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 (m TP53 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‐ MUT BP‐mTP53 compared to AML‐m TP53 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 m TP53 MUT detection, was similar between MPN‐BP‐m TP53 MUT (median 4.6 months) and MPN‐AP‐m TP53 MUT (5.6 months; p = 0.5) but both were inferior to MPN‐CP‐m TP53 MUT (11.6 months, p < 0.01). OS in MPN‐CP‐m TP53 MUT was similar to that of AML‐m TP53 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 m TP53 MUT on long‐term survival in MPN and AML and identifies predictors of short‐term survival.