Real World Predictors of Response and 24-month survival in high-grade TP53-mutated Myeloid Neoplasms

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of Chicago Medicine, Institutional Review Board IRB20-1250 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Relevant data can be shared upon reasonable request to corresponding author.