High-Dose Versus Intermediate Dose Cytosine Arabinoside Combined with Mitoxantrone for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia: Results of an Age Adjusted Randomized Comparison

Abstract

193 patients with relapsed or refractory acute myeloid leukemia (AML) were entered into a prospective randomized comparison of high-dose versus intermediate dose cytosine arabinoside (AraC) both combined with mitoxantrone (mitox) according to the previously established sequential HD-AraC/mitox regimen (S-HAM). AraC was administered by 3 hr inf. q 12 hrs on days 1, 2, and 8, 9 at randomly assigned doses of cither 3.0 versus 1.0 g/m² in pts. < 60 years of age or 1.0 versus 0.5 g/nm² in older pts. Mitox was given to all cases at a dose of 10 mg/m²/d on days 3, 4, and 10, 11. Randomization was stratified for primary refractoriness against induction therapy and the length of first remission in relapsed cases (<6 mths., 6–18 mths., >18 mths.). From 151 presently evaluable cases 72 pts (48%) achieved a complete remission (CR), 38 cases (25%) were non-responders (NR) and 41 pts. (27%) died within the first 6 weeks after the start of treatment (early death = ED). No significant differences were found in CR rates being 52% and 44% for the 3.0 versus 1.0 g/m² AraC regimens in pts. <60 years and 48% and 45% after 1.0 versus 0.5 g/m² AraC in older pts. No differences between the respective regimens emerged either for the time to CR (median 46 days) nor remission duration (median 4.5 mths.). Analysis of treatment failures, however, demonstrated a significantly higher rate of NR after the lower dose regimens in both age groups of 41% and 32% versus 11% and 14% in pts. receiving AraC at higher doses (p < 0.01). Correspondingly, more ED were observed in the latter groups. Furthermore, a significant advantage in favor of 3.0 g/m² AraC was found when analyzing cases <60 years of age with refractory AML separately as defined by patients with primary non-response to induction therapy, early relapse within 6 months or secondary and subsequent leukemic recurrences. In this subgroup CR rates were 48% after 3.0 g/m² AraC and 23% after the lower dose regimen (p < 0.05). In cases with later occurring relapses CR rates were almost identical with 55% remissions after 3.0 g/m² AraC and 60% after 1.0 g/m² AraC.

Based on these results the AraC dose should be adjusted according to disease status and age in future trials and patients with refractory AML and less than 60 years of age are recommended to receive 3.0 g/m² AraC while older patients and cases with first relapses after 6 months remissions duration should be treated with 1.0 g/m² AraC.