The Impact of Post-Transplant Interventions and Chronic GVHD on Survival in Myeloid Malignancies Harboring TP53 Alterations.

Myeloid malignancies with TP53 alterations are characterized by genomic instability, chemotherapy resistance, and very poor outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). Hypomethylating agents (HMAs), small molecule targeted therapies, and donor lymphocyte infusion (DLI) are often used post-transplant to mitigate relapse risk in high-risk myeloid malignancies, but their impact on survival in TP53-mutated disease remains uncertain. To evaluate the impact of post-transplant interventions and graft-versus-host disease (GVHD) on relapse and survival outcomes in patients with TP53-mutated or chromosomal 17p-deleted myeloid malignancies. This is a single-center retrospective study of adult patients with TP53-mutated and/or chromosomal 17p-deleted myeloid malignancies who underwent first allo-HCT between 2014 and 2023. Survival outcomes were assessed using the Kaplan-Meier method. Univariable Cox proportional hazards regression was used to assess associations of baseline characteristics with outcomes. Analyses of post-HCT interventions (maintenance/preemptive HMAs, targeted therapies, and/or DLI) and the development of chronic GVHD (classic chronic or acute/chronic overlap) were landmarked at 60 and 180 days, respectively, and both exposures were treated as time-dependent covariates. Cause-specific multivariable Cox proportional hazards regression models adjusted for baseline covariates were fitted to assess associations of outcomes with the time-dependent exposures. Prespecified subgroup analyses were performed for the ultra-high-risk group, defined as complex karyotype and/or ≥2 TP53/17p alterations. Among 158 patients (median age 65 years, IQR: 57- 70), acute myeloid leukemia (54%) and myelodysplastic syndromes (40%) were the most common myeloid malignancies. Complex karyotypes were present in 68%, and ultra-high-risk features were present in 73%. Reduced-intensity conditioning was used in 59%. Approximately 49% of patients received post-HCT interventions; 68% of these were administered before relapse (preemptively or as prophylaxis/maintenance). In a landmark analysis at day 60 post-HCT (N = 145), prerelapse HMA, targeted therapies, and/or DLI was not associated with improved overall survival (OS) (HR: .95; 95% CI: .56, 1.62; P = .80), progression free survival (PFS) (HR: .95; 95% CI: .49, 1.30; P = .40), or cumulative incidence of relapse (CIR) (HR: 1.05; 95% CI: .60, 1.85; P = .90) after adjusting for key baseline characteristics. Similarly, in a landmark analysis at day 180 post-HCT (N = 100), the occurrence of chronic GVHD was not associated with OS (HR: .78; 95% CI: .24, 2.61; P = .70), PFS (HR: .67; 95% CI: .20, 2.23; P = .50), or CIR (HR: .34; 95% CI: .05, 2.54; P = .30). Findings were similar in the ultra-high-risk subgroup (N = 115) where post-HCT interventions showed no association with OS (HR: .81; 95% CI: .45, 1.45; P = .50), PFS (HR: .72; 95% CI: .42, 1.24; P = .20), or CIR (HR: .87; 95% CI: .46, 1.62; P = .70). In this single center study, preemptive or prophylactic post-HCT interventions did not significantly improve survival or reduce relapse risk in patients with TP53-altered myeloid malignancies, including those with ultra-high-risk features. While the study was limited by its small sample size and heterogeneous interventions, these findings highlight the urgent need to develop novel therapeutic strategies for this high-risk population.