Who benefits from gilteritinib combination therapy amongst FLT3 ^mut R/R AML? Genomic insights.

e18522 Background: The outcome of FLT3 mut R/R AML is dismal. Use of Giltertinib monotherapy results in modest benefits with an improvement in EFS (2.8 months) and OS (9.3 months). Triplet (Azacytidine, Venetoclax and Giltertinib) and doublet combinations (Venetoclax and Gilteritinib) have shown high rates of CR/CRi, mCRc and longer survival. However, on cross-trial comparison, gilteritinib combinations have similar survival to monotherapy (ADMIRAL trial). We presented our experience of FLT3 mut R/R AML, where we showed that gilteritinib combinations resulted in better mCRc and higher transplant feasibility. In this analysis we intend to look at genomic predictors which could predict survival in this population. Methods: We conducted aretrospective, single center study to evaluate the impact of co-mutations on the survival outcomes associated with gilteritinib based therapy for FLT3 mut R/R AML. Results: A total of 68 FLT3 mut R/R AML patients were treated with Giltertinib or its combinations between January 2017 and March 2024. Giltertinib monotherapy was used in 47 while 21 received combination. Combinations included Giltertinib+ Venetoclax (n = 8), Giltertinib+ Azacytidine+ Venetoclax(n = 11) and Gilteritinib plus azacytidine (n = 2). The median OS with monotherapy and combination were 5.8 months and 14.9 months, respectively ( p = 0.0958). The most common co-occurring mutations were DNMT3A (44%), NPM1 (41%), RUNX1 (19%), ASXL1 (15%) and IDH2 (15%). Notably, 21 patients (30.8%) harbored co-mutations in NPM1 and DNMT3A (termed triple-mutated).Triple-mutated patients showed significantly higher rates of CR/CRi (42.9% vs 10.6%; p = 0.007), mCRc (71.4% vs 34%; p = 0.008), and a lower probability of an EFS event (52.4 % vs 91.5%; p = 0.001) or death (42.9% vs 87.2%; p < 0.001) in comparison to non-triple mutated patients. The median OS in the triple-mutated patients was 45 months (95%CI: 4.9 - NA) in comparison to 5.6 months (95%CI: 3.6 – 7.5) in the non-triple mutated patients ( p = 0.0003). Therapy stratification revealed that the 24-month OS for triple-mutated patients treated with combination therapy and monotherapy were 60.0% and 54.5%, respectively. In contrast, the 24-month OS in the non-triple mutated cohort treated with combination therapy and monotherapy were 17.3% and 8.7% respectively. Multivariable analysis using the cox proportional hazards model, the factors positively predicting survival included achievement of mCRc, undergoing transplant and the presence of triple mutation. Exposure to azacytidine-venetoclax predicted for poorer survival. Conclusions: Patients with triple mutation ( FLT3 /NPM1/DNMT3A co-mutation) is a distinct subset which responds particularly well to FLT3-inhibitor. Future studies should explore whether therapy selection (monotherapy or combination therapy) can be decided based on the presence or absence of triple mutation.