Background:TP53 encodes a tumor suppressor protein that plays a critical role in regulating cell division and apoptosis. While mutations in TP53 are established negative prognostic markers in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the clinical outcomes associated with acquisition of a TP53 mutation after initial diagnosis and treatment are less well understood. Thus, we sought to evaluate the characteristics and outcomes of patients who acquire TP53 mutations during their therapy as opposed to patients with a TP53 mutation at onset of disease.

Methods: We retrospectively reviewed and analyzed 23 patients with AML (n = 20) or high-grade MDS (n = 3) who lacked a TP53 mutation at initial diagnosis despite adequate genetic testing but subsequently were found to have a TP53 mutation at relapse (“acquired TP53” group) at Fred Hutchinson Cancer Center between April 2018 and April 2025. These patients were compared to 202 patients with AML who had a TP53 mutation at diagnosis (“baseline TP53” group). Patients were identified using our IRB-approved institutional database with direct review of electronic medical records. Statistical analysis included descriptive analysis, Kaplan-Meier modeling, and univariate analyses for overall survival based on age, sex, performance status, type of AML, white blood cell (WBC) count, platelet count, treatment-related mortality (TRM) score, European Leukemia Network (ELN) stratification, stage of treatment that patient acquired TP53, and TP53 variant allele frequency (VAF).

Results: Among patients with acquired TP53 mutations, n = 14 (61%) had ELN2022 adverse risk disease at baseline. Compared to patients in the baseline TP53 group, there were no differences in age [65 years (range 30-82) vs 66 years (21-100)], sex [n = 10 (43%) vs n = 84 (43%) for female gender], performance status [n = 17 (74%) vs n = 113 (56%) for ECOG 0-1], diagnosis [n = 20 (87%) vs n = 144 (71%) for AML], or disease-type [n = 9 (39%) vs n = 109 (54%) for de novo disease]. At baseline, patients in the acquired TP53 group had significantly higher WBC counts [8.25k/µL (range 1.38-500) vs 2.97k/µL (0.36-223.57), p = 0.035], higher platelet counts [78k/µL (12-907) vs 38.5k/µL (1-505), p = 0.0028], and lower TRM scores [2.865 (0.002-90.731) vs 7.821 (0.195-100), p = 0.0046]. In addition, concurrent chromosome 17 abnormalities were more frequent among the baseline TP53 group (n = 79/202, 39% vs 2/23 = 9%, p = 0.0028). Following induction chemotherapy, a greater proportion of acquired TP53 patients achieved a complete remission [61% (n = 14) vs 27% (n = 55), p = 0.0017]. There was no difference in the proportion of those with an early death [n =3 (14%) vs n = 53 (26%) for those who died on or before day 60].

With limited precision due to sample size, there was some evidence that patient with acquired TP53 had longer OS from time of TP53 mutation identification compared to patients with baseline TP53 (HR 0.61, 95% CI 0.36-1.03, p = 0.06). Within the acquired TP53 group, a univariate Cox regression model demonstrated that male gender (HR 3.19, 95% CI 1.63-34.25, p = 0.0097) and TP53 VAF (HR 1.04, 95% CI 1.01-1.07, p = 0.0067) were significantly associated with worse overall survival, though both had modest predictive abilities (C-statistics 0.7 and 0.66 respectively). Performance status of ECOG 2-4 (HR 3.19, 95% CI 0.99-10.3, p = 0.053) and TRM score (HR 1.02, 95% CI 1-10.5, p = 0.062) also trended towards having a significant association with worse overall survival.

Conclusions: While most patients who acquire a TP53 mutation during therapy have adverse risk disease at baseline, outcomes remain poor and long-term survival is rare. We found that acquired TP53 mutations are rarely ‘biallelic’. Initial remission rates are higher and there is a trend towards improved survival from the time of TP53 mutation identification compared to patients with baseline TP53 mutation, with the caveat that patients in the acquired TP53 group needed to survive long enough to acquire the mutation. Within the acquired TP53 group, higher TP53 VAF was significantly associated with worse survival though the effect size is modest. These findings clarify the clinical characteristics and outcomes of patients with acquired TP53 mutations and may inform future prognostic models and treatment decisions. Next steps include validation in larger cohorts to further explore the implications of acquiring a TP53 mutation during treatment.

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2025
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