Multi-Hit TP53 Linked to Shorter Survival in Chronic-Phase MPN Cohorts

Somatic TP53 mutations are uncommon in Philadelphia chromosome–negative myeloproliferative neoplasms (MPN) overall but cluster in myelofibrosis (MF) and accelerated- or blast-phase MPN (AP/BP-MPN), according to a systematic review published in eJHaem.¹ Pooled data also showed that allogeneic hematopoietic cell transplantation (allo-HCT) was used in only 16% of patients with TP53-mutated MPN.

“This systematic review represents, to our knowledge, the first comprehensive synthesis of the clinicopathologic characteristics and outcomes of somatic TP53 mutations across the full spectrum of Ph-negative MPN, addresses 3 major points: to define the frequency of TP53 mutations across MPN subtypes and disease phases; to characterize their allelic status and VAF level; and to illustrate their associated clinical outcomes, including OS, leukemic transformation, and allo-HCT utilization,” the authors wrote.

Why TP53 Status Matters in Myeloproliferative Neoplasms

Polycythemia vera (PV), essential thrombocythemia (ET), and MF are clonal stem cell disorders whose course ranges from indolent disease to rapid progression. TP53 alterations have well-established links to treatment resistance and poor outcomes in myelodysplastic syndromes and acute myeloid leukemia, and current International Consensus Classification and World Health Organization criteria recognize TP53-mutated myeloid neoplasms as distinct entities, the study authors noted.

Earlier studies have suggested a context-dependent effect. In a multicenter study of 114 patients with TP53-mutated MPN, multi-hit TP53 in chronic-phase MF was associated with shorter median survival than non-multi-hit disease (10 vs 35 months; HR, 2.9; P < .01).² Among 349 patients with MF who underwent transplant, those with TP53 mutations had a median OS of 1.5 years, compared with 13.5 years for patients with wild-type TP53.³ However, the authors wrote that no prior work had quantitatively pooled TP53 prevalence and outcomes across MPN subtypes.¹

Following PRISMA 2020 guidelines, the investigators searched EMBASE and PubMed through March 1, 2026, for studies of adults with MPN and somatic TP53 mutations confirmed by next-generation sequencing that enrolled at least 6 patients. Of 102 records identified, 23 full-text articles were assessed and 11 met inclusion criteria.

Across the 11 retrospective cohort studies included, the pooled prevalence of TP53 mutations was 3% (95% CI, 1%-13%; I² = 97%) in all MPN, rising to 10% (95% CI, 4%-24%; I² = 89%) in cohorts restricted to MF or AP/BP-MPN. Single-hit and multi-hit configurations occurred in similar proportions, and multi-hit status was associated with shorter survival in chronic-phase disease but not after progression to the accelerated or blast phase.

Allelic Status and Survival in TP53-Mutated MPN

Among patients with TP53 mutations, AP/BP-MPN was the most common disease context at 33% (95% CI, 26%-41%), followed by MF at 31% (95% CI, 15%-54%), ET at 16% (95% CI, 5%-41%), and PV at 11% (95% CI, 4%-27%). Multi-hit TP53 accounted for 48% (95% CI, 35%-60%) of cases and single-hit for 52% (95% CI, 39%-65%). The pooled mean variant allele frequency (VAF) was 37.48% (95% CI, 30.73%-44.24%), and 42% of patients had an unfavorable karyotype (95% CI, 11%-82%).

Median OS ranged from 37.4 to 72 months in PV, 44.4 to 54.6 months in ET, 11.6 to 24.7 months in MF, and 4.5 to 6 months in AP/BP-MPN. In chronic-phase MPN, 3 studies reported a median OS of 9.5 to 18.5 months with multi-hit TP53 vs 38 months to not reached with single-hit disease. In AP/BP-MPN, that gap disappeared, with medians of 5.27 vs 5.6 months in one study and 6 vs 3.5 months in another for multi-hit and single-hit disease, respectively.

“We hypothesize that this finding reflects the emergence of additional high-risk molecular co-events that override the prognostic influence of TP53 allelic status once blast transformation has occurred,” the authors wrote. “In chronic-phase disease, where the genomic landscape is less complex, allelic state retains its value.”

In the 2 cohorts that reported it, the pooled leukemic transformation rate was 35% (95% CI, 16%-60%). Allo-HCT use was low and consistent across studies at 16% (95% CI, 13%-19%; I² = 12%), which the authors said likely reflects uncertainty about transplant benefit in this population. “The consistently low allo-HCT utilization rate despite aggressive disease biology highlights a critical unmet need,” they wrote.

Study Limitations and Implications for MPN Risk Stratification

The review was limited by the retrospective, observational nature of the included studies, which could bias results toward patients with advanced disease who were more likely to undergo comprehensive molecular profiling. Heterogeneity across the studies also produced high I² values that limited the precision of pooled estimates, and 9 of the 11 studies did not report transformation rates among patients with TP53 mutations. The authors also acknowledged that publication bias may have led to overestimation of mutation frequency and adverse outcome rates.

The authors noted that current prognostic systems, including the Dynamic International Prognostic Scoring System Plus and the Mutation-Enhanced International Prognostic Score System 70+ version 2.0, do not account for TP53 allelic status or VAF as independent variables. They called for prospective multicenter registries with standardized sequencing panels, uniform definitions of multi-hit TP53, serial VAF monitoring, and prespecified survival and transformation end points stratified by allelic status and disease phase.

“Integration of TP53 mutational status—particularly allelic configuration and VAF—into prospective MPN risk stratification models should be a priority for the field,” the authors concluded.

References

1. Aldapt M, Kaddoura R, Saleh AO, et al. Clinicopathologic characteristics of somatic TP53 mutations in Philadelphia chromosome–negative myeloproliferative neoplasms: a systematic review. EJHaem. 2026;7(5):e70385. doi:10.1002/jha2.70385

2. Tefferi A, Abdelmagid M, Loscocco GG, et al. TP53 mutations in myeloproliferative neoplasms: context-dependent evaluation of prognostic relevance. Am J Hematol. 2025;100(4):552-560. doi:10.1002/ajh.27609

3. Gagelmann N, Badbaran A, Salit RB, et al. Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation. Blood. 2023;141(23):2901-2911. doi:10.1182/blood.2023019630