Publications by authors named "Meir Wetzler"

138 Publications

Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia.

Cancer Chemother Pharmacol 2020 09 3;86(3):325-337. Epub 2020 Aug 3.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA.

Background: AML patients with FLT3/ITD mutations have poor response to cytarabine-based chemotherapy. FLT3 inhibitors (FLT3i) may resensitize cells to cytarabine (CYT). Improving treatment outcome of this combination may benefit from a mechanistic extrapolation approach from in vitro data.

Methods: The effects of CYT and several FLT3i on cell proliferation and cell cycle kinetics were examined in AML cell lines. The effect of FLT3i (quizartinib, midostaurin, sorafenib) on cell proliferation and cell cycle kinetics was assessed in AML cell lines with differing FLT3 status; HEL (negligible expression of wild-type FLT3), EOL1 (wild-type FLT3), MV4-11 (FLT3-ITD resulting in constitutively active isoform). Semi-mechanistic cell cycle models for CYT and FLT3i were developed. Clinical CYT and quizartinib pharmacokinetic dosage regimens were modeled. Survival of AML patients was described via a hazard model. Simulations exploring different CYT/quizartinib regimens were conducted with the goal of improving treatment outcome.

Results: FLT3 status was associated with sensitivity to CYT (HEL cells most sensitive > EOL1 > MV4-11 cells). This order of sensitivity is reversed for FLT3i. Cytarabine induced apoptosis in the S-phase while all FLT3i induced apoptosis and cell cycle arrest at G1 phase. Simulations of candidate clinical regimens predict better cell kill upon adding quizartinib simultaneously with or immediately after CYT exposure. Overall survival was predicted to be significantly better with quizartinib 200 mg administered every 48 h vs every 24 h in patients with FLT3 aberrations.

Conclusion: Simultaneous administration of quizartinib and CYT every other day is a promising combination regimen for AML patients with FLT3 mutations.
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http://dx.doi.org/10.1007/s00280-020-04114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539618PMC
September 2020

Dexrazoxane for cardioprotection in older adults with acute myeloid leukemia.

Leuk Res Rep 2017 14;7:36-39. Epub 2017 Apr 14.

Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, USA.

Anthracyclines constitute the backbone of intensive adult acute myeloid leukemia (AML) therapy. Cardiotoxicity is one of its most serious adverse effects, and its incidence increases with cumulative dose. Dexrazoxane is a cardioprotective agent used in conjunction with anthracycline therapy. There is limited data of its usage in adult AML patients. We report the outcomes of six older adults at high risk of anthracycline-induced cardiotoxicity who received dexrazoxane during induction/re-induction therapy. Five had preserved left-ventricular function while two proceeded onto stem-cell transplantation. Additional investigation of dexrazoxane in adult leukemia therapy is warranted, particularly in older patients at highest risk for cardiovascular mortality.
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http://dx.doi.org/10.1016/j.lrr.2017.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402627PMC
April 2017

Adjustment to Acute Leukemia: The Impact of Social Support and Marital Satisfaction on Distress and Quality of Life Among Newly Diagnosed Patients and Their Caregivers.

J Clin Psychol Med Settings 2016 09;23(3):298-309

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

Little is known about the specific patterns of adjustment among newly diagnosed acute leukemia patients and their caregivers. This study examined the trajectories of patient and caregiver distress over time as well as the extent to which marital satisfaction and social support moderated these trajectories among those with significant-other caregivers. Forty six patient-caregiver dyads provided ratings at four time points: within 1 week of diagnosis (T1), 2 week follow-up (T2), 6 week follow-up (T3) and 12 week follow-up (T4). As anticipated, patients and caregivers reported higher levels of distress around the time of diagnosis than they did during subsequent time points. Marital satisfaction was a significant predictor of distress among patients, whereas among caregivers, social support predicted distress and quality of life. Results support the inclusion of relational variables such as social support and relationship satisfaction in the assessment of newly diagnosed patients and families in order to best identify those at risk for distress over time.
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http://dx.doi.org/10.1007/s10880-016-9459-6DOI Listing
September 2016

Evolution of acute myelogenous leukemia stem cell properties after treatment and progression.

Blood 2016 09 15;128(13):1671-8. Epub 2016 Jul 15.

