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

A total of 142 patients with myeloproliferative neoplasms (MPNs) or acute myeloid leukemia (AML) associated with multihit TP53 mutations (mTP53 MUT) 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 ASXL1 MUT, EZH2 MUT, IDH1,MUT and IDH2 MUT were more common in MPN-MUTBP-mTP53 compared to AML-mTP53 MUT. 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 mTP53 MUT detection, was similar between MPN-BP-mTP53 MUT (median 4.6 months) and MPN-AP-mTP53 MUT (5.6 months; p = 0.5) but both were inferior to MPN-CP-mTP53 MUT (11.6 months, p < 0.01). OS in MPN-CP-mTP53 MUT was similar to that of AML-mTP53 MUT (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 TET2 MUT or DNMT3A MUT (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 mTP53 MUT on long-term survival in MPN and AML and identifies predictors of short-term survival.