Multihit <scp><i>TP53</i></scp> 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.