Multi-hit TP53 mutation is an independent adverse prognostic factor in allogeneic hematopoietic stem cell transplantation for acute leukemia and myelodysplastic syndromes

Abstract Introduction TP53-mutated hematologic malignancies carry a notoriously poor prognosis, particularly in cases with multi-hit TP53 alterations. Recent WHO (2022) and ICC classifications define TP53-mutated myeloid neoplasms as a distinct entity. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative option for these patients. This study retrospectively assessed the outcomes of patients with TP53-mutated acute leukemia or myelodysplastic syndromes (MDS), focusing on the impact of mutation burden. Methods We retrospectively analyzed 272 patients with TP53-mutated hematologic malignancies who underwent allo-HSCT between January 2019 and December 2023 at Beijing and Hebei Yanda Lu Daopei Hospitals. TP53 status was classified per the 2022 ICC. Patients were grouped accordingly, and clinical and molecular features were compared. Results A total of 272 patients were included, comprising 124 (45.6%) in the single-TP53mut group and 148 (54.4%) in the multi-TP53mut group. The proportion of multi-TP53mut cases was similar across AML/MDS (53%, 55/104), ALL (54%, 88/162), and MPAL (83%, 5/6). First transplants accounted for 233 cases, and 39 patients received a second HSCT. Haploidentical donors (HID) were the most common, representing 77.6% (211/272), while matched unrelated or sibling donors (MUD/MSD) accounted for 22.4% (61/272). Baseline characteristics, including age, sex, conditioning regimens, donor type, and infused cell doses, were well balanced between groups (all P 0.05). Complex karyotypes were observed in 59% of all cases and were significantly more frequent in AML/MDS than in ALL (74% vs. 49%, P 0.05). Co-mutations were detected in 199 of 272 patients (73.2%), with the most commonly affected genes being EZH2 (8.1%), KMT2D (8.1%), PHF6 (8.1%), NRAS (8.1%), and NOTCH1 (7.4%). The prevalence of co-mutations was comparable between the single-TP53mut and multi-TP53mut groups (75.8% vs. 70.9%, P 0.05). As of January 2025, with a median follow-up of 13.8 months (range, 0.1–144.2), outcomes differed significantly by TP53 mutation burden in CR patients (n = 208). The single-TP53mut group (n = 100) had superior 2-year OS (62.8%, 95% CI: 53.1–72.5) and LFS (58.9%, 95% CI: 49.0–68.7) compared to the multi-TP53mut group (n = 108; OS: 45.5%, 95% CI: 35.9–55.0; LFS: 39.4%, 95% CI: 30.1–48.7), with P = 0.009 and P = 0.003, respectively. The 2-year cumulative incidence of relapse (CIR) was significantly lower in the single-TP53mut group (15.6%, 95% CI: 9.8–24.8) than in the multi-TP53mut group (35.5%, 95% CI: 27.5–45.8), P 0.001. However, non-relapse mortality (NRM) was comparable (26.7%, 95% CI: 19.2–37.2 vs. 31.9%, 95% CI: 24.2–42.1; P = 0.46). Among patients in NR/PR at transplant (n = 64), prognosis remained poor regardless of mutation burden. No significant differences were observed between single-TP53mut (n = 24) and multi-TP53mut (n = 40) groups in 2-year OS (25.0%, 95% CI: 7.7–42.3 vs. 15.0%, 95% CI: 3.9–26.1; P = 0.09), LFS (14.5%, 95% CI: 0–30.6 vs. 10.0%, 95% CI: 0.7–19.3; P = 0.14), CIR (47.8%, 95% CI: 31.2–73.3 vs. 37.5%, 95% CI: 25.1–55.9; P = 0.26), or NRM (37.5%, 95% CI: 22.4–62.9 vs. 57.5%, 95% CI: 44.1–75.1; P = 0.11). Multivariate Cox regression and Fine–Gray competing risk models identified several independent prognostic factors. Single-TP53mut status was associated with improved OS (HR = 0.78, P = 0.01) and LFS (HR = 0.77, P 0.001). MRD positivity at second transplant predicted inferior OS (HR = 0.72, P = 0.01), LFS (HR = 0.65, P 0.001), and elevated relapse risk (HR = 2.90, P 0.001). Achieving CR prior to HSCT was independently associated with better OS (HR = 0.69, P 0.001), LFS (HR = 0.73, P 0.001), and reduced NRM (HR = 2.22, P = 0.02). Use of a haploidentical donor was linked to increased relapse (HR = 1.96, P = 0.02), while age 14 years showed a borderline association with higher NRM (HR = 1.60, P = 0.05). Donor age, conditioning regimen, GVHD prophylaxis, and infused MNC, CD34⁺, or CD3⁺ cell doses had no significant impact on outcomes. Conclusion Allo-HSCT provides clinical benefit in TP53-mutated patients, especially those with single-hit mutations and pre-transplant remission. Multi-hit TP53 mutations are associated with higher relapse risk. Achieving remission before transplant is critical.