P565: IMPROVED OUTCOME OF PATIENS WITH ACUTE MYELOID LEUKEMIA HARBORING FLT3 MUTATION IN THE ERA OF TARGETED THERAPY

Abstract

Background: In recent years, the treatment of AML is rapidly evolving due to the advances in targeted therapy, risk-adapted protocols and MRD-guided decisions. The prognosis of patients harbouring FLT3-ITD differs according to its allelic ratio and the presence of NPM1 co-mutation (NPM1mut). Nonetheless, FLT3-ITD prognostic impact and allogeneic hematopoietic cell transplantation (alloHCT) indication in this setting might be redefined by the widespread use of FLT3 inhibitors. Since 2012, chemotherapy eligible patients are treated following a risk-adapted and MRD-guided protocol in the CETLAM group (AML-12). Since 2016, targeted therapy with midostaurin was progressively incorporated in the protocol for FLT3-mutated (FLT3mut) patients. Aims: To analyse the outcome of FLT3mut AML treated with a risk-adapted protocol in two different time periods, mainly differentiated by the advent of midostaurin. Methods: All adult patients with de novo AML and available FLT3 status treated with the intensive protocol AML-12 (clinicaltrials.gov #NCT04687098) in the Spanish CETLAM centres from 2012 to 2020 were retrospectively analysed. Molecular testing of NPM1, and FLT3-ITD and its allelic ratio were studied as previously described. Patients were divided into two study cohorts: the early (2012-2015) and the late cohort (2016-2020). All patients received the same chemotherapy protocol except for the addition of midostaurin since 2016 in most FLT3mut patients. Complete remission (CR), overall survival (OS), event-free survival (EFS) and risk of relapse (RR) followed ELN criteria. OS and EFS were studied with the Kaplan-Meier method and log-rank test, cumulative incidence and Grey test were used to estimate relapse risk (CIR) and non-relapse mortality (NRM). Results: A total of 906 patients were selected, 390 from the early and 516 from the late cohort. Median follow-up was 38 months; FLT3mut was present in 227 cases (25%) and constitute the focus of this study. There were not differences on main variables between cohorts (age, cytogenetic risk, ELN category, frequency of NPM1 mutation or FLT3-ITD allelic ratio). TKD mutations were only available since 2015. Midostaurin was administered to 62% of FLT3mut patients from the late cohort: 63 with ITDs (20 low and 43 high ratio) and 20 TKDs. CR rates were similar between cohorts. AlloHCT in first CR (CR1) was performed in 60% (early) and 67% (late) patients (p=ns). A higher RR was observed in the early group in comparison to the late cohort (2-year RR 42±11% vs 28±10%; p=0.014), without differences in NRM (Figure 1B), translating into an improved EFS (median EFS 9.4 vs. 26 months, p=0.014) and OS in the late cohort (median OS: 15 months vs. non-reached, p=ns, Figure 1A). Among NPM1mut AML patients, FLT3-ITD and ELN 2017 categories retained its prognostic value in the early cohort, with a worse OS, EFS, and higher RR among FLT3-ITD vs wt patients (HR for OS 1.9 95% CI 1.15-3.2, p=.011; figure 1C) and FLT3mut ELN-intermediate vs favourable patients (OS p<0.001; figure 1D). On the contrary, in the late cohort, FLT3-ITD and FLT3 high allelic ratio lost their adverse prognostic impact, with comparable RR, EFS, and OS regardless of FLT3-ITD status (Figure 1E and F). Image:Summary/Conclusion: This real-life study demonstrated an improved outcome among FLT3mut AML patients treated in the most recent period, probably reflecting the beneficial effect of midostaurin on relapse prevention in this context. Future analyses should revise the role of alloHCT in CR1 for non-favourable FLT3mut AML patients treated with FLT3 inhibitors who achieve MRD eradication.