Current Results of Intensive Therapy in Younger Adults with Acute Myeloid Leukemia (AML): The Large Randomized French Backbone Intergroup (BIG)-1 Study on Behalf of the Filo, ALFA, and SFGM-TC Study Groups

Introduction. This multicenter study randomly explored various standard intensive chemotherapy (ICT) strategies in adults with AML, namely higher-dose idarubicin (IDA) vs high-dose daunorubicin (DNR) and intermediate-dose (IDAC) vs high-dose (HDAC) cytarabine. The study was planned large enough to allow patient subgroup analysis. Treatments. Eligible patients (pts) were randomized (R1) to receive an induction course with either DNR at 90 mg/m 2/d for 3 days or IDA at 9 mg/m 2/d for 5 days combined with cytarabine at 200 mg/m 2/d CIV for 7 days. Since 09/2018, FLT3-mutated AML pts may also receive midostaurin 100 mg/d d8-21. Then, all pts alive without contra-indication for further ICT were randomized (R2) to receive a first consolidation (C1, if in CR/CRp/CRi) or salvage (if induction failure) with either HDAC (3g/m 2/12h) or IDAC (1.5g/m 2/12h) cytarabine at day 1, 3 and 5. Pts in CR/CRp/CRi after C1/salvage received two additional HDAC/IDAC cycles (C2, C3), according to R2 arm. In intermediate (int) or adverse (adv) risk AML pts as defined in the protocol, allogeneic HSCT from sibling or 10/10 (or even 9/10 if adv-risk) matched donors was offered after C1 (adv-risk) or C2 (int-risk). Conditioning regimens were myeloablative (MAC; Bu-Cy ± ATG) if age 2 in int-risk pts, and sequential FLAMSA/Bu-Cy-ATG in adv-risk pts. Fav-risk pts were also eligible for HSCT if late CR/CRp/CRi or suboptimal NPM1 MRD response. Alternative stem cells sources and conditioning regimens might also be offered to adv-risk pts. Patients & Methods. Pts aged 18-60y with de novo, post-MDS or therapy-related AML (CBF, APL, Ph+, and post-MPN excluded) were eligible if ECOG-PS ≤3, no active infection or neoplasia, no organ contra-indication, and a health insurance. Patient characteristics are shown in Table 1. Between 01/2015 and 05/2019, 1405 pts were enrolled and 1357 were evaluable. Among them, 1159 were randomized in R1 with the primary objective to increase 3-year OS from 45% in the DNR to 55% in the IDA arm. A total of 1221 pts were randomized in R2, including 198 pts after the end of the R1 inclusion period (they received DNR or IDA according to centers' preferences). Primary R2 objective was to show OS non-inferiority after IDAC vs HDAC in a per protocol (PP) set, defined as pts who received the planned HDAC/IDAC dose ± 20% during C1/salvage. The non-inferiority boundary was an upper limit of the hazard ratio [HR]