The association of IDH co-mutations with treatment outcomes and overall survival in TP53 -mutated acute myeloid leukemia.

6520 Background: In acute myeloid leukemia (AML), TP53 mutations confer a dismal prognosis, with a median survival of ~6 months. While characteristics of TP53 aberrancy (multi-hit status) define an even more aggressive subset, little is known about the effect of IDH co-mutations on outcomes. An analysis of the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND) cohort suggests that TP53 +/ IDH + subjects (n = 24) have prolonged survival compared to TP53+/IDHwt , a finding that could inform our treatment approach in these patients. We therefore aimed to validate this finding in a larger cohort within the Flatiron Health Research Database. Methods: Patients over 18 years with TP53 + AML and IDH1 or 2 testing at diagnosis were selected within Flatiron Health. Demographics, cytogenetic/molecular testing, and treatments were compared using standardized mean difference (SMD), with SMD > 0.2 indicating meaningful difference. Cox proportional hazards models controlling for age, sex, socioeconomic status, ECOG, multi-hit TP53 , secondary AML, and induction strategy were built to test the association of IDH co-mutations with Event Free Survival (EFS) and overall survival (OS). Sensitivity analyses considering receipt of an IDH inhibitor ( IDH i) and stem cell transplant (SCT) as time-varying covariates were also constructed. Finally, two subgroup analyses in the IDH + subcohort were performed to test associations between 1) IDH i in first line, and 2) hypomethylating agent/venetoclax (HMA/ven) in first line, and EFS and OS. Results: 753 TP53+ AML subjects with IDH testing at diagnosis were included. There were meaningful differences in the cytogenetic/mutational landscape of the IDH wt (n = 659) and IDH + (n = 94) cohorts, the latter with a lower incidence of multi-hit TP53 and myelodysplasia-related changes, and a higher incidence of ASXL1, DNMT3A, and TET2 co-mutations. In multivariable modeling, IDH co-mutations were not independently associated with EFS, though were strongly associated with improved overall survival (mOS 9.8 vs 6.1 months, HR 0.69, CI 0.52 – 0.92, p = 0.01). These associations persisted in sensitivity analyses treating IDH i and SCT as time-varying covariates. In analyses of the IDH + subcohort, receipt of IDH i or HMA/ven during first line did not associate with improved OS or EFS. Conclusions: In these data, IDH co-mutations are associated with improved OS in TP53 + AML, though there was no signal suggesting this was driven by choice of therapy. Our analysis is limited by its retrospective nature and a definition of “multi-hit” status that relied on concomitant presence of del17 and a TP53 point mutation. Though these results require further validation, they may currently inform the clinical approach to TP53 +/ IDH + AML by framing goals-of-care conversations. However, more work is needed to characterize the effect of treatment selection on outcomes in this population.