Impact of TP53 Mutation on Outcome after Allogeneic Stem Cell Transplantation for Patients with MDS/AML Not in Complete Remission

Introduction: The TP53-mutated MDS/AML patients have a dismal prognosis. Even after allo-SCT, the long-term survival remains low, which raises the question of whether these patients should be considered as potential candidates for this approach. Further, these patients represent a biologically and possibly clinically heterogeneous group that is not been extensively investigated in transplant settings. In this study, we analyzed post-transplant outcomes of these patients focusing on pre-transplant TP53 mutational status (multi-hit vs single-hit). Methods: Single-centre retrospective analysis of 81 adult MDS/AML patients with single-hit (n=30) or multi-hit TP53 mutation (n=51) receiving allogeneic SCT between 2014 and 2024 at the Department for Stem Cell Transplantation of University Medical Center Hamburg/Germany. Pre-transplant remission status was assessed using cytomorphologic, NGS and cytogenetic methods. Multi-hit patients included the presence of two or more distinct TP53 mutations, each with VAF ≥10%, or a single hit TP53 mutation with VAF ≥50%, or a single TP53 mutation with VAF ≥10% accompanied by a cytogenetically apparent del (17p13.1), copy neutral loss of heterozygosity (LOH) at the 17p TP53 locus, or in the absence of LOH information, complex karyotype. Single-hit patients included the presence of a single TP53 mutation with VAF ≤ 50%, absence of del (17p13.1), and absence of complex karyotype. Results: There were 42 males, and the median age of the included patients was 63 years (18-78). The majority of the patients were in non-CR (77%), received allografts from unrelated donors (75%) after RIC (62%). The 3-year overall survival (OS) and leukemia-free survival (LFS) were 25% and 23% in AML patients and 43% and 30% in MDS patients (p=0.20 and p=0.29, respectively). Patients in non-CR and in CR at allogeneic SCT had similar 3-year OS and LFS rate of 34% and 32% and 33% and 26% (p=0.77 and p= 0.51, respectively). Patients with single-hit TP53 mutation had a 3-year OS rate of 35% compared to patients with multi-hit of 27% (p=0.15). The 3-year LFS rate in the single-hit cohort was 26% compared to 18% in the multi-hit cohort (p=0.047). The cumulative relapse incidence (CRI) at 3 years was similar in both cohorts with 51% (p=0.37). The patients with multi-hit status developed relapses earlier (median: 80 days (8-1107) vs 128 days (78-794), p=0.037). The poor prognosis of early relapses may explain the significant difference in LFS. The cumulative incidence of non-relapse mortality at 3-years was 19% in the single-hit cohort and 29% in the multi-hit cohort (p=0.27). Conclusion: MDS/AML patients with multi-hit TP53 mutation had significantly lower LFS rate compared to patients with single-hit TP53 mutation. However, patients with single or multi-hit TP53 may achieve a long-term survival rate of around 30% and should be considered as transplant candidates, even if they are not in complete remission.