Department of Medicine, J. P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY;

Most cancers evolve over time as patients initially responsive to therapy acquire resistance to the same drugs at relapse. Cancer stem cells have been postulated to represent a therapy-refractory reservoir for relapse, but formal proof of this model is lacking. We prospectively characterized leukemia stem cell populations (LSCs) from a well-defined cohort of patients with acute myelogenous leukemia (AML) at diagnosis and relapse to assess the effect of the disease course on these critical populations. Leukemic samples were collected from patients with newly diagnosed AML before therapy and after relapse, and LSC frequency was assessed by limiting dilution analyses. LSC populations were identified using fluorescent-labeled cell sorting and transplantation into immunodeficient NOD/SCID/interleukin 2 receptor γ chain null mice. The surface antigen expression profiles of pretherapy and postrelapse LSCs were determined for published LSC markers. We demonstrate a 9- to 90-fold increase in LSC frequency between diagnosis and relapse. LSC activity at relapse was identified in populations of leukemic blasts that did not demonstrate this activity before treatment and relapse. In addition, we describe genetic instability and exceptional phenotypic changes that accompany the evolution of these new LSC populations. This study is the first to characterize the evolution of LSCs in vivo after chemotherapy, identifying a dramatic change in the physiology of primitive AML cells when the disease progresses. Taken together, these findings provide a new frame of reference by which to evaluate candidate AML therapies in which both disease control and the induction of more advanced forms of disease should be considered.
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http://dx.doi.org/10.1182/blood-2016-02-695312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5043124PMC
September 2016

A phase I study of intermediate dose cytarabine in combination with lenalidomide in relapsed/refractory acute myeloid leukemia.

Leuk Res 2016 Apr 16;43:44-8. Epub 2016 Feb 16.

Department of Medicine, Roswell Park Cancer Institute, Elm & Carlton Sts, Buffalo, NY 14263, United States.

Relapsed/refractory (r/r) Acute Myeloid Leukemia (AML) remains a therapeutic challenge. Cytarabine arabinoside (AraC) forms the backbone of most regimens, with complete responses (CR) ranging from 17 to 20%. Lenalidomide (Len) is approved by the FDA for multiple myeloma and myelodysplasia and has demonstrated activity in AML. We developed a phase I study to evaluate the safety and tolerability of Len in combination with intermediate dose AraC (1.5 g/m(2)/day given on days 1-5) in adults with r/r AML. The maximally tolerated dose for this combination was 10mg daily on days 6-26 of a 28 day cycle. Dose de-escalation from 25mg was required due to rash, liver function abnormalities, and hypokalemia. Of 32 evaluable patients, five achieved CR (16%), 5CRi (16%) and 3 had hematological improvements for an overall response rate of 41% (13/32). Median overall survival (95% confidence interval) for patients treated on study was 5.8 (2.5-10.6) months and disease free survival was 3.4 (2.3-6.2) months. This single institute phase I trial of Len and intermediate dose AraC was associated with marked skin and other toxicities. At the dose and schedule tested, this combination did not appear to result in improved CR over single agent AraC for r/r AML.
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http://dx.doi.org/10.1016/j.leukres.2016.02.003DOI Listing
April 2016

Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665.

Leuk Lymphoma 2016 10 18;57(10):2298-306. Epub 2016 Feb 18.

a Department of Medicine , University of Chicago Medical Center , Chicago , IL , USA ;

Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+)  acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph + ALL. Of the 58 enrolled, 22 relapsed. By direct sequencing, an ABL1 kinase mutation known to induce imatinib resistance was present at relapse in 13 of 20. Using quantitative PCR assays, the mutations were detectable at diagnosis or early during treatment in most (62%) relapsed patients. Aberrations in IKZF1, CDKN2A/B, and PAX5 were assessed in 28 samples using SNP arrays and genomic DNA sequencing. Of these, 22 (79%) had IKZF1 deletion. The combination of IKZF1 deletion and p210 BCR-ABL1 (p < 0.0001), high white blood cell count (p = 0.021), and minimal residual disease (p = 0.013) were associated with worse disease-free survival.
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http://dx.doi.org/10.3109/10428194.2016.1144881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008253PMC
October 2016

Clinical updates in adult acute lymphoblastic leukemia.

Crit Rev Oncol Hematol 2016 Mar 19;99:189-99. Epub 2015 Dec 19.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, United States.

