Characteristics and clinical outcomes of newly diagnosed acute myeloid leukemia with MAPK pathway mutations: A referral-center retrospective analysis.

Abstract

e18506 Background: Somatic mutations in the MAPK signaling pathway are frequently identified and implicated in the disease biology in patients with newly diagnosed acute myeloid leukemia (NDAML), but the real-world clinical experience on treatment response and long-term survival remains incompletely characterized. Methods: We conducted a retrospective analysis of adult patients with NDAML harboring mutations in the MAPK pathways seen at the University of Iowa Health Care between March 2015 and December 2024. The primary endpoint was overall survival (OS), and the secondary endpoint was composite complete remission (CRc), defined as complete remission (CR), CR with incomplete hematologic recovery (CRi), or CR with partial hematologic recovery (CRh) following induction therapy. Intensive induction regimens (IIR) were anthracycline-based, while non-intensive regimens (NIR) were hypomethylating agent with or without venetoclax. The effect of patient, disease, and treatment characteristics on the odds of CRc or allogeneic stem cell transplant (HSCT) was evaluated using logistic regression and OS was evaluated using Cox regression. Results: Among the 74 patients identified (median age 66, 35% female), the following MAPK pathway mutations were found: NRAS only (N=45), KRAS only (N=19), NRAS/KRAS (N=5), BRAF (N=4), and HRAS (N=1). G12D was the most common variant in both KRAS and NRAS . 39 patients received IIR (median age 52), 23 patients received NIR (median age 73), and 12 did not receive treatment (NT) (median age 74). At a median follow-up of 7.9 months, 49 patients had died. Median OS for IIR, NIR and NT were 58.7, 7.5, and 0.2 months, respectively. On multivariable analysis (MVA) among those who received treatment (N=62), European LeukemiaNet (ELN) 2022 adverse risk (Hazard Ratio (HR): 3.56, 95% Confidence Interval (CI): 1.52-8.32) and KRAS mutation (HR: 2.14, 95% CI: 1.10-4.17) conferred inferior OS, while age and treatment intensity were not significantly associated with OS. The CRc rate was 53%. On MVA, abnormal karyotype (Odds Ratio (OR): 0.25, 95% CI: 0.07-0.89) and increasing age (OR: 0.97, 95% CI: 0.94-0.99) were associated with decreased odds of achieving a CRc while ELN 2022 risk was not. 22 patients underwent HSCT, and on MVA, only increasing age (OR: 0.93, 95% CI: 0.89-0.97) was associated with decreased odds of receiving a HSCT whereas treatment intensity was not. Conclusions: In this real-world clinical experience of MAPK-mutated NDAML, KRAS mutation conferred an inferior effect on OS but not CRc. Treatment intensity also did not have a significant effect on OS and the odds of CRc. We speculate that the adverse effect of KRAS mutation may be confounded by older age, abnormal cytogenetics, and adverse ELN risk. Larger, multi-center analyses are needed to confirm these findings.