Multihit TP53 Mutations in Myeloproliferative Neoplasms and Acute Myeloid Leukemia: Comparative Analysis of Survival and Risk Factors in 142 Informative Cases

Abstract

A total of 142 patients with myeloproliferative neoplasms (MPNs) or acute myeloid leukemia (AML) associated with multihit TP53 mutations (mTP53MUT) were accessed from the Mayo Clinic database and included (i) chronic phase MPN (MPN-CP; N = 19), (ii) accelerated phase MPN (MPN-AP; N = 14), (iii) blast phase MPN (MPN-BP; N = 28), and (iv) AML (N = 81). Concurrent ASXL1MUT, EZH2MUT, IDH1,MUT and IDH2MUT were more common in MPN-MUTBP-mTP53 compared to AML-mTP53MUT. At median of 11.6 months follow-up, 124 (87%) deaths and 19 (13%) allogeneic stem cell transplantations (ASCT) were documented. Overall survival (OS), calculated from the time of mTP53MUT detection, was similar between MPN-BP-mTP53MUT (median 4.6 months) and MPN-AP-mTP53MUT (5.6 months; p = 0.5) but both were inferior to MPN-CP-mTP53MUT (11.6 months, p < 0.01). OS in MPN-CP-mTP53MUT was similar to that of AML-mTP53MUT (median 7.4 months, p = 0.07). In multivariable analysis, OS was favorably affected by ASCT (HR 0.4, p = 0.03) and disease stage (i.e., chronic phase disease) or achieving response to pre-transplant chemotherapy (HR 0.2, p < 0.01) and unfavorably by the presence of concurrent TET2MUT or DNMT3AMUT (HR 2.7, p < 0.01). Based on these risk factors, a 3-tiered risk model was constructed: low (no risk factors; N = 18; median OS 23.8 months); intermediate (one risk factor; N = 44; 11.1 months); and high (two or more risk factors; N = 80; 4 months; p < 0.01). The current study highlights the equally detrimental impact of mTP53MUT on long-term survival in MPN and AML and identifies predictors of short-term survival.