Moshe Y. Levy M.D.

Mazharuddin, S., A. Chattopadhyay, M. Y. Levy and R. L. Redner (2018). “IRF2BP2-RARA t(1;17)(q42.3;q21.2) APL blasts differentiate in response to all-trans retinoic acid.” Leuk Lymphoma 59(9): 2246-2249.

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To date three reports of IRF2BP2-RARA have been published. Response to ATRA has been inconsistent. In the first publication, Yin et al. reported a 19-year-woman who initially responded to a combination of ATRA, arsenic, and gemtuzumab ozogamicin (though the patient exhibited an atypically prolonged time for normalization of her coagulopathy). She received an 8-month course of consolidation with ATRA and arsenic, but relapsed 2 months later, and received salvage therapy with ATRA, arsenic, and idarubicin, followed by allogeneic bone marrow transplant. The second case, reported by Shimomura et al. was of a 68-year-woman initially treated with ATRA, in which idarubicin and cytarabine was added on day 12. She did not achieve a complete remission, and was re-induced with gemtuzumab ozogamicin, only to relapse 1 year later. The third case was of a 37-year-man who achieved a morphological, but not molecular remission with single agent ATRA; he achieved molecular remission only after addition of Programa para el Tratamiento de Hemopatías Malignas (PETHEMA)-based induction chemotherapy. Herein, we describe the fourth case of t(1;17) APL. A 34-year-old white male presented in March 2016 with WBC 4100 × 106/L, hemoglobin 9.3 g/dL, and platelets 23,000 × 106/L with 40% neutrophils, 9% bands, 45% lymphocytes, 2% monocytes, and 4% blasts. Prothrombin time (PT) was 15.9 s, d-dimer 37.21 mg/L, fibrinogen 397 mg/dL. Over the first week of his hospitalization, the patient was given single agent ATRA 24 mg/m2 daily while the diagnosis of APL was being confirmed. Over this time, the white blood cells (WBC) rose to over 30,000 × 106/L. A bone marrow aspirate and biopsy revealed 89% immature cells expressing CD13, CD33, CD38(dim), CD45, CD117, CD123(dim), and myeloperoxidase[bright]; negative for HLA-DR. Cytogenetics revealed 45, X, -Y, t(1;17)(q42;q21), i(8)(q19). FISH and PCR did not reveal PML-RARA rearrangement. FISH using Vysis LSI RARA Dual Color, Break Apart Rearrangement Probe revealed one orange, one green and one fusion (1O1G1F) signal pattern, consistent with a variant RARA rearrangement. FISH also revealed a gain of RUNX1T1, consistent with the finding of iso(8)(q19). (Excerpt from text, p. 2246; no abstract available.)

Levy, M. Y., L. J. McGarry, H. Huang, S. Lustgarten, S. Chiroli and S. Iannazzo (2018). “Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison.” Curr Med Res Opin Aug 24: 1-9. [Epub ahead of print].

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OBJECTIVE: Comparing the benefit-risk profiles of ponatinib vs. bosutinib in third-line (3L) treatment of chronic phase chronic myeloid leukemia (CP-CML) is challenging because their pivotal trials lacked comparator arms. To characterize the overall benefit-risk profile in 3L CP-CML patients treated with bosutinib vs. ponatinib, a matching-adjusted indirect comparison (MAIC) was performed to compare efficacy outcomes and treatment duration after adjusting for trial subjects’ baseline characteristics, and tolerability was assessed with an unadjusted comparison of study-drug discontinuation. METHODS: The MAIC was performed using published data from the pivotal bosutinib trial and the most recent individual-patient-level data on file from the pivotal ponatinib trial. RESULTS: Responses were more frequent and durable with ponatinib (n = 70 MAIC-adjusted) than with bosutinib (n = 119) – complete cytogenetic response (CCyR): 61% vs. 26%; Kaplan-Meier estimate of maintaining CCyR at 4 years: 89% vs. 54%. Median treatment duration was longer with ponatinib than with bosutinib: 38.4 vs. 8.6 months. Only 9% of ponatinib patients (n = 97 unadjusted) vs. 42% of bosutinib patients discontinued due to death, disease progression or unsatisfactory response; 19% vs. 24% discontinued due to adverse events. CONCLUSIONS: Based on these surrogate measures of patient benefit-risk profiles, ponatinib appears to provide a net overall benefit vs. bosutinib in 3L CP-CML.

Fathi, A. T., H. P. Erba, J. E. Lancet, E. M. Stein, F. Ravandi, S. Faderl, R. B. Walter, A. S. Advani, D. J. DeAngelo, T. J. Kovacsovics, A. Jillella, D. Bixby, M. Y. Levy, M. M. O’Meara, P. A. Ho, J. Voellinger and A. S. Stein (2018). “A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33 positive AML.” Blood Jul 25. [Epub ahead of print].

