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.

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2025
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