Impact of TP53 Allelic State on Outcomes of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Neoplasm

Background : Tumor protein p53 ( TP53) mutations are associated with dismal outcomes in myelodysplastic neoplasms (MDS). However, the impact of TP53 allelic state in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for MDS has not been fully explored.

Method: We conducted a multi-center study in 347 MDS patients undergoing allo-HSCT between January 2017 and October 2022, with the median follow-up time among survivors of 28.6 (range, 4.7 - 76.6) months, and 45 had TP53 mutations among them.

Results: Twenty-one patients were detected with TP53 monoallelic mutations ( TP53^1mut), while 24 had multiple hits ( TP53^multi). Complex karyotype was more common in patients with mutated TP53 (52.4% of patients with TP53^1mutand 75.0% of patients with TP53^multi), whereas this proportion was only 10.6% in patients with wild-type TP53 ( TP53^wt). The prognosis varied according to different TP53 state, showing the 2-year overall survival (OS) rates of 51.4% (95% confidence interval [CI]: 33.7% - 78.6%) for TP53^1mut group versus 15.8% (95% CI: 3.3% - 76.4%) for TP53^multi group versus 73.5% (95% CI: 68.5% - 78.9%) for TP53^wt group ( P<0.001), and the 2-year cumulative incidence of relapse (CIR) rates of 28.6% (95% CI: 11.2% - 48.8%) for TP53^1mut group versus 47.3% (95% CI: 18.3% - 71.9%) for TP53^multi group versus 10.8% (95% CI: 7.5% - 14.9%) for TP53^wt group ( P<0.001). Similarly, the leukemia-free survival (LFS) and graft-versus-host disease-free/relapse-free survival (GRFS) of patients with TP53^1mut or TP53^multi were obviously lower than those with TP53^wt (both P<0.001). However, there was no significant difference on non-relapse mortality among these three groups ( P=0.424). The adverse effects of TP53 mutationson OS, LFS, GRFS and CIR were also found in patients undergoing haploidentical HSCT or those with molecular International Prognostic Scoring System high- and very high-risk categories (all P<0.05). In the subgroup with complex karyotype ( n = 32 with non-mutated TP53 and n = 29 with mutated TP53), significantly inferior OS, LFS and GFRS and higher CIR were observed in patients with mutated TP53 while in the subgroup without complex karyotype ( n = 270 with non-mutated TP53 and n = 16 with mutated TP53), there were no differences in these prognostic indicators (all P>0.05). Notably, among patients who received conventional conditioning regime without hypomethylating agents (HMA) ( n = 264 with non-mutated TP53 and n = 38 with mutated TP53), the inferior 2-year OS, LFS and GRFS rates, and the higher 2-year CIR rate of patients still presented in TP53 mutant patients(all P<0.05), but among those receiving conditioning regime containing HMA, similar outcomes were found between mutated ( n = 7) and non-mutated ( n = 38) TP53 groups (all P>0.05). Multivariable cox proportional hazards models demonstrated that monoallelic TP53 state was an independent risk factor for survival and relapse (HR _OS=2.859, 95% CI: 1.372 - 5.957, P=0.005; HR _LFS=2.566, 95% CI: 1.342 - 4.905, P=0.004; HR _GRFS=2.146, 95% CI: 1.106 - 4.163, P=0.024; HR _CIR=2.507, 95% CI: 1.033 - 6.086, P=0.042), and multi-hit TP53 state also predicted worse outcomes (HR _OS=3.038, 95% CI: 1.453 - 6.356, P=0.003; HR _LFS=2.716, 95% CI: 1.383 - 5.336, P=0.004; HR _GRFS=1.882, 95% CI: 1.002 - 3.535, P=0.049).

C onclusions: Monoallelic and multi-hit TP53 state identify a high-risk group for poor outcomes in MDS patients undergoing allo-HSCT, complex karyotype could amplify the adverse prognostic effect of TP53, and these patients might benefit from receiving conditioning regime containing HMA.