Current therapies for high-grade TP53-mutated myeloid neoplasms (≥ 10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of response and outcomes, we assembled a cohort of 234 individuals with well-annotated clinical, molecular and pathology data, evaluating CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.0 years) with 73.4% receiving frontline non-intensive regimens (hypomethylating agents with or without venetoclax), we identified several novel factors predictive of inferior CR1 including male gender (P = .019), ≥ 2 autosomal monosomies (P < .001), -17/17p (P = .008), multi-hit TP53 allelic state (P < .001) and CUX1 alterations (P = .009). Inferior OS24 was predicated by ≥ 2 monosomies (P = .004), TP53 VAF>25% (P < .001), and TP53 splice junction mutations (P = .007). In addition, mutations/deletions in any of six genes including CUX1, U2AF1, epigenetic regulators (EZH2, TET2), or RAS pathway genes (CBL, KRAS) (termed 'EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < .0001). A risk score incorporating these accessible binary factors in a multivariable model stratified 3 prognostic distinct groups: favorable, intermediate, and poor with significantly different median (15.4, 9.2, 3.5 months) and 24-month (48.4%, 14.3%, 0.5%) survival (OS24) (P < .0001). For the first time, in a seemingly monolithic high-risk cohort, our data provides means to tease out small subgroups at baseline with superior or very poor outcomes.