Outcomes and characteristics of patients treated with frontline intensive chemotherapy versus hypomethylating agent/venetoclax-based therapy in DDX41-mutated Acute Myeloid Leukemia (AML)

Abstract Introduction: DDX41-mutated AML comprises 2–5% of new AML cases, often seen in males, and is frequently associated with germline mutations, a normal karyotype, and an indolent course. Prior studies show that both intensive chemotherapy (IC) and hypomethylating agent plus venetoclax (HMA/VEN) can achieve high response rates and favorable overall survival (OS), but the optimal treatment strategy remains undefined. The aim of this study is to compare real-world outcomes and genomic features of DDX41-mutated AML treated with frontline IC vs. HMA/VEN based therapy. Methods: We performed a retrospective review of AML patients at Moffitt Cancer Center diagnosed between 9/2017 and 3/2025. Patients with DDX41 mutations detected on next generation sequencing at diagnosis who received upfront IC or HMA/VEN based therapywere included. If DDX41 mutations were detected during treatment or at relapse, patients were included if a double hit was present or if the variant allelic frequency was 45% (range: 46.1 to 51) suggesting germline mutation. Type and locus of DDX41 mutations were collected when available. Patients were stratified by their initial treatment: IC vs. HMA/VEN based. Kaplan-Meier analysis with log-rank test was used to estimate relapse free survival (RFS) and OS from the time of AML diagnosis. Impact of clinical variables on survival in the two arms was evaluated using Cox proportional hazards modeling. Results: We identified a total of 51 patients (IC: n=21, HMA/VEN: n=30). Median age at diagnosis was significantly higher in the HMA/VEN (75 years; range 60-84) vs. IC cohort (66 years; range 31-75), (p0.001). The majority were male (IC: 81% 17/21, HMA/VEN: 83% 25/30, p=0.83) and White (IC: 86% 18/21, HMA/VEN: 100% 30/30, p=0.10). ELN 2022 risk stratification showed favorable risk in 5% (1/21) vs 0% (0/30), intermediate in 62% (13/21) vs 50% (15/30), and adverse in 33% (7/21) vs 50% (15/30) of IC and HMA/VEN patients, respectively (p=0.28). Relapse was noted in 33% (7/21) in IC and 40% (12/30) in HMA/VEN cohort (p=0.63). Allo-HCT was performed in 48% (10/21) of IC and 40% (12/30) of HMA/VEN patients (p=0.59); ECOG performance status did not differ significantly (p=0.35). Among all patients (n=51), dual DDX41 mutations were noted in 17 (33.3%) and the co-mutations were noted in 29 (57%), while 22 (43%) patients had no additional mutations beyond DDX41. The most common co-mutations in IC cohort were TP53 (14%) and ASXL1 (14%); in HMA/VEN, TP53 (20%) and SRSF2 (17%) were most frequent. The most common DDX41 mutations in IC cohort were R525H (8/21, 38%) and D140Gfs2 (3/21, 14%); and R525H (8/30, 27%) and T529Nfs13 (4/30, 13%) in HMA/VEN cohort. AML myelodysplasia-related (WHO 2022) was seen in 6/21 (29%) of IC and 8/30 (27%) of HMA/VEN patients; TP53 mutations were seen in 3/21 IC (14%) and 6/30 HMA/VEN (20%), with the majority (5/9) having a prior myeloid malignancy. With a median follow up of 22 months, the median OS of all patients (n=51) was 40 months (95% CI: 31.4 – not reached NR). There was no significant difference in median OS of IC vs. HMA/VEN cohort (NR vs. 33.7 months, p=0.18). For the non-allo-HCT patients in IC (n=11) and HMA/VEN (n=18), there was no significant difference in OS (p=0.20). The median RFS was NR for both cohorts (p=0.31). On multivariable analysis of all patients (n=51), increasing age was independently associated with worse OS (HR: 1.10 per year; 95% CI: 1.03–1.17; p=0.004). Moreover, patients with ELN 2022 favorable/intermediate risk AML had a non-significant trend toward improved OS vs. adverse risk (HR: 0.70; 95% CI: 0.27/1.84; p=0.47), and allo-HCT was independently associated with improved OS (HR: 0.17; 95% CI: 0.05–0.65; p=0.009). With Cox proportional hazards modeling adjusting for age, ELN 2022 risk group, and allo-HCT status; survival analysis showed no significant difference in OS of IC and HMA/VEN cohorts (HR: 0.62; 95% CI: 0.23–1.71; p=0.36). Conclusions: In patients with DDX41-mutated AML, OS does not significantly differ between those treated with IC and those receiving HMA/VEN-based therapy after adjustment for age, ELN 2022 risk, and allo-HCT status. Older age is significantly associated with worse OS, while allo-HCT is associated with improved OS. Survival outcomes with HMA/VEN-based therapy are comparable to IC, supporting HMA/VEN based therapy as a viable frontline option in this AML subtype.