Acute lymphoblastic leukemia (ALL) is a clonal disease characterized by B or T lineage. Here we cover the clinical manifestations, pathophysiology and therapy for ALL. Additionally, we will discuss the evidence for minimal residual disease assessment, novel molecular targets and newly developed targeted therapies. The separation of ALL into Philadelphia chromosome positive and recently into Philadelphia-like disease represents the most exciting developments in this disease. Finally, the advent of new immunotherapeutic approaches led us to predict that in few years, ALL therapy might be based heavily on non-chemotherapeutic approaches.
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http://dx.doi.org/10.1016/j.critrevonc.2015.12.007DOI Listing
March 2016

Swallowing a bitter pill-oral arsenic trioxide for acute promyelocytic leukemia.

Blood Rev 2016 05 3;30(3):201-11. Epub 2015 Dec 3.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute,Elm and Carlton Streets, Buffalo, NY 14263, USA. Electronic address:

Parenteral arsenic trioxide (ATO) has been firmly established as a standard therapy for acute promyelocytic leukemia (APL). Despite widespread use of oral arsenicals in medicine historically, they had disappeared from modern pharmacopeia until oral ATO was redeveloped in Hong Kong in 2000. Since then, over 200 patients with leukemia (predominantly APL) have been treated with oral ATO in Hong Kong and China. Oral arsenic trioxide and other formulations of arsenic appear to have a clinical efficacy comparable to that of IV formulations. These drugs given orally also appear to have a slightly better safety profile, lower operational costs and improved convenience for patients. The clinical experience with oral ATO has previously been reported piecemeal as case series, pilot studies or subgroup analyses rather than in a comprehensive cohort. In this report we attempt to synthesize the published English language literature on oral arsenicals and present the argument for further development of these compounds. Systematic study of this drug with well-designed randomized multi-center clinical trials is needed to accelerate its development and incorporation into clinical practice.
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http://dx.doi.org/10.1016/j.blre.2015.11.004DOI Listing
May 2016

Polo-like kinase inhibitors in hematologic malignancies.

Crit Rev Oncol Hematol 2016 Feb 4;98:200-10. Epub 2015 Nov 4.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Electronic address:

Polo-like kinases (Plk) are key regulators of the cell cycle and multiple aspects of mitosis. Two agents that inhibit the Plk signaling pathway have shown promising activity in patients with hematologic malignancies and are currently in phase III trials. Volasertib is a Plk inhibitor under evaluation combined with low-dose cytarabine in older patients with acute myeloid leukemia (AML) ineligible for intensive induction therapy. Rigosertib, a dual inhibitor of the Plk and phosphatidylinositol 3-kinase pathways, is under investigation in patients with myelodysplastic syndrome (MDS) who have failed azacitidine or decitabine treatment. The prognosis for patients with AML, who are ineligible for intensive induction therapy, and for those with MDS refractory/relapsed after a hypomethylating agent, remains poor. Novel approaches, such as Plk inhibitors, are urgently needed for these patients. Here, we provide a comprehensive overview of the current state of development of Plk inhibitors for the treatment of hematologic malignancies.
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http://dx.doi.org/10.1016/j.critrevonc.2015.10.013DOI Listing
February 2016

Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate.

Leuk Lymphoma 2016 5;57(3):654-65. Epub 2015 Oct 5.

b The University of Texas MD Anderson Cancer Center , Houston , TX , USA .

Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment.
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http://dx.doi.org/10.3109/10428194.2015.1071486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552050PMC
December 2016

Decitabine and Sorafenib Therapy in FLT-3 ITD-Mutant Acute Myeloid Leukemia.

Clin Lymphoma Myeloma Leuk 2015 Jun;15 Suppl:S73-9

Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY.

Background: Acute myeloid leukemia (AML) characterized by Feline McDonough Sarcoma-like tyrosine kinase-3 (FLT-3) internal tandem duplication (ITD) mutations have poor outcomes. Treatment options are limited, because these mutations confer resistance to conventional chemotherapy. FLT-3 inhibitors such as sorafenib have been studied as a single agent and in combination with conventional chemotherapy or azacytidine with fair responses.

Patients And Methods: Here we describe our preclinical and clinical experience with the combination of the DNA hypomethylating agent, decitabine and sorafenib for the treatment of FLT-3 ITD-mutant AML.

