Background: TP53 mutations are among the most clinically significant genetic alterations in myelodysplastic syndromes (MDS), frequently associated with complex karyotypes, therapy-related MDS, and adverse outcomes. Recent studies suggest that TP53 allelic status (mono- vs. multi-hit) and variant allele frequency (VAF) influence prognosis. VAF serves as a marker of clonal dominance and may help define disease risk. Although allogeneic stem cell transplantation (HSCT) is the only curative option for MDS, outcomes remain poor for TP53-mutated patients. We conducted a meta-analysis to evaluate the prognostic implications of TP53 allelic status and VAF in MDS, including outcomes after HSCT.

Methods: A comprehensive meta-analysis was conducted to investigate the prognostic impact of TP53 mutation status and variant allele frequency (VAF) in patients with myelodysplastic syndromes (MDS), including post–stem cell transplant outcomes. Eligible studies were identified through a systematic search and included those reporting hazard ratios (HRs) for overall survival (OS) stratified by TP53 status (wild-type, single-hit, multi-hit) and VAF thresholds (<30% vs. ≥30%). In total, data was extracted from 33 unique studies, comprising 2,526 participants in the exposure group and 8,428 in control group. HRs and corresponding 95% confidence intervals (CIs) were extracted from studies. A random-effects model using inverse-variance weighting was applied to calculate pooled HRs. Heterogeneity between studies was assessed using the I² statistic. Four primary analyses were performed: (1) OS comparison between TP53-mutated and wild-type patients. (2) OS analysis within TP53-mutated patients based on VAF (<30% vs. ≥30%). (3) Comparison of outcomes between wild-type and multi-hit TP53 subtypes. (4) Post-transplant OS stratified by TP53 mutation status immediately at time of transplant. Subgroup analyses further evaluated the interaction between TP53 allelic state, VAF, and transplant outcomes. All statistical analyses were performed using R (packages: meta, survival), with statistical significance defined as α = 0.05.

Results: Across included studies, patients with any TP53 mutation had significantly inferior overall survival (OS) compared to wild-type, with a pooled HR of 2.34 [95% CI: 1.92–2.86] (p<0.001). When stratifying by allelic complexity, patients with single-hit mutations exhibited a HR: 1.59 [1.08–2.33] (p=0.018). Multi-hit mutations exhibited aHR: 1.53 [1.15–2.05] (p=0.004).

Variant allele frequency (VAF) was also associated with differential outcomes: patients with high VAF (≥30%) showed significantly reduced OS (HR: 2.16 [1.79–2.61]) versus those with low VAF (<30%) (HR: 1.60 [1.29–1.97]), with statistically significant subgroup differences (p=0.035).

Among the transplant cohort, TP53-mutated patients undergoing allogeneic hematopoietic stem cell transplant (HSCT) had worse post-transplant survival compared to wild-type counterparts (HR: 1.99 [1.68–2.35], p<0.001). These findings highlight the independent prognostic significance of TP53 mutation status, allelic complexity, and VAF in both general and transplant-eligible MDS populations.

Conclusions: This meta-analysis confirms that both TP53 mutation status and VAF independently predict poorer outcomes in MDS, including among HSCT recipients. Elevated VAF reflects clonal dominance and is associated with more aggressive disease. VAF should be incorporated into MDS risk stratification models and may guide transplant decisions and future therapeutic strategies.

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2025
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