DP092 | MOLECULAR BACKGROUND OF NPM1-MUTATED ACUTE MYELOID LEUKEMIA RECEIVING INTENSIFIED FLUDARABINE-BASED INDUCTION: EXPLORING THE ROLE OF “SECONDARY TYPE” AND HIGH RISK MUTATIONS

Background: NPM1-mutated AML (NPM mut AML) is typically associated with favorable prognosis, but recent studies highlight biological and molecular heterogeneity. FLT3-ITD mutation is used for further risk stratification, while DNMT3A mutations have also been linked to poorer outcomes. The ELN 2022 classification places secondary-type mutations (STM)—including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG—in the adverse risk group, but their impact in NPM mut AML remains unclear. Most data on co-mutations stem from patients treated with 3+7 induction, and evidence is lacking for fludarabine-based regimens (FLAI). Our group previously reported that FLAI may mitigate the adverse effect of FLT3-ITD in NPM mut AML. However, the prognostic impact of STM or DNMT3A mutations in this context is unknown. Aim: To assess the prognostic impact of STM and/or DNMT3A mutations on MRD clearance and survival in NPM mut AML treated with FLAI. Methods: We retrospectively analyzed 44 patients (median age 56, range 29–59) with WHO2022-defined NPM mut AML treated with FLAI. NGS was performed at diagnosis using the SOPHiA Genetics Myeloid Solution panel (34 genes) on Illumina MiSeq; analysis used SOPHiA DDM®. MRD was assessed via RT-PCR in all patients achieving CR. Results: Six patients (14%) had STM, 9 (21%) had DNMT3A mutations, and 3 had both. FLT3-ITD was found in 18/43 (42%) and 3/44 (7%) had high-risk cytogenetics (complex karyotype). After one FLAI cycle, 41/44 (94%) achieved CR, 2 (4%) were resistant, and 1 (2%) died before evaluation. MRD was negative after cycle 2 in 34/41 (83%) of responders. CR and MRD negativity were not influenced by STM, DNMT3A, FLT3-ITD, or cytogenetics. Interestingly, the two resistant cases had normal cytogenetics and no STM or DNMT3A mutations but harbored KMT2A mutations—the only such cases in the cohort. At a median follow-up of 59 months (CI 95% 41.3–68.6), median OS and DFS were not reached. OS and DFS were unaffected by STM, DNMT3A, FLT3-ITD, or cytogenetics (p=n.s.), but MRD negativity after cycle 1 was associated with significantly longer OS and DFS (p<0.05). Conclusion: FLAI induced high MRD-negative CR rates and long-term survival in NPM mut AML, regardless of co-occurring STM, DNMT3A, or FLT3-ITD mutations. HSCT was rarely required, in contrast to standard 3+7 treatment. KMT2A mutations, though rare, appeared linked to resistance; further studies are needed to clarify their prognostic role.