Results: In vitro treatment of the human FLT-3 ITD-mutant AML cell line, MV4-11, with both drugs significantly improved growth inhibition over single-agent therapy and resulted in synergistic antitumor effects (combination index < 1). A case series of 6 patients treated with off protocol combination of decitabine and sorafenib demonstrated overall responses in 5 patients (83%) with a median survival of 155 days. Four of the 5 patients (80%) with relapsed/refractory AML achieved complete responses with incomplete count recovery. The combination was also well tolerated.

Conclusion: Further investigation is warranted to confirm these responses.
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http://dx.doi.org/10.1016/j.clml.2015.02.033DOI Listing
June 2015

Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide.

Br J Haematol 2015 Nov 24;171(4):471-7. Epub 2015 Jul 24.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Treatment of acute promyelocytic leukaemia (APL) with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is highly effective first-line therapy, although approximately 5-10% of patients relapse. Tamibarotene is a synthetic retinoid with activity in APL patients who relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA. We report on a phase II study of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (n = 14). Participants were treated with tamibarotene (6 mg/m(2) /d) during induction and for up to six cycles of consolidation. The overall response rate was 64% (n = 9), the rate of complete cytogenetic response was 43% (n = 6) and the rate of complete molecular response was 21% (n = 3). Relapse was frequent with 7 of 9 responders relapsing after a median of 4·6 months (range 1·6-26·8 months). The median event-free survival (EFS) was 3·5 months [95% confidence interval (CI) 0-8·6 months] and the median overall survival (OS) was 9·5 months (95% CI 5·9-13·1 months). These results demonstrate that tamibarotene has activity in relapsed APL after treatment with ATO and ATRA and further studies using tamibarotene as initial therapy and in combination with ATO are warranted.
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http://dx.doi.org/10.1111/bjh.13607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770883PMC
November 2015

Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.

Nature 2015 Jul 1;523(7559):183-188. Epub 2015 Jul 1.

Brigham and Women's Hospital, Division of Hematology, Boston, Massachusetts, USA.

Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases.
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http://dx.doi.org/10.1038/nature14610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853910PMC
July 2015

Blinatumomab: enlisting serial killer T-cells in the war against hematologic malignancies.

Expert Opin Biol Ther 2015 Jun;15(6):895-908

Roswell Park Cancer Institute, Department of Pharmacy, Elm and Carlton Streets, Buffalo, NY 14263, USA.

Introduction: The approval of blinatumomab signals the long awaited arrival of immunotherapy for acute lymphoblastic leukemia (ALL). Previous options for relapsed or refractory disease were restricted to cytotoxic chemotherapy with limited efficacy and significant toxicity. Through an innovative mechanism of action, blinatumomab stimulates a polyclonal antitumor T-cell response, yielding unprecedented single agent efficacy in the relapsed/refractory setting. Success comes at the cost of immunological toxicities rarely encountered with previous therapies and challenging administration logistics requiring clinical expertise.

Areas Covered: All published clinical and preclinical studies using blinatumomab were reviewed in addition to all registered ongoing clinical trials and data published in abstract form. The search was limited to the English language. The pharmacology, clinical efficacy, toxicity profile, and logistical considerations for drug administration are discussed.

Expert Opinion: Blinatumomab is an exciting addition to the treatment armamentarium for relapsed/refractory ALL, yet several questions remain regarding optimal implementation into the current treatment paradigm. A unique toxicity profile should be weighed against promising benefits in a poor prognosis population. Other emerging therapies, such as chimeric antigen receptor-modified T-cells and inotuzumab ozogamicin, with different side effect profiles and administration schedules, may prove to be more beneficial for specific patient populations.
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http://dx.doi.org/10.1517/14712598.2015.1041912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994468PMC
June 2015

Historical views, conventional approaches, and evolving management strategies for myeloproliferative neoplasms.

