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Sequential Flavopiridol, Cytosine Arabinoside, and Mitoxantrone: A Phase II Trial in Adults with Poor-Risk Acute Myelogenous Leukemia

Authors' Affiliations: ¹ Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland and ² Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Judith E. Karp, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, CRB Room 289, 1650 Orleans Street, Baltimore, MD 21231-1000. Phone: 410-502-7726; Fax: 410-614-1005; E-mail: jkarp2{at}jhmi.edu.

Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of flavopiridol followed by 1-ß-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 II study of sequential flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML.

Experimental Design: Flavopiridol (50 mg/m²) was given by 1-h infusion daily x 3 beginning day 1 followed by 2 gm/m²/72 h ara-C beginning day 6 and 40 mg/m² mitoxantrone on day 9.

Results: Flavopiridol 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-AML 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.