What question did this study set out to answer?

To determine the impact of TP53 mutations and prior cytotoxic exposure on survival in CCUS patients.

December 8, 2025Open Access

Reduced overall survival in TP53-mutated ccus is driven by prior cytotoxic exposure and cytopenia rather than leukemic progression

YJYazan Khair Eldien JabbanMayo Clinic WHWilliam J. HoganMayo Clinic in Arizona MPMrinal M. PatnaikMayo Clinic

Key Points

To determine the impact of TP53 mutations and prior cytotoxic exposure on survival in CCUS patients.
Evaluated adult patients with CCUS at Mayo Clinic and South Australian MDS Registry.
Defined CCUS and MDS based on WHO classification excluding MDS-defining cytogenetics.
Conducted next-generation sequencing for mutations and assessed survival using Kaplan-Meier and Cox regression.
15.6% of CCUS cases harbored TP53 mutations, which are linked to poorer survival outcomes.
Prior cytotoxic exposure and cytopenia, particularly anemia, were significant factors impacting survival.
TP53 mutations did not independently predict inferior survival outcomes or leukemia transformation in CCUS.

Abstract

Abstract Background: TP53-mutated (TP53mut) myeloid neoplasms (MN) are a biologically and clinically distinct subgroup of blood cancers associated with extremely poor outcomes and limited response to conventional therapies. In some patients, MN are preceded by clonal cytopenia of undetermined significance (CCUS). Prior cytotoxic exposure (treatment related, TR) is an independent predictor for survival in CCUS (Li et al, Blood Adv. 2024). As TP53mut CCUS and MN are enriched in TR cases, the interaction between cytotoxic exposure and TP53mut status on the risk of progression and survival remains unclear. Methods: Adult patients with CCUS who were evaluated at the Mayo Clinic or South Australian myelodysplastic syndrome (MDS) Registry (Adelaide, Australia) were included. CCUS and MDS were defined according to the 5th edition of the WHO classification for MN (Khoury et al, 2022), except for the exclusion of cases harboring MDS-defining cytogenetics. Next-generation sequencing was performed using a targeted panel covering genes commonly mutated in MN. In cases with 1 TP53mut, VAFs were summed. Survival outcomes were assessed by Kaplan-Meier with log-rank testing. Univariate and multivariate analyses were estimated using Cox proportional hazards regression. Results: Of 320 CCUS cases, 50 (15.6%) harbored TP53mut (TP53mut CCUS), whereas 270 (84.4%) were wild-type (TP53wt CCUS). Median age at diagnosis was 71 years (range 16-99). TP53mut CCUS had a greater proportion of females (60% vs 33.7%, p0.001) and TR (66% vs 23%, p0.001) compared to TP53wt. Hematologic parameters including hemoglobin, red cell distribution width, mean corpuscular volume, white blood count, absolute neutrophil count, platelets, and bone marrow blasts were comparable between the two groups. Almost all TP53mut (n=48, 96%) were located in the DNA-binding domain and the median variant allele frequency (VAF) was 9% (range 2-46%). Five (10%) cases harbored 2 TP53mut. The distribution of TP53mut VAF among patients was as follows: ≤2.5% (n=2), 2.5-5% (n=10), 5-10% (n=19), 10-20% (n=11), and ≥20% (n=7). The proportion of cases with cytogenetic abnormalities was smaller in TP53mut compared to TP53wt CCUS(12% vs 25.9%, p=0.035). Both cohorts had a comparable median number of mutations: 2 (range 0-7) in TP53mut and 2 (range 0-5) in TP53wt. The most common co-mutations in TP53mut CCUS were TET2 (n=8, 17.8%), PPMD1 (n=7, 15.6%), DNMT3A (n=6, 13.3%), ASXL1 (n=6, 13.3%), and SRSF2 (n=4, 8.9%). At last follow up, the rate of progression was comparable between TP53mut and TP53wt CCUS (12% vs 22%, p=0.13). Median time to MN progression was not reached in TP53mut and 6.25 months in TP53wt CCUS (p=0.5197). A significantly higher proportion of TP53mut cases acquired complex cytogenetics compared to TP53wt cases (33% vs 2%, p=0.024) at MN progression. Of 20 deaths observed in the TP53mut cohort, non-myeloid hematologic malignancies (n=6, 30%), infections (n=5, 25%), and TP53mut MN (n=4, 20%) were the 3 most common causes. With a median follow-up of 4 years (IQR 1.2-4.8), median OS was longer in de novo (dn) cases (8.7 years for dn TP53wt; not reached for dn TP53mut) and shorter in TR cases (3.3 years for TR TP53wt; 4.8 years for TR TP53mut). Notably, TP53mut showed no independent prognostic impact in the entire cohort, or when stratified by TR vs dn CCUS. On multivariate analysis that included TP53mut status, factors independently associated with inferior OS included prior therapy (HR 2.21, 95% CI 1.41-3.45, p0.001), anemia (HR 4.1, 95% CI 1.88-8.99, p0.001), and thrombocytopenia (HR 2.38, 95% CI 1.43-3.95, p0.001). Similarly, TR CCUS (HR 1.6, 95% CI 1.06-2.4, p=0.03) and anemia (HR 2.15, 95% CI 1.25-3.7, p=0.006) were independently associated with inferior progression free survival. Conclusion: TP53 mut in CCUS did not independently predict inferior survival or increase leukemic transformation. While TP53mut CCUS were less likely to harbor cytogenetic abnormalities at diagnosis, significantly more cases harbored genomic instability at leukemic transformation. The poor outcomes attributed to TP53mut CCUS were driven by prior cytotoxic exposure, cytopenia – particularly anemia, and non-leukemic causes of death. These findings suggest risk stratification in CCUS should prioritize clinical context over TP53mut status alone.

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