Randomized study of high-dose cytarabine with or without dexamethasone as post-remission therapy 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

Abstract

Abstract Introduction The BIG-1 multicenter study was a prospective trial for younger AML patients with multiple randomizations at each stage of treatment, including induction, post-induction and allo-HSCT (Hunault M, NEJM Evid 2025). BIG-1 was designed to allow sequential evaluation of several agents in consolidation through nested randomized phase 2-3 trials over the trial period. Studies of adding either venetoclax or vosaroxin to IDAC vs IDAC alone have been completed (Vey N, ASH 2020; Gastaud L, ASH 2023). Based on recent preclinical data showing that cytarabine resistance acquisition is associated with increased glucocorticoid sensitivity, as well as the clinical impact of dexamethasone (DEX) in hyperleukocytic AML, we aimed to establish whether adding DEX to HDAC could reduce the relapse risk in patients who had achieved first remission (Récher C, Front Oncol 2021). Methods Patients (pts) aged 18-60y with newly diagnosed AML, post-MDS AML, or t-AML were eligible if they were included in BIG-1, in first CR/CRi after 1 or 2 chemotherapy courses, classified in the favorable or intermediate risk group according to the protocol classification, randomized in the HDAC post-induction arm, ECOG PS ≤ 2, without active infection or organ dysfunction. APL, Ph+ AML, CBF AML, or post-MPN AML pts were not eligible. Pts were randomly assigned to receive either HDAC alone (3g/m²/12h, d1-3-5) or HDAC combined with dexamethasone (10 mg/12h, d1-3-5, i.v). The protocol planned for 2 cycles in pts with allo-HSCT indication or 3 cycles in favorable-risk pts or for those without the possibility of allo-HSCT. Minimization factors for randomization were CR after 1 vs 2 cycles, WBC (< 30 vs ≥ 30 G/L) and NPM1 gene mutation. The primary endpoint was relapse-free survival (RFS). Evaluations of treatment effects were adjusted on ELN-2022 risk groups, anthracycline used in induction (daunorubicin vs idarubicin), and time-dependent HSCT in first CR. According to French's regulation, no racial or ethnic data were collected. Results 220 eligible pts were included from 01/2018 to 04/2021, 111 in the HDAC arm and 109 in the HDAC-DEX arm. Pts characteristics were well balanced between the two arms. Median age was 50y and 112 pts (51%) were female. According to ELN-2022, 101 (53%), 67 (26%) and 35 (16%) were favorable, intermediate or adverse risk; 11 pts (5%) were non-classified. Median CRP was 4 mg/L. Because dexamethasone was recommended in pts with high WBC at diagnosis, 50 pts were pre-exposed to dexamethasone during induction, 27 in the HDAC arm and 23 in the HDAC-DEX arm. There were no difference regarding antimicrobial prophylaxis or G-CSF use between the two arms. Allo-HSCT in first CR was performed in 29 and 48 pts in the HDAC and HDAC-DEX arm, respectively. With a median follow-up of 49.3 months, estimated 5y-RFS was 46% (95% CI, 36-56) in the HDAC arm vs 39% (95% CI, 29-49) in the HDAC-DEX arm (adjusted HR, 0.94 [95% CI, 0.62-1.43], p=0.77). When evaluated in patient subgroups including ELN-2022 risk group, anthracycline used in induction, WBC or allo-HSCT in first remission, no significant interactions with the HDAC-DEX vs HDAC treatment effect were observed for RFS. 5y-OS was 62% (95% CI, 51-71) in the HDAC arm vs 63% (95% CI, 51-72) in the HDAC-DEX arm (adjusted HR, 0.93 [95% CI, 0.54-1.62], p=0.81). 5y-CIR was 43% (95% CI, 34-52) in the HDAC arm vs 42% (95%CI, 31-52) in the HDAC-DEX arm (adjusted HR, 0.77 [95% CI, 0.46-1.29], p=0.32). The severity of HDAC-induced myelosuppression was lower in the HDAC-DEX arm. During the whole HDAC consolidation cycle period, the mean number of days with neutrophils <0.5 G/L was 20.7 (+/-13.2) with HDAC vs 15.4 (+/-11.4) with HDAC-DEX (p=0.002). The mean number of days with platelets < 20 G/L was 18.6 (+/-18.9) with HDAC vs 13.9 (+/-13.0) with HDAC-DEX (p=0.033). There were also lower needs for RBC and platelets transfusions with HDAC-DEX. The rate of fungal infections was lower in the HDAC-DEX arm (2.9%) vs HDAC arm (12.7%) (p=0.008). The rate of vomiting was also significantly reduced by DEX. Of note, post-hoc analysis showed that the 77 pts with CRP ≥ 5mg/L before consolidation had worse CIR, RFS and OS compared to pts with CRP < 5mg/L. Conclusions With the dosing schedule used in this trial, DEX did not improve RFS but did markedly improve tolerability of HDAC. Further studies are needed to investigate the prognostic role of inflammatory markers in AML.