Clinicopathologic Characteristics of SomaticMutations in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Systematic Review.
Key claim: TP53 mutations are uncommon in chronic-phase Ph-negative MPN but enriched in MF and AP/BP disease, carry high clonal burden with roughly equal single- and multi-hit configurations, and confer a steep survival gradient in which multi-hit status worsens OS only in chronic-phase disease.
Abstract
BACKGROUND: mutations (m) are uncommon in chronic-phase Ph-negative myeloproliferative neoplasms but become enriched in myelofibrosis (MF) and accelerated/blast phase myeloproliferative (AP/BP-MPN). Their prevalence, allelic distribution, and phase-stratified outcomes have not been systematically synthesized. METHODS: A PRISMA-guided systematic review of EMBASE and PubMed identified cohort studies of adult Ph-negative MPN with molecularly confirmedm. Pooled proportions with 95% CI were generated using random-effects models; survival outcomes were summarized descriptively. RESULTS: Eleven retrospective cohort studies (= 603) met inclusion criteria.m were uncommon overall (3%, 95% CI: 1-13;= 97%) but substantially enriched in MF or AP/BP-MPN cohorts (10%, 95% CI: 4-24;= 89%). Amongm patients, disease distribution included AP/BP-MPN (33%, 95% CI: 26-41), MF (31%, 95% CI: 15-54), ET (16%, 95% CI: 5-41), and PV (11%, 95% CI: 4-27). Single- and multi-hitwere present in comparable proportions (52% vs. 48%), with a pooled mean VAF of 37.48% (95% CI: 30.73-44.24;= 97%). Unfavorable karyotype was identified in 42%. Median OS was: 37.4-72 months in PV, 44.4-54.6 months in ET, 11.6-24.7 months in MF, and 4.5-6 months in AP/BP-MPN. In CP-MPN, multi-hitconferred worse OS (9.5-18.5 months) versus single-hit disease (38 months to not reached); this distinction was absent in AP/BP-MPN. Leukemic transformation occurred in 35% (95% CI: 16-60;= 93%) across two reporting cohorts, and allo-HCT was utilized in only 16% (95% CI: 13-19;= 12%). CONCLUSIONS: m Ph-negative MPN are enriched in advanced-phase disease, carry comparable proportions of single-hit and multi-hit allelic configurations with high clonal burden, and demonstrate a clinically important survival gradient. Allelic status is a key prognostic determinant in CP-MPN but loses significance in AP/BP-MPN where outcomes are uniformly dismal. Standardized molecular reporting and prospective clinical trials are needed. TRIAL REGISTRATION: The authors have confirmed clinical trial registration is not needed for this submission.
Why this matters
For the transplant-decision question, TP53 status behaves differently by disease phase: in chronic-phase MPN/MF, detecting a multi-hit TP53 configuration flags a substantially worse OS trajectory that current DIPSS/MIPSS70-based referral norms may miss, arguing for earlier transplant consideration. In AP/BP, TP53 is common but multi-hit status no longer discriminates outcome — so it should not gate or delay bridging decisions in that setting. The synthesis reframes TP53 from a uniformly bad marker to a phase-conditional referral modifier.