Real life treatments and outcomes of older patients aged more than 60 years with FLT3-mutated acute myeloid leukemia: Report from the multicentric french observational ALFA-PPP study

Abstract

Abstract Introduction. Based on the results of the phase 3 RATIFY trial (Stone et al, NEJM, 2017), 7+3 (daunorubicin/cytarabine) plus midostaurin is considered the standard of treatment for acute myeloid leukemia (AML) with FLT3 mutation (ITD and TKD) in patients aged <60 years. In this trial, patients who completed the consolidation phase and were not allotransplanted received a maintenance therapy with single-agent midostaurin. In the phase 2 AMLSG 16-10 trial (Schlenk et al, Blood, 2019), the same schedule was safely administered and was shown to be effective in older patients up to 70 years. Another option for maintenance therapy in these patients is oral azacitidine (AZA) as demonstrated in a post-hoc analysis of the phase 3 QUAZAR AML-001 trial (Döhner et al, Blood, 2022). Methods.In 2022, the Acute Leukemia French Association (ALFA) group initiated a multicentric prospective observational study (ALFA-PPP, NCT04777916) aiming to collect clinical data and biosamples in all AML patients aged ≥18y referred to 27 ALFA centers. Clinical data and samples were structured by approved therapies. Here we report data on treatments and outcomes of FLT3-mutated AML cases aged ≥60y included between April 2022 and August 2024 in the multicentric French Observational ALFA-PPP study and treated upfront, with a specific focus on intensively-treated patients. Results. We analysed treatments and outcomes of 149 patients aged ≥60y. In all, 80 (53.7%) received intensive therapy (median age 68.5y, 60-78) while 60 (40.3%) underwent a non-intensive treatment, mainly AZA plus venetoclax for 81% of them (median age 77y, 64-98); 3 received best supportive care and 6 died before treatment initiation. 16 patients (10.7%) were included in a clinical trial: they were excluded from further analyses. Henceforth, our specific focus was on the 70 patients who were intensively treated outside of a clinical trial, among whom 7 were aged ≥75y. In all, 70%, 22.8% and 7.2% had a FLT3-ITD, FLT3-TKD or both mutations, respectively. For other molecular events of interest, NPM1, IDH, RAS and secondary AML-type mutations were identified in 68.5%, 21.4%, 37% and 36%, respectively. According to ELN-2022, 13%, 63% and 24% were classified as favorable, intermediate and poor-risk. Intensive approaches were as follows: 7+3 for 57 (81%), CPX-351 for 11 (16%), 7+3 plus GO for one patient (1%) and amsacrine/cytarabine for the last patient (1%). Specifically in the 7+3 subcohort, the majority received 7+3 with midostaurin (n=39, 68%; idarubicin 28, daunorubicin 11); 17 were treated without midostaurin (30%; ida 11, dauno 6). The overall complete remission rate (CR/CRi) was 62.7%. After remission, 16 patients (23%) were allotransplanted, 26 (37%) did not receive any maintenance therapy (14 because of a refractory/relapsed status, 9 died before) and 27 (38.5%) received an oral continuous maintenance therapy detailed as follows: midostaurin for 5 patients, 17 switched from midostaurin to oral AZA and 5 received gilteritinib. In the 70 intensively treated patients, overall survival (OS) was estimated at 58% (95% CI, 44-70) at 2 years. We performed a time-dependent multivariable Cox regression analysis using the following covariates in these patients: age, ECOG, HCT-CI comorbidity index, ELN-2022 risk category, NPM1, FLT3-ITD and TKD, secondary AML-type mutations, leukocyte count, maintenance therapy as a time-dependent variable with different categories (allotransplantation, FLT3 inhibitor midostaurin/gilteritinib, oral AZA, no maintenance). In this analysis, allotransplantation (HR, 0.09 [95% CI, 0.01-0.78]; p=0.029) or maintenance therapy with midostaurin/gilteritinib (HR, 0.17 [95% CI, 0.03-0.93]; p=0.041) were associated with prolonged OS, while maintenance with oral AZA was not (HR, 0.41 [95% CI, 0.12-1.43]; p=0.16). Conclusions. In the ALFA-PPP real-life cohort of FLT3-mutated AML patients aged ≥60y treated frontline, few were included in clinical trials. The majority of intensively-treated patients received intensive chemotherapy cycles plus midostaurin. However, for maintenance therapy, oral AZA was often preferred to FLT3 inhibitors while oral AZA did not significantly improve survival in the multivariable analysis. Notably, frontline allogeneic transplantation or maintenance therapy with FLT3 inhibitors significantly prolonged OS and could therefore be considered in patients who receive intensive treatment.