Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia

Abstract

Background: Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of flavopiridol followed by ara-C and mitoxantrone with flavopiridol given by 1-h bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease-free survival of 13.6 months.

Design and methods: We compared bolus flavopiridol (50 mg/m(2)/day, Arm A) versus 'hybrid' flavopiridol (30 mg/m(2) over 30 min followed by 40 mg/m(2) over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder.

Results: Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B.

Conclusions: Both flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966.

Trial registration: ClinicalTrials.gov NCT00407966.

Figure 1.

Total (A) and unbound (B) flavopiridol concentrations at various time points during and after administration by bolus (filled circles) and hybrid (open circles) schedules.

Figure 2.

(A) Overall survival for 24 CR/CRi patients treated in Arm A (—) and for 29 CR/CRi patients treated in Arm B (---). (B) Disease-free survival for 24 CR/CRi patients treated in Arm A (—) and for 29 CR/CRi patients treated in Arm B (---).

Figure 3.

(A) and (B) Overall and disease-free survivals (OS, DFS) for patients with secondary AML. For Arm A (—), median OS (26 patients) = 10.7 months (95% CI: 6.64, Inf) and median DFS (17 patients) = 18.5 months (95% CI: 8.13, Inf). For Arm B (---), median OS (28 patients) = 13 months (95% CI: 7.0, Inf) and median DFS (20 patients) = 9.6 months (6.8-inf). (C) and (D) Overall and disease-free survivals (OS, DFS) for patients with adverse cytogenetics. For Arm A (—), median OS (23 patients) = 9 months (4.0, Inf) and median DFS (14 patients) = 14.3 months (95% CI: 8.1, Inf). For Arm B (---), median OS (25 patients) = 12.6 months (95% CI: 7.0, Inf) and median DFS (18 patients) = 9.6 months (4.1, Inf).