A Phase I-II trial of escalating doses of mitoxantrone with fixed doses ofcytarabine plus fludarabine as salvage therapy for patients with acute leukemia and the blastic phase of chronic myelogenous leukemia

BACKGROUND, Cytarabine is an essential drug for inducing remission of acute myelogenous leukemia, and it is also one the mast effective drugs used as salvage therapy for patients with all types of relapsed acute leukemia. Nev ertheless, there is considerable room for improvement in the treatment of p atients with relapsed leukemia in terms of both the reinduction rate and th e duration of response. Fludarabine has been shown to augment responses to cytarabine, possibly by increasing the intracellular concentrations of the active metabolite cytarabine triphosphate. Higher-than-standard doses of mi toxantrone have been shown to augment responses to cytarabine, possibly by increasing the DNA strand breaks induced by topoisomerase TT; these strand breaks cannot be effectively repaired in the presence of cytarabine triphos phate. This preliminary study was designed to determine whether moderately high doses of mitoxantrone could be added to the combination of fludarabine and cytarabine in an attempt to improve the combination's antileukemic eff icacy. METHODS. Fifty-five adults with relapsed or refractory acute leukemia or th e blastic phase of chronic myelogenous leukemia (CML) received salvage ther apy with the FLAM regimen, which consisted of fludarabine, cytarabine, and increasing doses of mitoxantrone. RESULTS. Even with doses of mitoxantrone escalated to as much as 60 mg/m(2) over 4 days, dose-limiting toxicity was not observed. Overall, the complet e response rate was 27.3% (15 of 55 patients, including 4 of 17 with acute myelogenous leukemia [AML], 4 of 12 with acute lymphocytic leukemia [ALL], and 7 of 26 with the blastic phase of CML). The median time to complete res ponse was 42 days. Toxicity other than myelosuppression was manifested prim arily as hyperbilirubinemia, which was reversible in all cases. Poor perfor mance status and undifferentiated blastic phase of CML were poor prognostic factors for response to FLAM. CONCLUSIONS. The FLAM regimen is an active salvage regimen and should be fo rmally evaluated in Phase II studies of patients with AML, ALL, and the mye loid and lymphoid blastic phases of CML. (C) 1999 American Cancer Society.