Clinical interrogation of TP53 aberrations and its impact on survival in patients with myeloid neoplasms

In myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with TP53 aberrations, dissecting the interaction amongst patient, disease and treatment factors are important for therapeutic decisions and prognostication. This retrospective analysis included patients with newly diagnosed MDS (>5% blasts) and AML with TP53 mutation(s) treated at MD Anderson Cancer Center. We factored patient age, TP53 aberration burden, therapy intensity and use of venetoclax in the AML subgroup, and allogeneic hematopoietic stem cell transplantation (HSCT) to interrogate outcomes. TP53 was annotated as high-risk (TP53HR) if >1 mutation, one mutation plus allelic deletion or a single mutation with variant allele frequency (VAF) ≥40%; TP53 low-risk (TP53LR) included a single TP53 mutation VAF <40%. Four-hundred and thirteen patients (291 AML, 122 MDS) at a median age of 69.4 years were included, 350 (85%) with TP53HR (253 AML [87%], 97 [79%] MDS). Overall response (OR) rate was 53% in AML and 62% in MDS. OR and composite complete response (CRc) rates was similar in patients with AML irrespective of treatment intensity, but higher when treated with venetoclax. At a median follow-up of 77 months, median OS was superior in patients with MDS than AML (10.8 vs. 5.9 months). On multivariate analysis (MVA) MDS had lower hazards of death compared to AML, as was TP53LR and HSCT. In the AML cohort, TP53LR and HSCT were favorable on MVA, though venetoclax did not improve survival. Both the diagnosis of MDS or AML and burden of TP53 aberrations dictated outcomes in our analysis and HSCT consistently led to improved survival outcomes.