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

Background:TP53-mutated (TP53^mut) 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 TP53^mut CCUS and MN are enriched in TR cases, the interaction between cytotoxic exposure and TP53^mut 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 5^th 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 TP53^mut, 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 TP53^mut (TP53^mut CCUS), whereas 270 (84.4%) were wild-type (TP53^wt CCUS). Median age at diagnosis was 71 years (range 16-99). TP53^mut CCUS had a greater proportion of females (60% vs 33.7%, p<0.001) and TR (66% vs 23%, p<0.001) compared to TP53^wt. 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 TP53^mut (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 TP53^mut. The distribution of TP53^mut 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 TP53^mut compared to TP53^wt CCUS(12% vs 25.9%, p=0.035). Both cohorts had a comparable median number of mutations: 2 (range 0-7) in TP53^mut and 2 (range 0-5) in TP53^wt. The most common co-mutations in TP53^mut 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 TP53^mut and TP53^wt CCUS (12% vs 22%, p=0.13). Median time to MN progression was not reached in TP53^mut and 6.25 months in TP53^wt CCUS (p=0.5197). A significantly higher proportion of TP53^mut cases acquired complex cytogenetics compared to TP53^wt cases (33% vs 2%, p=0.024) at MN progression. Of 20 deaths observed in the TP53^mut cohort, non-myeloid hematologic malignancies (n=6, 30%), infections (n=5, 25%), and TP53^mut 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 TP53^wt; not reached for dn TP53^mut) and shorter in TR cases (3.3 years for TR TP53^wt; 4.8 years for TR TP53^mut). Notably, TP53^mut showed no independent prognostic impact in the entire cohort, or when stratified by TR vs dn CCUS. On multivariate analysis that included TP53^mut status, factors independently associated with inferior OS included prior therapy (HR 2.21, 95% CI 1.41-3.45, p<0.001), anemia (HR 4.1, 95% CI 1.88-8.99, p<0.001), and thrombocytopenia (HR 2.38, 95% CI 1.43-3.95, p<0.001). 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 TP53^mut CCUS were less likely to harbor cytogenetic abnormalities at diagnosis, significantly more cases harbored genomic instability at leukemic transformation. The poor outcomes attributed to TP53^mut 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 TP53^mut status alone.