Background:

Optimal management of TP53-mutated acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) remains an unmet need. These diseases predominantly affect older adults, who often present with high-risk cytogenetics and genomic instability. Many are ineligible for curative-intent therapies, and palliative care is often pursued. American Society of Hematology Clinical Practice Guidelines for older adults with AML provide limited consensus for management of TP53-mutated AML (Sekeres et al., Blood Adv 2020). The recent ENHANCE-2 trial of precision therapeutics failed to improve overall survival for TP53-mutated AML, leaving a large care gap (Zeidner et al., Blood 2025). It has been proposed that AML-directed therapy may not benefit these patients, who may also face high healthcare utilization (Badar et al., J Clin Oncol, 2025).

Methods:

We retrospectively analyzed patients ≥75 years with TP53-mutated AML and MDS at our institution from January 2014 to June 2025 using the UMass Leukemia Registry. Overall survival (OS) was measured as days from initial bone marrow biopsy to death and compared using Kaplan-Meier analyses and log-rank tests. Mean number of transfusions, inpatient days (excluding initial diagnosis admission), and hospice days were compared between treated and untreated patients for non-transplant candidates. Trends of first-line treatments were evaluated. Variant allele frequency (VAF) was defined as the combined variable allele frequency of all TP53-mutant alleles.

Results: Among 151 patients with TP53-mutated MDS or AML, 52 (34.4%) were ≥75 years at diagnosis; 22 had AML and 30 had MDS. One patient was excluded due to lack of survival data. Most patients (96.1%) were transplant-ineligible. For AML, median OS (mOS) was 2.7 months (95% CI: 1.4–5.4), and for MDS, mOS was 7.3 months (95% CI: 4.6–25.8). Treated MDS patients had longer mOS compared to untreated patients (9.1 months [95% CI: 7.2–25.9] vs. 0.7 months [95% CI: 0.5–N/A], p < 0.05). Treated AML patients had no significant survival benefit compared to untreated patients (mOS 2.9 months [95% CI: 1.5–N/A] vs. 1.0 months [95% CI: 0.3–N/A], p = 1.0) but had higher healthcare utilization, including more For those patients with TP53-mutated AML who achieved a complete remission on their second bone marrow biopsy, there was a trend towards longer mOS compared to all other patients with AML (8.1 months [95% CI: 3.1–N/A] vs. 1.8 months [95% CI: 1.1 months–N/A], p = 0.07). TP53 VAF < 50% correlated with longer mOS (9.2 months [95% CI: 2.7–N/A] vs. 4.6 months [95% CI: 1.5–7.2], p < 0.05).

All but two patients in the study were offered treatment, and three patients declined treatment in favor of best supportive care. Before 2018, 5 of 6 (83.3%) treated patients received induction chemotherapy. Since 2018, hypomethylating agent (HMA)-based therapies predominated (34 of 35 patients, 97.1%), with HMA/venetoclax combinations used in 5 of 10 (50%) patients treated in 2024–2025. For AML, mOS was 13.7 months (95% CI: 1.4–N/A) with induction, 1.3 months (95% CI: 0.5–N/A) with HMA alone, and 3.1 months (95% CI: 1.3–N/A) with HMA-combination therapy. Best supportive care had a mOS of 1.8 months (95% CI: 0.5–N/A). In MDS, mOS was 12.2 months (95% CI: 4.6–N/A) with HMA monotherapy; supportive care had a mOS of 1.8 months (95% CI: 0.1–N/A).

Conclusions:

In our study, AML-directed therapies did not prolong survival for older patients with TP53-mutated AML and were linked to increased healthcare burden. Supportive care may be appropriate for this population. Patients with treated TP53-mutated MDS showed survival benefits. Frailty assessments should inform treatment decisions. Study limitations include relatively small sample size and retrospective design. Further studies are needed to guide optimal management of older adults with TP53-mutated AML and MDS.

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2025
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