J Natl Compr Canc Netw 2015 Apr;13(4):424-34

From Northwestern University Feinberg School of Medicine, Chicago, Illinois; Stanford Cancer Institute, Stanford University, Stanford, California; Duke Cancer Institute, Duke University, Durham, North Carolina; University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; University of California, San Francisco, San Francisco, California; Johns Hopkins University School of Medicine, Baltimore, Maryland; Moores Cancer Center, UC San Diego, San Diego, California; University of Colorado Cancer Center, Aurora, Colorado; Fred Hutchinson Cancer Research Center, Seattle, Washington; Dana Farber Cancer Institute, Boston, Massachusetts; Memorial Sloan Kettering Cancer Center, New York; New York; Moffitt Cancer Center and Research Institute, Tampa, Florida; The Ohio State University, Columbus, Ohio; Fred & Pamela Buffett Cancer Center, Omaha, Nebraska; Fox Chase Cancer Center, Philadelphia, Pennsylvania; Roswell Park Cancer Institute, Buffalo, New York; Washington University-Siteman Cancer Center, St Louis, Missouri; St. Jude Children's Research Hospital, Memphis, Tennessee; University of Alabama at Birmingham, Birmingham, Alabama; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; Yale University School of Medicine; New Haven, Connecticut; University of Utah, Salt Lake City, Utah; University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan; City of Hope Cancer Center, Los Angeles, California; The University of Texas MD Anderson Cancer Center, Houston, Texas; and Mayo Clinic Cancer Center, Scottsdale, Arizona.

The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN), which include essential thrombocythemia, polycythemia vera, and myelofibrosis (MF), are in a new era of molecular diagnosis, ushered in by the identification of the JAK2(V617F) and cMPL mutations in 2005 and 2006, respectively, and the CALR mutations in 2013. Coupled with increased knowledge of disease pathogenesis and refined diagnostic criteria and prognostic scoring systems, a more nuanced appreciation has emerged of the burden of MPN in the United States, including the prevalence, symptom burden, and impact on quality of life. Biological advances in MPN have translated into the rapid development of novel therapeutics, culminating in the approval of the first treatment for MF, the JAK1/JAK2 inhibitor ruxolitinib. However, certain practical aspects of care, such as those regarding diagnosis, prevention of vascular events, choice of cytoreductive agent, and planning for therapies, present challenges for hematologists/oncologists, and are discussed in this article.
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http://dx.doi.org/10.6004/jnccn.2015.0058DOI Listing
April 2015

Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old.

Am J Hematol 2015 Jul;90(7):639-46

Leukemia Service, Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York.

Older patients with acute myeloid leukemia (AML) have poor outcomes with standard induction chemotherapy. We retrospectively reviewed our institute's experience with epigenetic (Epi) versus cytarabine- and anthracycline-based intensive chemotherapy (IC) as induction in newly diagnosed AML patients aged 60 years and older. One hundred sixty-seven patients (n = 84, IC; n = 83, Epi) were assessed; 69 patients received decitabine and 14 azacitidine. Baseline characteristics between the IC and Epi patient cohorts were not statistically different except for age, initial white blood cell count, and comorbidity index. Overall response rate (ORR, 50% vs. 28%, respectively, P < 0.01) and complete response rate (CRR, 43% vs. 20%, respectively, P < 0.01) were superior following IC vs. Epi. Although univariate analysis demonstrated longer overall survival after IC (10.7 vs. 9.1 months, P = 0.012), multivariate analysis showed no independent impact of induction treatment. Treatment-related mortality was not statistically different in the two groups. Outcomes of patients with secondary, poor cytogenetic risk, FLT-3 mutated AML, or relapsed/refractory disease after IC or Epi were not significantly different. Outcomes of patients receiving IC versus a 10-day decitabine regimen (n = 63) also were not significantly different. Our results suggest that IC and Epi therapy are clinically equivalent approaches for upfront treatment of older patients with AML and that other factors (feasibility, toxicity, cost, etc.) should drive treatment decisions. Prospective randomized trials to determine the optimal induction approach for specific patient subsets are needed.
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http://dx.doi.org/10.1002/ajh.24016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791130PMC
July 2015

Phase III open-label randomized study of cytarabine in combination with amonafide L-malate or daunorubicin as induction therapy for patients with secondary acute myeloid leukemia.

J Clin Oncol 2015 Apr 2;33(11):1252-7. Epub 2015 Mar 2.

