Clinicopathologic Characteristics of Somatic TP53 Mutations in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Systematic Review.
TP53 mutations (TP53m) 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.
A PRISMA-guided systematic review of EMBASE and PubMed identified cohort studies of adult Ph-negative MPN with molecularly confirmed TP53m. Pooled proportions with 95% CI were generated using random-effects models; survival outcomes were summarized descriptively.
Eleven retrospective cohort studies (N = 603) met inclusion criteria. TP53m were uncommon overall (3%, 95% CI: 1-13; I 2 = 97%) but substantially enriched in MF or AP/BP-MPN cohorts (10%, 95% CI: 4-24; I 2 = 89%). Among TP53m 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-hit TP53 were present in comparable proportions (52% vs. 48%), with a pooled mean VAF of 37.48% (95% CI: 30.73-44.24; I 2 = 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-hit TP53 conferred 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; I 2 = 93%) across two reporting cohorts, and allo-HCT was utilized in only 16% (95% CI: 13-19; I 2 = 12%).
TP53m 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.
The authors have confirmed clinical trial registration is not needed for this submission.
A PRISMA-guided systematic review of EMBASE and PubMed identified cohort studies of adult Ph-negative MPN with molecularly confirmed TP53m. Pooled proportions with 95% CI were generated using random-effects models; survival outcomes were summarized descriptively.
Eleven retrospective cohort studies (N = 603) met inclusion criteria. TP53m were uncommon overall (3%, 95% CI: 1-13; I 2 = 97%) but substantially enriched in MF or AP/BP-MPN cohorts (10%, 95% CI: 4-24; I 2 = 89%). Among TP53m 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-hit TP53 were present in comparable proportions (52% vs. 48%), with a pooled mean VAF of 37.48% (95% CI: 30.73-44.24; I 2 = 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-hit TP53 conferred 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; I 2 = 93%) across two reporting cohorts, and allo-HCT was utilized in only 16% (95% CI: 13-19; I 2 = 12%).
TP53m 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.
The authors have confirmed clinical trial registration is not needed for this submission.
Authors
Aldapt Aldapt, Kaddoura Kaddoura, Saleh Saleh, Najim Najim, Salem Salem, Al-Mashdali Al-Mashdali, Muthanna Muthanna, Aweer Aweer, Rabadi Rabadi, Mohamed Mohamed
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