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Treatment of acute myeloid leukemia (AML) among the elderly is challenging due to intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33 directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMA followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMA. Those eligible had Eastern Cooperative Oncology Group (ECOG) status 0-1, previously untreated CD33 positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 mug/kg on last day of HMA (azacitidine or decitabine) infusion, in four week cycles. Among 53 patients treated, median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose limiting toxicities were reported. Majority of adverse events were due to myelosuppression, with some causing therapy delays. Thirty- and 60 day mortality rates were 2% and 8%. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery [CRi]) was 70%. Fifty one percent of remissions were minimal residual disease (MRD) negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged >/=75 years, and with adverse cytogenetic risk. Median relapse free survival and overall survival were 7.7 and 11.3 months, respectively.

Hansen, V. L., M. Coleman, S. Elkins, J. P. Letzer, M. Y. Levy, L. Seneviratne, J. Rine, M. White and E. T. Kuriakose (2018). “An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Previously Treated Myeloma.” Clin Lymphoma Myeloma Leuk 18(6): 400-407.e401.

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BACKGROUND: Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received >/= 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability. PATIENTS AND METHODS: In treatment phase 1, patients received panobinostat 20 mg 3 times per week plus bortezomib 1.3 mg/m(2) twice weekly with dexamethasone 20 mg on the days of and after bortezomib treatment. Patients with no change or better in treatment phase 1 proceeded to treatment phase 2, when bortezomib was reduced to once weekly. Unlike in the phase III trial, PANORAMA-1 (panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma), bortezomib could be administered either subcutaneously or intravenously. RESULTS: Thirty-nine patients with a median number of previous treatments of 4 (range, 1-12) were enrolled; most received subcutaneous bortezomib (87%). The overall response rate (partial response or better) was 56%. Grade 3/4 adverse events included thrombocytopenia (47%), fatigue (31%), dehydration (26%), and diarrhea (18%). Among the patients who received subcutaneous bortezomib, relatively low rates of peripheral neuropathy (all grade, 15%) and notable grade 3/4 adverse events (thrombocytopenia, 47%; diarrhea, 12%) were observed. CONCLUSION: Overall, data from the PANEX trial support regulatory approval of panobinostat plus bortezomib and dexamethasone and suggest the potential tolerability benefits of subcutaneous bortezomib in this regimen.

Mazharuddin, S., A. Chattopadhyay, M. Y. Levy and R. L. Redner (2018). “IRF2BP2-RARA t(1;17)(q42.3;q21.2) APL blasts differentiate in response to all-trans retinoic acid.” Leuk Lymphoma: Jan 19: 1-4. [Epub ahead of print].

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To date 11 variant translocations have been characterized in acute promyelocytic leukemia (APL), all of which share the same C-terminal domains of RARA as in t(15;17)(q24;q21) PML-RARA [1 de The H, Lavau C, Marchio A, et al. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. To date three reports of IRF2BP2-RARA have been published. Herein, we describe the fourth case of t(1;17) APL. A 34-year-old white male presented in March 2016 with WBC 4100 × 106/L, hemoglobin 9.3 g/dL, and platelets 23,000 × 106/L with 40% neutrophils, 9% bands, 45% lymphocytes, 2% monocytes, and 4% blasts. Prothrombin time (PT) was 15.9 s, d-dimer 37.21 mg/L, fibrinogen 397 mg/dL. Over the first week of his hospitalization, the patient was given single agent ATRA 24 mg/m2 daily while the diagnosis of APL was being confirmed. Over this time, the white blood cells (WBC) rose to over 30,000 × 106/L. A bone marrow aspirate and biopsy revealed 89% immature cells expressing CD13, CD33, CD38(dim), CD45, CD117, CD123(dim), and myeloperoxidase[bright]; negative for HLA-DR. Cytogenetics revealed 45, X, -Y, t(1;17)(q42;q21), i(8)(q19). FISH and PCR did not reveal PML-RARA rearrangement. FISH using Vysis LSI RARA Dual Color, Break Apart Rearrangement Probe revealed one orange, one green and one fusion (1O1G1F) signal pattern, consistent with a variant RARA rearrangement. FISH also revealed a gain of RUNX1T1, consistent with the finding of iso(8)(q19). We confirmed the presence of an IRF2BP2-RARA fusion in our patient by RT-PCR and sequencing of the amplified transcript.[Excerpt from text; abstract unavailable.]