DP031 | PROGNOSTIC IMPACT OF HIGH-RISK MUTATIONS IN SECONDARY AML TREATED WITH CPX-351: A FOCUS ON MOLECULAR PREDICTORS OF RESPONSE AND SURVIVAL

Background: Acute Myeloid Leukemia (AML) is a heterogeneous disease driven by somatic mutations. The ELN 2022 classification designated several mutations (e.g., TP53, ASXL1, SRSF2) as adverse with conventional chemotherapy. However, their prognostic significance may differ with newer treatments like hypomethylating agents plus venetoclax (HMA+VEN), where alternative mutations (RUNX1, FLT3-ITD, N/KRAS, CBL and KIT) predict resistance. CPX-351 is approved for secondary AML (s-AML), a setting where high-risk mutations are common, yet their impact on CPX-351 outcomes remains unclear. Aims: To evaluate the prognostic role of high-risk mutations and molecular predictors of response in s-AML patients treated with CPX-351. Methods: Eighty-one patients (median age 69, range 37–77) with s-AML (n=55) or therapy-related AML (t-AML, n=26) per WHO 2016 received CPX-351. Baseline NGS was performed using the SOPHiA Genetics Myeloid panel (34 genes), analyzed via Illumina MiSeq and SOPHiA DDM® Software. MRD was assessed in CR patients by multicolor flow cytometry (threshold 0.1%). Results: By ELN 2022, 10% of patients were favorable, 6% intermediate, and 84% adverse. Median mutation count was 7 (range 2-14); 36% had ≥8 mutations. High-risk ELN mutations were found in 88%, secondary-type mutations (STMs) in 68%, and 73% had HMA+VEN resistance-associated profiles. Common mutations included ASXL1 (36%), RUNX1 (35%), TP53 (26%), and SRSF2 (23%). After one CPX-351 cycle, 81% (66/81) achieved CR; with MRD negativity in 61% (40/66). ELN risk, STMs, and HMA+VEN resistance profiles did not significantly affect CR or MRD negativity. DNA methylation gene mutations correlated with higher CR rates (p<0.05). After a median follow-up of 34 months (95% CI: 23.2–64.8), median OS was 15 months (95% CI: 10.7–19.3); 1-year OS was 52.7%. OS was not affected by ELN high-risk mutations, STMs or HMA+VEN resistance profile. Landmark analysis showed improved OS in CR patients undergoing HSCT (n=24) vs. non-HSCT (n=41; p<0.05). Among HSCT patients, survival was mutation-independent. In non-HSCT patients, cohesion gene mutations predicted worse OS (p<0.05), while DNA methylation gene mutations were associated to better outcomes (p<0.05). Conclusion: CPX-351 induces high MRD-negative CR rates in s-AML, independent of adverse mutational profiles. DNA methylation gene mutations may confer favorable prognosis, while cohesin gene mutations indicate poor outcome in patients not undergoing HSCT.