Richard M. Stone, Emanuele Mazzola, and Donna Neuberg, Dana-Farber Cancer Institute, Boston; Ante S. Lundberg, Antisoma, Cambridge, MA; Steven L. Allen, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success; Meir Wetzler, Roswell Park Cancer Institute, Buffalo; Martin S. Tallman, Memorial Sloan Kettering Cancer Center, New York, NY; Arnaud Pigneux, Hopital Haut-Leveque, Pessac, France; Robert K. Stuart, Medical University of South Carolina, Charleston, SC; David Rizzieri, Duke University Medical Center, Durham; Bayard Powell, Wake Forest University Comprehensive Cancer Center, Winston Salem, NC; Harry P. Erba, University of Michigan Health System, Ann Arbor, MI; Lloyd Damon, University of California San Francisco, San Francisco, CA; Jun-Ho Jang, Samsung Medical Center, Seoul, Korea; Krzysztof Warzocha, Institute of Hematology and Transfusiology, Warsaw, Poland; Támas Masszi, Szent Istvan and Szent Laszlo Corporate Hospital, Budapest; Miklos Egyed, Kaposi Mor County Teaching Hospital, Kasposvar, Hungary; Mikkael A. Sekeres, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Heinz-August Horst, Universitatsklinikum Schleswig-Holstein, Kiel, Germany; Dominik Selleslag, Algemeen Ziekenhuis Sint-Jan, Brugge, Belgium; Scott R. Solomon, Blood and Marrow Transplant Program and Northside Hospital, Atlanta, GA; and Parameswaran Venugopal, Rush University Medical Center, Chicago, IL.

Purpose: Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non-ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML.

Patients And Methods: Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m(2) continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m(2) IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m(2) IV over 30 minutes once per day on days 1 to 3 (D + C arm).

Results: The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A + C arm and 13% and 21% in D + C arm, respectively.

Conclusion: Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML.
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http://dx.doi.org/10.1200/JCO.2014.57.0952DOI Listing
April 2015

An oncologist's perspective on metformin use and acute lymphoblastic leukemia outcomes.

J Pharm Pract 2015 Feb;28(1):46-7

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

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http://dx.doi.org/10.1177/0897190014557627DOI Listing
February 2015

Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia.

Am J Hematol 2015 May 27;90(5):E77-9. Epub 2015 Feb 27.

School of Medicine, Department of Internal Medicine, University of Maryland Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland.

Mutations in IDH1 and IDH2 occur in 15-20% of AML cases, resulting in the production of 2-hydroxyglutarate, which promotes aberrant hypermethylation of DNA in leukemic cells. Although these mutations have been shown to have prognostic implications for patients with AML, optimal treatment strategies have yet to be defined. We retrospectively identified forty-two patients with AML treated with DNA methyltransferase inhibitors (DNMTIs) decitabine (n = 36) or azacitidine (n = 6) and performed analysis of stored samples for the presence of IDH1 and IDH2 mutations. Of the forty-two samples analyzed, seven (16.7%) had IDH mutations. Thirteen patients (31%) achieved remission [(complete remission (CR)/complete remission with incomplete count recovery (CRi)/partial response (PR)] after treatment with a DNMTI, five of seven (71.4%) with IDH mutations and eight of thirty-five (22.9%) without IDH mutations (P = 0.01). When adjusted for age at diagnosis, sex, bone marrow blast percentage and cytogenetic, the odds of achieving response after administration of a DNMTI among patients with an IDH mutation was 14.2 when compared to patients without an IDH mutation (95%CI: 1.3-150.4). IDH1 and IDH2 mutations may predict a favorable response to DNMTI in patients with AML.
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http://dx.doi.org/10.1002/ajh.23965DOI Listing
May 2015

Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy.

Blood Rev 2015 Jul 10;29(4):243-9. Epub 2015 Jan 10.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. Electronic address:

Acute lymphoblastic leukemia (ALL) is a relatively rare disease in adults accounting for no more than 20% of all cases of acute leukemia. By contrast with the pediatric population, in whom significant improvements in long term survival and even cure have been achieved over the last 30years, adult ALL remains a significant challenge. Overall survival in this group remains a relatively poor 20-40%. Modern research has focused on improved pharmacokinetics, novel pharmacogenetics and personalized principles to optimize the efficacy of the treatment while reducing toxicity. Here we review the pharmacogenetics of medications used in the management of patients with ALL, including l-asparaginase, glucocorticoids, 6-mercaptopurine, methotrexate, vincristine and tyrosine kinase inhibitors. Incorporating recent pharmacogenetic data, mainly from pediatric ALL, will provide novel perspective of predicting response and toxicity in both pediatric and adult ALL therapies.
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http://dx.doi.org/10.1016/j.blre.2015.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494870PMC
July 2015

Acceptability, feasibility, and efficacy of a supportive group intervention for caregivers of newly diagnosed leukemia patients.

J Psychosoc Oncol 2015 ;33(2):163-77

a Department of Psychology, State University of New York at Buffalo , Buffalo , NY , USA.

