Sequential flavopiridol, cytosine arabinoside, and mitoxantrone: A phase II trial in adults with poor-risk acute myelogenous leukemia

Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of flavopiridol followed by 1-beta-D-arabinofuranosylcytosine (ara-C) and mitoxantrone, overall response rate for adults with relapsed and refractory acute myelogenous leukemias (AML) was 31 %. We have now completed a phase 11 study of sequential flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML. Experimental Design: Flavopiriclol (50 mg/m(2)) was given by 1 -h infusion daily x 3 beginning day 1 followed by 2 gm/m(2) /72 h ara-C beginning day 6 and 40 mg/m(2) mitoxantrone on day 9. Results: Flavopiriclol caused a >= 50% decrease in peripheral blood blasts in 44% by median day 2 and >= 80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three (5%) died during therapy (2 multiorgan failure and 1 fungal pneumonia). Complete remissions (CR) were achieved in 12 of 15 (75%) newly diagnosed secondary AML, 18 of 24 (75%) first relapse after short CR (median CR, 9 months, including prior allotransplant), and 2 of 13 (15%) primary refractory but 0 of 10 multiply refractory AML. Disease-free survival for all CR patients is 40% at 2 years, with newly diagnosed patients having a 2-year disease-free survival of 50%. Conclusions: Flavopiridol has anti-AMIL activity directly and in combination with ara-C and mitoxantrone. This timed sequential regimen induces durable CRs in a significant proportion of adults with newly diagnosed secondary AML (including complex cytogenetics) and adults with AML in first relapse after short first CR.