Impact of germline and somatic TP53 mutations on allogeneic HSCT outcomes in hematologic malignancies

Abstract Introduction TP53 mutations (TP53mut) are strongly associated with chemoresistance, early relapse, and inferior survival in hematologic malignancies such as AML, MDS, and ALL. However, the prognostic impact of TP53 mutations-particularly germline variants-on outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear and controversial. Methods Among 5,829 hematologic malignancy patients (pts) who underwent allo-HSCT between December 2016 and May 2024 at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital, 233 (4%) harbored TP53mut. Somatic or germline origin was determined via bone marrow and paired non-hematopoietic samples (buccal swabs, fingernails, remission marrow/PB, or saliva). After excluding 59 cases with indeterminate germline status, 174 pts were classified into three groups: somatic TP53mut (TP53sm), pathogenic/likely pathogenic germline (P/LP TP53gm), and non-pathogenic/likely benign germline (non-P/LP TP53gm). All pts were followed through January 1, 2025. Results Among 174 pts (107 males, 67 females; median age, 17 years [range, 2–69]), the majority received grafts from haploidentical donors (HID, 74.1%), followed by matched unrelated donors (MUD, 16.1%) and matched sibling donors (MSD, 9.8%). Diagnoses included ALL (n=99), AML/MDS (n=72), and MPAL (n=3). TP53sm accounted for 79.9% (139/174), non-P/LP TP53gm for 14.4% (25/174), and P/LP TP53gm for 5.7% (10/174). Among TP53sm pts, ALL predominated (57.6%), while AML/MDS was more frequent in non-P/LP TP53gm pts (60%). Notably, P/LP TP53gm was exclusively observed in B-ALL (p=0.02). Baseline characteristics including gender, age, conditioning regimen, cell doses, GVHD prophylaxis, and donor type were comparable across groups. Neutrophil engraftment was achieved in 98.9% (n=172) at a median of 15 days (range, 8–30), and platelet engraftment in 90.2% (n=157) at a median of 13 days (range, 5–46). At a median follow-up of 13.9 months (range, 0.5–144.2) by January 2025, 90 pts had died, with 83.3% (75/90) within the first year. Median OS was 20.4 months. Estimated 2-year OS and LFS for the entire cohort were 48.2% (95% CI, 40.6–55.8) and 44.8% (95% CI, 37.2–52.3), respectively. The 2-year CIR and NRM were 29.5% (95% CI, 23.3–37.2) and 31.1% (95% CI, 24.8–38.9). Pts in complete remission (CR) prior to transplant (n=134) had significantly superior outcomes compared to those with non-remission/partial remission (NR/PR, n=40), with 2-year OS of 55.3% (95% CI, 46.7–63.9) vs. 25.0% (95% CI, 11.6–38.4; P<0.001) and LFS of 52.0% (95% CI, 43.4–60.6) vs. 20.5% (95% CI, 7.8–33.2; P<0.001).CR status also correlated with significantly lower 2-year CIR (26.7%, 95% CI: 18.3–38.5% vs. 42.6%, 95% CI: 29.1–59.6%; P=0.03) and NRM (26.9%, 95% CI: 18.1–39.0% vs. 45.0%, 95% CI: 30.6–62.6%; P=0.01). Among CR pts, the non-P/LP TP53gm group (n=20) had the most favorable prognosis, followed by the TP53sm group (n=104), while the P/LP TP53gm group (n=10) had the poorest. 2-year OS was 70.0% (95% CI: 49.9–90.1) vs. 54.0% (95% CI: 44.1–63.9) vs. 40.0% (95% CI: 9.6–70.4), P=0.36; and LFS was 70.0% (95% CI: 49.9–90.1) vs. 49.4% (95% CI: 39.5–59.3) vs. 40.0% (95% CI: 9.6–70.4), P=0.27. Similarly, 2-year CIR was lowest in the non-P/LP TP53gm group at 5.0% (95% CI: 0.7–33.8), compared to 29.8% (95% CI: 22.0–40.3) and 40.0% (95% CI: 18.7–85.5), P=0.049. NRM was 30.0% (95% CI: 15.4–58.6) vs. 23.8% (95% CI: 16.8–33.8) vs. 50.0% (95% CI: 26.9–92.9), P=0.25, though not statistically significant, possibly due to limited sample size. The 100-day cumulative incidence of grade II–IV aGVHD was 16.0% (95% CI, 6.5–39.3) in the non-P/LP TP53gm group, 30.9% (95% CI, 24.1–39.7) in the TP53sm group, and 50.0% (95% CI, 26.9–92.9) in the P/LP TP53gm group (p = 0.23). For grade III–IV aGVHD, incidences were 8.0% (95% CI, 2.1–30.2), 20.1% (95% CI, 14.5–28.1), and 20.0% (95% CI, 5.8–69.1), respectively (p = 0.53). Although not statistically significant, a clear trend toward increased aGVHD was observed in patients with P/LP TP53gm. Conclusion Allo-HSCT is effective for TP53-mutated hematologic malignancies. Non-P/LP TP53 germline mutations are associated with better outcomes, while TP53 somatic mutations and P/LP TP53 germline mutations confer poorer prognosis due to higher relapse and transplant-related mortality.