Induction chemotherapy with a single anthracycline-containing cycle in younger adults with newly diagnosed AML – the french backbone intergroup (BIG)-1 study on behalf of the filo, ALFA, and SFGM-TC study groups Free

Introduction The BIG-1 multicenter study was a prospective trial designed for younger AML patients with multiple randomizations at each stage of treatment, including induction, post-induction and hematopoietic stem-cell transplantation. Results of the post-induction randomization (intermediate vs high dose cytarabine) have been already reported (Hunault M et al, NEJM Evid 2025). Here, we report the results of the first randomization that compared high dose idarubicin (IDA, 45 mg/m² total dose) to high dose daunorubicin (DNR, 270 mg/m² total dose) during the first and unique induction cycle containing anthracyclines.

Methods Patients (pts) aged 18-60 years with newly diagnosed AML, untreated post-MDS AML, or t-AML were eligible if they had an ECOG performance status ≤3, normal cardiac, liver and renal functions, no active infection or neoplasia. Pts with APL, Ph+ AML, CBF AML, or post-MPN AML were not eligible. Pts were randomly assigned to receive either daunorubicin (90 mg/m², d1-3) or idarubicin (9 mg/m², d1-5), combined with cytarabine 200 mg/m² (d1-7). The protocol planned for a single cycle of anthracycline. All patients alive after this first cycle, including those not achieving CR/CRi, underwent a second randomization to compare post-induction IDAC vs HDAC. The primary endpoint was overall survival (OS). Evaluations of treatment effects were adjusted on ELN-2022 risk, post-induction IDAC vs HDAC randomization, and time-dependent HSCT in first CR/CRi. According to French's regulation, no racial or ethnic data were collected.

Results 1,159 pts were included from 01/2015 to 05/2018, 578 in the DNR arm and 581 in the IDA arm. Baseline characteristics were well balanced between the two arms. Median age was 50y, 563 pts were female. According to ELN-2022, 308 (27%), 330 (28%), 464 (40%) and favorable, intermediate or adverse risk; 57 pts (5%) were non-classified. With a median follow-up of 5.6y, 5-year OS was 51.8% (95% CI, 47.5-55.9) in the DNR arm vs 50.3% (95% CI, 46.0-54.5) in the IDA arm (adjusted HR, 1.03 [95% CI, 0.87-1.22], p= 0.75). When evaluated in patient subgroups including ELN-2022 risk groups, post-induction IDAC vs HDAC, and allo-HSCT in first remission, no significant interactions with the DNR vs IDA treatment effect were observed for OS. 5y-estimates of EFS (38 vs 38%), RFS (41 vs 44%), and cumulative incidence of relapse (43 vs 41%) did not differ between the two arms. Following induction, there was no difference in remission rate (CR+ CRi, 72.0 vs 73.7%) or early death (2.8 vs 2.8%) in the DNR and IDA arms, respectively. After salvage chemotherapy, the rates of CR/CRi, persistent AML, and early death were 85.6 vs 81.6%, 10.6 vs 13.9%, and 3.8 vs 4.5% in the DNR and IDA arms, respectively. Post-induction CR/CRi (DNR vs IDA) by ELN-2022 groups were: 96 vs 95%, 73 vs 78%, 55 vs 56% in favorable, intermediate and adverse groups respectively, whereas post-salvage CR/CRi were 97 vs 98%, 87 vs 84% and 76 vs 68%. 5y-OS by ELN-2022 groups was 73 vs 74%, 60 vs 58% and 38 vs 38% in favorable, intermediate and adverse groups, respectively. The severity of chemotherapy-induced myelosuppression and the incidences of adverse events were lower after DNR with shorter durations of thrombocytopenia and neutropenia, lower needs for RBC transfusions, number of days on antibiotics, and frequency of fungal infections. The rate of allo-HSCT in first CR/CRi was 43% in the DNR arm and 42% and the IDA arm.

The BIG-1 trial enrolled more pts in further phase 2 studies planned in the protocol. Since there was no difference in efficacy and treatment-related mortality between DNR and IDA, we pooled the two arms to build a cohort of 2023 pts included between 01/2015 and 06/2021. To determine the crude contribution of first-line chemotherapy to OS in selected subgroups, we computed the salvage-free, transplantation-free survival (STFS) as the time between the date of inclusion until treatment failure, salvage treatment, morphological or molecular relapse, allo-HSCT or death. 5y-STFS was 52%, 31%, 15%, 11% and 2% in pts with CEBPA-bZIP, NPM1, IDH2, IDH1 mutations or KMT2A rearrangement (except KMT2A-MLLT3), respectively.

Conclusions The first two randomizations of the BIG-1 study allowed us to establish a simplified treatment regimen consisting of a single cycle of daunorubicin 90 for induction and IDAC for consolidation. We now consider this regimen as a standard backbone on which new molecules can be added to improve results.