of Science ID 000291200700026

  View details for PubMedID 21631342

• 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

• Influence of residual normal metaphases in acute myeloid leukemia patients with monosomal karyotype HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Xie, B., Othus, M., Medeiros, B. C., Fang, M., Appelbaum, F. R., Estey, E. H. 2011; 96 (4): 631–32

  View details for DOI 10.3324/haematol.2010.037838

  View details for Web of Science ID 000289658600025

  View details for PubMedID 21330329

  View details for PubMedCentralID PMC3069244

• 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

• 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

  View details for Web of Science ID 000289662203644

• Update of a Phase I/II Trial of 5-Azacytidine Prior to Gemtuzumab Ozogamicin (GO) for Patients with Relapsed Acute Myeloid Leukemia with Correlative Biomarker Studies Ball, E. D., Medeiros, B. C., Balaian, L., Roque, T., Corringham, S., Rajwanshi, R., Coutre, S., Gotlib, J. R., Bashey, A., Messer, K. AMER SOC HEMATOLOGY. 2010: 1346

  View details for Web of Science ID 000289662203617

• The Novel, Investigational NEDD8-Activating Enzyme Inhibitor MLN4924 In Adult Patients with Acute Myeloid Leukemia (AML) or High-Grade Myelodysplastic Syndromes (MDS): A Phase 1 Study Swords, R. T., Erba, H. P., DeAngelo, D. J., Smith, P. G., Pickard, M. D., Dezube, B. J., Giles, F. J., Medeiros, B. C. AMER SOC HEMATOLOGY. 2010: 288

  View details for Web of Science ID 000289662200659

• Influence of Residual Normal Metaphases In Patients with Monosomal Karyotype. Xie, B., Othus, M., Medeiros, B. C., Fang, M., Appelbaum, F. R., Estey, E. H. AMER SOC HEMATOLOGY. 2010: 701

  View details for Web of Science ID 000289662201772

• 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

  View details for Web of Science ID 000289662203619

• 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

  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 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 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

  View details for Web of Science ID 000279051300074

• 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

  View details for Web of Science ID 000272725801195

• The PI3K Inhibitor GDC-0941 Induces Growth Arrest and Apoptosis of Acute Myeloid Leukemia Cells Sun, L., Berry, L., Du, C., Ma, X., Shi, L., Medeiros, B. C., Ebens, A. J. AMER SOC HEMATOLOGY. 2009: 1456

  View details for Web of Science ID 000272725804451

• A Phase I/II Trial of 5-Azacytidine Prior to Gemtuzumab Ozogamicin (GO) for Patients with Relapsed Acute Myeloid Leukemia with Correlative Biomarker Studies. Ball, E. D., Medeiros, B. C., Balaian, L., Roque, T., Corringham, S., Rajwanshi, R., Coutre, S., Gotlib, J. R., Bashey, A., Messer, K. AMER SOC HEMATOLOGY. 2009: 809

  View details for Web of Science ID 000272725802417

• High Risk of Early Mortality in Adult Patients with Acquired Hemophagocytic Lymphohistiocytosis. Logan, A. C., Su, R., George, T. I., Kohrt, H. E., Medeiros, B. C., Alizadeh, A. A. AMER SOC HEMATOLOGY. 2009: 554

  View details for Web of Science ID 000272725801539

• 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

  View details for Web of Science ID 000272725801797

• 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

  View details for Web of Science ID 000271335700002

• 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

  View details for Web of Science ID 000276606605042

• Baseline status of O (6)-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and effect of protracted doses of temozolomide on MGMT in acute leukemia. Medeiros, B., Khan, S., Rajwanshi, R., Jones, C., Zehnder, J. AMER ASSOC CANCER RESEARCH. 2009

  View details for Web of Science ID 000209702702111

• CD38(hi)CD138(+) bone marrow cells from multiple myeloma patients engraft into human bone microenvironments in humanized mice. Kim, D., Medeiros, B., Weissman, I. AMER ASSOC CANCER RESEARCH. 2009

  View details for Web of Science ID 000209702603182

• 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

• 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

• 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

• 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

  View details for Web of Science ID 000262486301256

• Tailored Temozolomide Therapy for Elderly Patients with Acute Myeloid Leukemia. Medeiros, B. C., Gotlib, J. R., Coutre, S. E., Mignea, A., Zehnder, J. AMER SOC HEMATOLOGY. 2008: 351

  View details for Web of Science ID 000262104701178

• 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