This study describes the development of a supportive group-based intervention for family caregivers of newly diagnosed leukemia patients. We assessed the feasibility, acceptability, and efficacy of the group on caregiver distress and quality of life, as well as patient distress utilizing a sequential cohort design comparing a pre-intervention control group with the intervention group. Patients and caregiver dyads completed measures at 4 time points: within 1 week of diagnosis (T1), 2-week follow-up (T2), 6-week follow-up (T3), and 12-week follow-up (T4). Significant interaction effects were observed for both caregiver distress and quality of life, whereby those receiving the intervention demonstrated improved quality of life and reduced distress over time. Overall, results support the acceptability, feasibility, and preliminary efficacy of the group intervention.
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http://dx.doi.org/10.1080/07347332.2014.992086DOI Listing
June 2015

Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up.

Cancer 2015 May 13;121(10):1637-44. Epub 2015 Jan 13.

University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Omacetaxine, a protein synthesis inhibitor, is indicated in the United States for the treatment of patients with chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors.

Methods: The final analysis, with 24 months of follow-up, included additional efficacy and safety analyses to assess the benefit of long-term omacetaxine administration (1.25 mg/m(2) twice daily for 14 days every 28 days followed by 7 days every 28 days) in CP-CML and AP-CML patients receiving >3 cycles.

Results: Eighteen percent of CP-CML patients achieved a major cytogenetic response (MCyR) with a median duration of 12.5 months (95% confidence interval [CI], 3.5 months to not reached [NR]); responses were maintained for ≥12 months in 3 of 14 responders, and the median overall survival (OS) was 40.3 months (95% CI, 23.8 months to NR). Among patients with AP-CML, 14% achieved or maintained a major hematologic response for a median of 4.7 months (95% CI, 3.6 months to NR); MCyR was not achieved, and the median OS was 14.3 months (95% CI, 6.7-18.7 months). In patients with CP-CML and patients with AP-CML who received >3 cycles of treatment (n = 50 and n = 14, respectively), the median OS was 49.3 months (95% CI, 23.8 months to NR) and 24.6 months (95% CI, 12-37.2 months), respectively. Grade 3 or higher hematologic toxicities were the major side effects (79% and 73% for CP-CML and AP-CML, respectively), with discontinuation due to toxicity in 10% of CP patients and in 5% of AP patients.

Conclusions: These results suggest that the long-term administration of omacetaxine is feasible with dose adjustments to manage toxicities and that omacetaxine provides a durable benefit for some patients.
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http://dx.doi.org/10.1002/cncr.29240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650096PMC
May 2015

How we will treat chronic myeloid leukemia in 2016.

Blood Rev 2015 Mar 17;29(2):137-42. Epub 2014 Dec 17.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address:

Imatinib will become generic in 2016; assuming that its price will decrease precipitously, we expect that the economic forces will change our current practice habits. We reviewed the literature on the current recommendations to treat chronic myeloid leukemia and highlight how we plan to deal with these changes. Specifically, we propose to better characterize patients according to prognostic scores, to allow more attention to those at high risk for disease progression, e.g., 3-month guidelines and BCR/ABL1 message half-time, emphasize compliance by using contemporary technologies, and increase the importance of early monitoring. We hope that our message will open communication between providers, insurance companies and healthcare authorities to offer the best care for our patients.
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http://dx.doi.org/10.1016/j.blre.2014.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385463PMC
March 2015

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.

Blood 2015 Feb 30;125(9):1367-76. Epub 2014 Dec 30.

Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.
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http://dx.doi.org/10.1182/blood-2014-11-610543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342352PMC
February 2015

Bosutinib for the Treatment of Philadelphia Chromosome-Positive Leukemias.

Expert Opin Orphan Drugs 2015 16;3(5):599-608. Epub 2015 Apr 16.

Leukemia Section, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

Introduction: Bosutinib is a dual ABL1 and SRC third generation tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with chronic myelogenous leukemia (CML) resistant to or intolerant of other BCR-ABL1 inhibitors. Bosutinib is active against leukemia cells expressing imatinib-resistant mutations. Mechanistically, this agent may also be beneficial for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) because in preclinical animal models, SRC accelerates ALL disease development.

