ALFA-9000 Trial - An Analysis of Cytogenetic Subsets: Significant Long-Term Benefit of Early Induction Reinforcement Is Observed in CBF-AML Only.

Abstract

We have recently reported the results of the ALFA-9000 randomized trial in which younger adults with AML had a significant better long-term relapse-free interval when receiving a timed-sequentially reinforced induction (arm C) as compared to either standard 3+7 (arm A) or double (arm B) induction (Castaigne et al, Blood 2004). Both arms B and C included the same induction reinforcement with mitoxantrone and intermediate-dose cytarabine (ID-AraC) systematically administered at day 20 in arm B or at day 8 in arm C. Although patients aged between 15 and 65 years were included in this study, the gain in relapse incidence associated with arm C was observed in those less than 50 years of age only. We report here the outcomes of cytogenetic subsets, according to the arm C versus arm A/B stratification. Overall, 405 karyotypes were available (68%) and classified according to the SWOG classification as 56 favorable (CBF-AML, 46/56 under the age of 50 years), 215 intermediate (including 194 normal), 91 unfavorable, and 43 of unknown significance. Outcome of unfavorable and unknown subsets did not differ significantly in C versus A/B. Patients with complex karyotype or chromosome 7, 5q, or 3q abnormalities, as well as those with 11q23 abnormalities, had a similar outcome whatever their induction arm. Similarly, no benefit of early reinforcement was observed in the intermediate group, nor in patients with a normal karyotype even after adjustment on WBC or when considering only those aged less than 50 years. In the favorable subset, patients with either t(8;21) (N=30) or inv(16) (N=26) had identical long-term outcome. Contrary to other subsets, this outcome differed strikingly among induction arms with better disease-free survival in arm C (64% versus 28% at 5 years, P=.05 after adjustment on WBC) with a similar trend observed for event-free survival. The value of higher than standard doses of cytarabine in CBF-AML patients, either during induction or as post-remission therapy, has been demonstrated by several cooperative groups. Our results do suggest that early introduction of ID-AraC is also associated with long-term benefit in this favorable subgroup of patients, even greater when made at day 8 instead of day 20. We will evaluate prospectively this induction approach in the next French Intergroup CBF-AML study, in which all patients will then receive high-dose cytarabine during post-remission therapy.