Moshe Y. Levy M.D.

Shah, N. P., V. Garcia-Gutierrez, A. Jimenez-Velasco, S. Larson, S. Saussele, D. Rea, F. X. Mahon, M. Y. Levy, M. T. Gomez-Casares, F. Pane, F. E. Nicolini, M. J. Mauro, O. Sy, P. Martin-Regueira and J. H. Lipton (2020). “Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study.” Leuk Lymphoma 61(3): 650-659.

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Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (>/=median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.

Chari, A., D. T. Vogl, M. Gavriatopoulou, A. K. Nooka, A. J. Yee, C. A. Huff, P. Moreau, D. Dingli, C. Cole, S. Lonial, M. Dimopoulos, A. K. Stewart, J. Richter, R. Vij, S. Tuchman, M. S. Raab, K. C. Weisel, M. Delforge, R. F. Cornell, D. Kaminetzky, J. E. Hoffman, L. J. Costa, T. L. Parker, M. Levy . . . and S. Jagannath (2019). “Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.” New England Journal of Medicine 381(8): 727-738.

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BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor kappaB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

Levy, M. Y., L. J. McGarry, H. Huang, S. Lustgarten, S. Chiroli and S. Iannazzo (2019). “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 35(3): 479-487.

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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 132(11): 1125-1133.

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Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of 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, HMAs 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 HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and 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 4-week cycles. Among 53 patients treated, the 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. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

Zeidner, J. F., M. C. Foster, A. L. Blackford, M. R. Litzow, L. E. Morris, S. A. Strickland, J. E. Lancet, P. Bose, M. Y. Levy, R. Tibes, I. Gojo, C. D. Gocke, G. L. Rosner, R. F. Little, J. J. Wright, L. A. Doyle, B. D. Smith and J. E. Karp (2018). “Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML).” Leuk Res 72: 92-95.

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Despite recent advances in the management of subpopulations of AML, overall outcomes remain unsatisfactory. Encouraging results were seen with alvocidib (formerly known as flavopiridol), a CDK9 inhibitor with pan-cyclin-dependent kinase (CDK) activity, followed by cytarabine and mitoxantrone (FLAM) in serial phase I-II studies in newly diagnosed AML patients. Therefore, we conducted a randomized phase II clinical trial comparing FLAM to cytarabine and daunorubicin (7 + 3) in newly diagnosed AML patients 18–70 years of age with non-favorable risk cytogenetics. We previously published results of this trial revealing no significant differences in overall survival (OS) between FLAM and 7 + 3 despite significantly higher complete remission (CR) rates with FLAM. It is imperative to analyze long-term OS on this study as a secondary endpoint. Furthermore, we hypothesized that the survival trends may change with longer follow-up. We report the final long-term OS results of this trial. This study randomized 165 patients between FLAM (n = 109) and 7 + 3 (n = 56) with a median age of 59 years (range: 19–70 years) across 10 institutions. Overall, 41% of patients had adverse-risk features based on 2010 European Leukemia Net Guidelines. The primary endpoint of this trial was the rate of CR (including CR with incomplete hematologic recovery: CRi) with FLAM and 7 + 3. FLAM led to significantly increased CR rates when compared with 7 + 3 with 1 or 2 cycles of treatment (70% vs. 47%, p = 0.003, and 70% vs. 57%, p = 0.08, respectively). Despite the improvement in CR rates with FLAM, our earlier published results did not reveal significant differences in overall survival (OS) and event-free survival (EFS) between the arms, with median follow-up 811 days (range: 1–1217 days) by reverse Kaplan-Meier methodology . . . Our final analysis reveals that FLAM leads to higher CR rates compared with 1 or 2 cycles of 7 + 3 induction in newly diagnosed AML patients 18–70 years with non-favorable cytogenetics but no significant difference was seen in OS or EFS. Subset analyses suggest that younger patients are more likely to achieve CR on FLAM compared with 7 + 3. Ongoing trials of alvocidib will provide further direction for its role in the current treatment armamentarium for AML. (Excerpt from text, p. 92, 94; no abstract available.)