TP53 Mutations Determine Outcome of Patients (pts) with High-Risk Myelodysplastic Syndrome (HRMDS) and Acute Myelogenous Leukemia (AML) Regardless of Karyotype and ELN Risk Stratification

Background: Cytogenetic and molecular abnormalities are the backbone of risk stratification for pts with AML/MDS. Yet, the current stratification systems still fail to identify some pts at high risk for treatment failure. TP53 mutations have been linked to poor outcome and treatment resistance in many malignancies. We conducted a retrospective case-control study of pts with HRMDS and AML with TP53 mutations (TP53 m) to define disease characteristics, response, and outcome after transplant (HSCT).

Methods: Twenty-one consecutive pts with HRMDS or AML were treated between January 2014 and March 2016 who wereTP53 m. The pts were compared to a control cohort of 46 pts with wild type TP53 (TP53 wt). Mutation analysis was performed using next generation sequencing. All AML pts were treated with a standard 3+7 induction protocol. Pts were excluded for incomplete cytogenetic and molecular data.

Results: A total of 21 patients were identified with TP53 m (14 HRMDS, 11 AML). The median age of the 21 pts was 64 years (range 32-84). Pts with TP53 m were older (median age 64 vs 55 years, p=.0256) and exhibited a higher rate of adverse cytogenetics (71% vs 30.4%, p=.043) when compared to TP53 wt. Secondary AML was also more common with TP 53 m (57% vs 31%, p=.05). Pts with TP53 m were less likely to achieve CR (33% vs 74%, p=.009). Three pts with TP53 m proceeded to transplant (2 with HRMDS and 1 with AML).

With a median follow up of 3.4 months (range 0.3-73) the estimated PFS and OS at 18 months was superior in TP 53 wt compared to TP 53 m (17% vs 69%, p=.037 and 17% vs 50%, p=.0095 respectively). HSCST was associated with a 70% reduction in mortality, but this was not statistically significant (p=.067).

Conclusion: TP 53 mutations in pts with HRMDS and AML are associated with advanced age, high risk cytogenetic abnormalities, and secondary AML. Our findings demonstrate that TP53 m in HR MDS and AML is associated with poor clinical outcome including lower CR rates, and lower PFS and OS. Different treatment strategies need to be devised for these pts.