Dose-escalation study of single dose mitoxantrone in combination with timed sequential chemotherapy in patients with refractory or relapsing acute myelogenous leukemia

A dose-escalation study was realized in order to assess the maximally toler ated dose (MTD) of high-dose mitoxantrone in a single injection combined wi th cytarabine and etoposide (EMA regimen) in refractory or relapsed acute m yelogenous leukemia (AML). Between July 1997 and June 1998, 24 patients wit h relapsed or refractory AML entered the study. All but one patient had nor mal left ventricular ejection fraction (LVEF) at baseline. Performance stat us according to World Health Organization (WHO) criteria was less than two in all cases. All patients have been previously treated by mitoxantrone or anthracyclines. Four cohort of ten patients were scheduled with the followi ng doses: (1) mitoxantrone 36 mg/m(2) on day 1; (2) mitoxantrone 45 mg/m(2) on day 1; (3) mitoxantrone 60 mg/m(2) on day 1; (4) mitoxantrone 75 mg/m(2 ) on day 1 in combination with cytarabine 500 mg/m(2) per day (days 1-3, an d days 8-10), and etoposide 200 mg/m(2) per day (days 8-10). All patients r eceived the full doses of the three drugs. The limiting toxicity was define d as WHO grade 4 nonhematologic toxicity and for impairment of cardiac func tion by Alexander's criteria (moderate or severe toxicity). The occurrence of limiting toxicity in at least three patients from the same dose level de termined the MDT. No limiting toxicity was observed in mitoxantrone dose le vel 1. Two limiting toxicities were observed in mitoxantrone dose level 2 ( one mucositis, one moderate cardiac toxicity), and three limiting toxicitie s in mitoxantrone dose level 3 (1 high transaminase levels, two moderate ca rdiac toxicities) ending the assay. Overall, 16 patients (67%) achieved com plete remission (CR). One drug-addict patient died from cerebral hemorrhage due to severe aspergillosis and was not considered as a limiting toxicity. After EMA chemotherapy, 13 patients received subsequent chemotherapy cours es involving anthracyclines or their derivatives. Six patients underwent al logeneic bone marrow transplantation. No late toxicity occurred. The median survival of the entire cohort was 41.4 weeks. We conclude that (i) EMA che motherapy using a single injection of mitoxantrone is effective in the trea tment of refractory or relapsing AML; (ii) the recommended phase II dose of mitoxantrone is 45 mg/m(2) administered over 30 min as a single dose in co mbination with cytarabine and etoposide. (C) 2000 Elsevier Science Ltd. All rights reserved.