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Published on: September 20, 2016
Clinicopathologic Characteristics of Somatic TP53 Mutations in Philadelphia Chromosome-Negative Myeloproliferative
Mahmood Aldapt1, Rasha Kaddoura2, Ahmed O Saleh3
1Division of Hematology and Medical Oncology Mayo Clinic Jacksonville Florida USA.
Background:
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.
Methods:
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.
Results:
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%).
Conclusions:
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.
Trial Registration:
The authors have confirmed clinical trial registration is not needed for this submission.
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