Introduction: Mutations in TP53 are recurrent in myeloid neoplasms and are often associated with complex cytogenetics, therapy-related disease, chemotherapy resistance, and poor outcomes. “Double-hit” TP53 status (i.e., multiple mutations or a mutation plus a chromosome 17 aberration), high variant allele frequency (VAF), and concurrent complex cytogenetics are independently associated with treatment resistance and worse survival. In this study, we sought to examine outcomes of a cohort of patients with confirmed TP53-mutated acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at the University of Washington / Fred Hutchinson Cancer Center.

Methods: We performed a retrospective cohort analysis of 197 adults diagnosed with TP53-mutated myeloid neoplasms from 2015 onward, coinciding with the initiation of next-generation sequencing (NGS)-based clinical testing. Data collected included demographics; TP53 mutation features, co-mutational profiles; karyotype (complex/monosomal); treatment intensity (induction vs hypomethylating agent-based vs supportive care alone); response rates, i.e. complete remission (CR) or CR without full count recovery (CRi, CRh, CRp); receipt of allogeneic hematopoietic cell transplant (HCT); overall survival (OS), and progression-free survival (PFS). Measurable residual disease (MRD) was assessed from bone marrow aspirate by multiparameter flow cytometry. Multivariable regression was used to assess the prognostic value of VAF thresholds, allelic status, karyotype complexity, and mutation subtype. Cox regression was used to evaluate OS, logistic regression to evaluate response, and cause-specific models were used for time to transplant (death prior to transplant analyzed as a competing event).

Results: The study included 197 patients with a median age of 66 years (range 21–100); 43% female and 57% male. Performance status (PS) was 0–1 in 56% and 2–4 in 44%. Most patients had AML (71%), followed by MDS (28%) and other (1%).​ About half (53%) had de novo disease, while 47% had secondary or treatment-related disease. Complex karyotype was present in 87% of patients, and 39% had chromosome 17 abnormalities. Two TP53 mutations was observed in 20%, and 21% had additional MDS-associated mutations. Of the 197 adults, 83 (42%) achieved a treatment response, defined as CR, CRi, CRh, or CRp, together composite CR (CRc). Among responders, 35 were MRD-negative and 48 were MRD-positive. The remaining 114 patients (58%) did not achieve a remission. Additionally, 127 (64%) received high-intensity treatment, 44 (22%) received low-intensity treatment, and 26 (13%) received supportive care. Median TP53 VAF was higher in patients who did not achieve response (CRc) compared to responders: 48.0% (non-responders) vs. 28.8% (MRD-negative) and 36.5% (MRD-positive) (p=0.0044). TP53 VAF was the only factor significantly associated with response in multivariable analysis (MVA). TP53 VAF was associated with worse OS when modeled as a continuous variable (HR=1.01 for a 1% increase in VAF, 95% CI: 1.00–1.01). Additionally, lower TRM score (HR = 1.01 per 1 unit increase; 95% CI: 1.00–1.03), receipt of low-intensity treatment (HR = 0.54; 95% CI: 0.36–0.82), and alloHCT (time-dependent HR = 0.30; 95% CI: 0.17–0.51) were associated with improved OS in MVA, while complex karyotype and double-hit TP53 status were independently associated with worse OS and time to transplant. VAF thresholds alone (i.e., ≥50% or <50%) were not significantly associated with survival once cytogenetics and allelic status were accounted for. Notably, patients with de novo disease and non-complex karyotypes had improved outcomes, regardless of VAF. We also examined the association between TP53 point mutations identified in our cohort with the prognostic scoring predicted by a CRISPR-associated mutation score (Funk et al. Nature Genetics, 2025) and found no correlation with outcomes.

Conclusions: In this cohort of TP53-mutated AML and MDS patients, clinical and genomic variables—including lower TRM score, treatment intensity, TP53 VAF, and chromosome 17 abnormalities—were associated with survival and time to transplant. Higher TP53 VAF was a significant predictor of worse response and survival. However, no single factor reliably predicted response, and existing risk models failed to stratify outcomes, highlighting the need for improved, personalized prognostic tools in this high-risk population.

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2025
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