Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia

Abstract

Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 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 (age 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 re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points 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 III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.

Trial registration: ClinicalTrials.gov NCT01349972.

Copyright© Ferrata Storti Foundation.

Figures

Figure 1.

Consort Diagram. 172 patients were randomized between FLAM (n = 114) and 7+3 (n = 58), 109 patients on FLAM and 56 patients on 7+3 were analyzed for response and overall survival (OS). 2 patients did not receive FLAM after randomization: progressive deterioration of performance status (n=1), exceeded maximum prior anthracycline dose (n=1) 2 patients did not receive 7+3 after randomization: withdrawal of consent (n=1), death before intervention (n=1). 3 patients were excluded from the analysis after initiating treatment with FLAM due to ineligibility: T-cell acute lymphoblastic leukemia (n=1), Favorable-risk cytogenetics: t(8;21) (n=1), Prior treatment for AML (n=1). 7 patients treated with FLAM and one patient treated with 7+3 were non-evaluable (NE) for response due to early death.

Figure 2.

Subset analyses. Forest plot of odds ratios for complete remission in patient subgroups, plotted on a log scale. P values were derived from likelihood ratio tests of logistic regression models for interaction between treatment: (A) FLAM vs. 7+3 and (A) FLAM vs. 7+3+/−5+2, and patient subgroup on complete remission. To provide information about patients in the ‘no poor-risk features’ subgroup, 0.5 was added to all cell counts in this analysis for calculating odds ratios and 95% confidence intervals.

Figure 3.

Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS). (A). OS for the entire cohort and treatment arm measured by Kaplan-Meier methodology. OS is defined as the date of randomization to date of last follow up or death. (B). EFS for the entire cohort and treatment arm measured by Kaplan-Meier methodology. EFS is defined as time from randomization to persistent AML after one cycle of induction therapy, relapse, death, or date of last follow up (censored).