Somatic co-alteration signatures are prognostic in high-grade TP53-mutated myeloid neoplasms.

To assess the relevance of co-occurring somatic mutations in TP53-mutated myeloid neoplasms with ≥10% blasts, we pooled 325 individuals from 10 centres. We focused on comparing three published somatic co-alteration signatures comprising (1) nine MDS-related genes ('ICC-MDSR'), (2) ICC-MDSR + additional secondary mutations-related genes ('Tazi signature') and (3) EPI6 (comprising six genes). Outcomes examined were 24-month overall survival (OS24) and front-line complete response (CR1). The median age was 69 years with 77% receiving front-line hypomethylating agents (HMA). All three signatures ICC-MDSR (p = 0.009), Tazi signature (p = 0.001) and EPI6 (p = 0.025) predicted inferior CR1. In the low-intensity (HMA) subgroup, only Tazi signature (p = 0.026) predicted inferior CR1. In OS24 analysis of the HMA-treated subgroup (N = 200), only Tazi signature was adverse (hazard ratio, HR = 1.6 [1.1-2.2]; p = 0.011). However, a forward stepwise multivariable age-adjusted Cox model including all three signatures picked EPI6 as the sole significant adverse predictor in the entire cohort (p = 0.0001) as well as within the HMA-treated subgroup (p = 0.0071). These data confirm the value of testing co-occurring somatic alterations even within a high-grade TP53-mutated myeloid neoplasm cohort.