Myelodysplasia-related mutation dynamics and outcomes in newly diagnosed (ND) acute myeloid leukemia (AML) treated with low-intensity therapy (LIT).

6531 Background: Outcomes of patients (pts) with ND AML with myelodysplasia related gene mutations (MRMs), while traditionally adverse, appear to be better with LIT regimens + venetoclax (Ven). The impact of MRMs as a minimal residual disease (MRD) marker warrants investigation. Methods: We retrospectively analyzed the impact of persistence/clearance of MRM at VAF <2% at best response of CR/CRi, in pts with LIT treated ND AML (with available genomic data), treated at our institution between 2017 – 2025 and had ≥1 MRM ( ASXL1, BCOR, EZH2, STAG2, SF3B1, SRSF2, U2AF1 , and/or ZRSR2 ) at diagnosis, at a VAF of ≥2%. We excluded pts with CBF-AML, APL, or treated secondary AML. MRM dynamics were tracked at baseline and best response (CR/CRi) and correlated with relapse free/overall survival (RFS/OS). Results: A total of 185 pts, median (med) age 69 yrs (range, 56-87 yrs), were included; 96% were ≥ 60 yrs. The common baseline MRM were SRSF2 (54%), ASXL1 (32%), STAG2 (16%) and BCOR (14%); 16% had >1 MRM. Overall, 17% had concurrent NPM1 mutation (mut), 9% FLT3 -ITD (AR>0.05), 22% RAS , 32% RUNX1 , 8% TP53 , and 32/183 pts (17%) had ELN2017 adverse cytogenetics (CTG). 171 pts (92%) were treated with LIT+Ven and 14 (8%) LIT without Ven; 105 (57%) received hypomethylating agents based, and the rest (43%) received cladribine + low-dose cytarabine based LIT. Overall, 148 (80%) achieved CR and 37 (20%) CRi. 117/168 (70%) pts with available data were MRD negative (-) by flow cytometry (FCM; <0.01%) at CR/CRi. At CR/CRi, 49 (26%) cleared their MRMs (MRM-) while 136 (74%) retained MRMs (MRM+); among pts with FCM MRD- CR/CRi, 33/117 (28%) were MRM- and 84/117 (72%) MRM+. Med cycle to CR/CRi was 1 (IQR 1-2). Pts with MRM- at CR/CRi had superior med RFS (24 [95% CI 9-18] vs. 14 mos [16-NR], p=0.008) and OS (54 [25-NR] vs. 21 mos [15-27], p=0.01) compared to MRM+ pts. Among 117 FCM MRD- pts, med RFS (NR vs. 14 mos [9-23], p=0.001) and med OS (NR vs. 19 mos [14-36], p=0.003) was still superior among MRM- pts (n=33) vs. MRM+ (n=84). 67 pts (36%) underwent a hematopoietic stem cell transplantation (HSCT) in CR1, 26/49 (53%) MRM- and 41/136 (30%) MRM+. Among FCM MRD- pts who did not undergo HSCT, 2-yr OS rate (86% vs. 48%, p=0.04) was better in MRM- pts (n=15) vs. MRM+ pts (n=58); among FCM MRD- pts who had HSCT, 2-yr OS rate trended to favor MRM- pts (n=18) (77% vs. 55%, p=.14) vs. MRM+ pts (n=26). On backward selected Cox MVA, clearance of MRMs at CR/CRi was independently associated with favorable OS (HR=0.54, 95% CI 0.31-0.95, p=0.03), along with BCOR, IDH2 mut, and HSCT, while RAS mut, FLT3 -ITD, and adverse CTG were unfavorable. Finally, among FCM-MRD- pts at CR/CRi, using the same Cox model, clearance of MRMs was independently favorable for OS (HR=0.42, 95%CI 0.20-0.93, p=0.03). Conclusions: In our analysis, the status of MRM clearance at CR/CRi in LIT treated AML with baseline MRM affected survival outcomes, including in pts FCM MRD- at CR/CRi.