Areas Covered: Here we review the current scientific and medical literature on the role of bosutinib for the treatment of CML. We address the unique therapeutic advantages of this agent, specifically its ability to inhibit mutant BCR-ABL1 kinases conferring resistance to other TKIs and its unique safety profile consisting of mainly manageable self-limited diarrhea, not cardiovascular, side effects. Long-term toxicities reported with dasatinib, nilotinib and ponatinib have not been described with bosutinib. Lastly, we present preclinical data demonstrating that bosutinib inhibits a broader range of tyrosine kinases than any other TKI, including those implicated in acute leukemia.

Expert Opinion: We propose that future studies should explore the use of bosutinib in Ph+ ALL due to its multi-kinase inhibitory activity and its relatively long-term safety compared to other second and third generation TKIs.
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http://dx.doi.org/10.1517/21678707.2015.1036027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684277PMC
April 2015

Expression and prognostic impact of lncRNAs in acute myeloid leukemia.

Proc Natl Acad Sci U S A 2014 Dec 15;111(52):18679-84. Epub 2014 Dec 15.

The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210;

Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival.
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http://dx.doi.org/10.1073/pnas.1422050112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284555PMC
December 2014

Pharmacological targeting of β-catenin in normal karyotype acute myeloid leukemia blasts.

Haematologica 2015 Feb 7;100(2):e49-52. Epub 2014 Nov 7.

Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

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http://dx.doi.org/10.3324/haematol.2014.113118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803144PMC
February 2015

Deletion and deletion/insertion mutations in the juxtamembrane domain of the FLT3 gene in adult acute myeloid leukemia.

Leuk Res Rep 2014 16;3(2):86-9. Epub 2014 Oct 16.

Molecular Diagnostics Laboratory, Department of Pathology and Laboratory Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, United States.

In contrast to FLT3 ITD mutations, in-frame deletions in the FLT3 gene have rarely been described in adult acute leukemia. We report two cases of AML with uncommon in-frame mutations in the juxtamembrane domain of the FLT3 gene: a 3-bp (c.1770_1774delCTACGinsGT; p.F590_V592delinsLF) deletion/insertion and a 12-bp (c.1780_1791delTTCAGAGAATAT; p.F594_Y597del) deletion. We verified by sequencing that the reading frame of the FLT3 gene was preserved and by cDNA analysis that the mRNA of the mutant allele was expressed in both cases. Given the recent development of FLT3 inhibitors, our findings may be of therapeutic value for AML patients harboring similar FLT3 mutations.
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http://dx.doi.org/10.1016/j.lrr.2013.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220013PMC
November 2014

Chronic myelogenous leukemia, version 1.2015.

J Natl Compr Canc Netw 2014 Nov;12(11):1590-610

Chronic myelogenous leukemia (CML) is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase (accelerated or blast phase) CML. Tyrosine kinase inhibitors (TKIs) have been shown to induce favorable response rates in patients with accelerated and blast phase CML. The addition of TKIs to chemotherapy has also been associated with improved outcomes in patients with blast phase CML. Allogeneic hematopoietic stem cell transplant remains a potentially curative option for patients with advanced phase CML, although treatment with a course of TKIs will be beneficial as a bridge to transplant. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with advanced phase CML.
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http://dx.doi.org/10.6004/jnccn.2014.0159DOI Listing
November 2014

Omacetaxine mepesuccinate in chronic myeloid leukemia.

Expert Opin Pharmacother 2014 Nov;15(16):2397-405

Roswell Park Cancer Institute, Department of Medicine, Leukemia Section , Elm and Carlton Street, Buffalo, NY 14263 , USA +001 716 845 8447 ; +001 716 845 2343 ;

Introduction: Homoharringtonine (HHT) and other alkaloid esters were originally isolated from the Cephalotaxus evergreen tree and have been used in traditional Chinese medicine since the 1970s to treat a variety of malignancies. Although HHT was investigated for the treatment of chronic myeloid leukemia (CML) in the 1990s with good results, the advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) at that time rapidly established a new standard of care for CML. Omacetaxine mepesuccinate is a semisynthetic derivative of HHT with known clinical activity in relapsed or refractory CML following TKI therapy.

Areas Covered: In this review, we summarize the biologic effects of HHT and its derivative, omacetaxine, in CML. Additionally, we analyze the concepts learned from the early trials using these drugs. Data from clinical trials resulting in drug approval are also reviewed.

Expert Opinion: Omacetaxine has a clear role in the CML armamentarium for patients in chronic and accelerated phase who have failed or were intolerant to two or more TKIs.
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http://dx.doi.org/10.1517/14656566.2014.964642DOI Listing
November 2014