Moshe Y. Levy M.D.

Pearson, E., L. McGarry, S. Gala, C. Nieset, M. Nanavaty, M. Mwamburi and Y. Levy (2016). “Disease-related mortality exceeds treatment-related mortality in patients with chronic myeloid leukemia on second-line or later therapy.” Leuk Res 43: 1-8.

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Treatment of newly-diagnosed patients with chronic-phase chronic myeloid leukemia (CP-CML) with tyrosine kinase inhibitors (TKIs) results in near-normal life expectancy. However, CP-CML patients resistant to initial TKIs face a poorer prognosis and significantly higher CML-related mortality. We conducted a systematic literature review to evaluate the specific causes of deaths (diseases progression versus drug-related) in CP-CML patients receiving second- or third-line therapy. We identified eight studies based on our criteria that reported causes of death. Overall, 5% of second-line and 10% of third-line patients died during the study follow-up period. For second-line, (7 studies, n=1926), mortality was attributed to disease progression for 41% of deaths, 2% to treatment-related causes, 3% were treatment-unrelated, and 50% were unspecified adverse events (AEs), not likely related to study drug. In third-line, (2 studies, n=144), 71% deaths were attributed to disease progression, 7% treatment-related AEs, 14% treatment-unrelated and 7% unspecified AEs. Annual death rates for second- and third-line therapy were significantly higher than for general population in similar age group. Our findings suggest death attributed to disease progression is approximately 10 times that due to treatment-related AEs in patients with CP-CML receiving second- or third-line therapy. Therefore, the potential benefits of effective treatment for these patients with the currently available TKIs outweigh the risks of treatment-induced AEs.

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 (2015). “Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia.” Haematologica 100(9): 1172-1179.

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Serial studies have demonstrated that induction therapy with FLAM [flavopiridol 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not retreated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between 1 cycle of FLAM and 1 cycle of 7+3. Secondary endpoints included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%, p=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%, p=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase 3 study is currently in development.