Double induction strategy for acute myeloid leukemia: The effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: A randomized trial by the German AML Cooperative Group

Early intensification of chemotherapy with high-dose cytarabine either in t he postremission or remission induction phase has recently been shown to im prove long-term relapse-free survival (RFS) in patients with acute myeloid leukemia (AML). Comparable results have been produced with the double induc tion strategy. The present trial evaluated the contribution of high-dose ve rsus standard-dose cytarabine to this strategy. Between March 1985 and Nove mber 1992, 725 eligible patients 16 to 60 years of age with newly diagnosed primary AML entered the trial. Before treatment started, patients were ran domized between two versions of double induction: 2 courses of standard-dos e cytarabine (ara-C) with daunorubicin and 6-thioguanine (TAD) were compare d with 1 course of TAD followed by high-dose cytarabine (3 g/m(2) every 12 hours for 6 times) with mitoxantrone (HAM). Second courses started on day 2 1 before remission criteria were reached, regardless of the presence or abs ence of blast cells in the bone marrow. Patients in remission received cons olidation by TAD and monthly maintenance with reduced TAD courses for 3 yea rs. The complete remission (CR) rate in the TAD-TAD compared with the TAD-H AM arm was 65% versus 71% (not significant [NS]), and the early and hypopla stic death rate was 18% versus 14% (NS). The corresponding RFS after 5 year s was 29% versus 35% (NS). An explorative analysis identified a subgroup of 286 patients with a poor prognosis representing 39% of the entire populati on; they included patients with more than 40% residual blasts In the day-16 bone marrow, patients with unfavorable karyotype, and those with high leve ls of serum lactate dehydrogenase. Their CR rate was 65% versus 49% (p = .0 04) in favor of TAD-HAM and was associated with a superior event-free survi val (median, 7 v 3 months; 5 years, 17% v 12%; P = .012) and overall surviv al (median, 13 v 8 months; 5 years, 24% v 18%; P = .009). This suggests tha t the incorporation of high-dose cytarabine with mitoxantrone may contribut e a specific benefit to poor-risk patients that, however, requires further substantiation. Double induction, followed by consolidation and maintenance , proved a safe and effective strategy and a new way of delivering early in tensification treatment for AML. (C) 1999 by The American Society of Hemato logy.