TP53 and Complex Karyotype Represent a Very High-Risk Group in Myelofibrosis Undergoing Hematopoietic Stem Cell Transplantation: An International Collaborative Analysis

BackgroundTP53 mutations (TP53^MT) have been associated with poor outcomes in various hematologic malignancies, but no data exist on its role in patients with myelofibrosis undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Although HSCT remains the only curative treatment for myelofibrosis and its numbers continue to increase worldwide, its inherent treatment-related morbidity and mortality make adequate patients counseling crucial. Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53^MT in this setting.

Patients and Methods Clinical data on myelofibrosis patients undergone first HSCT in 7 US and European centers, with detailed information on cytogenetics and NGS-based TP53^MT at the time of transplant were collected.

Results Among 349 included patients, 49 (13%) had detectable TP53^MT, of whom 16 showing a multi-hit configuration. Median variant allele frequency (VAF) was 20.3% (range, 2.9-97.6%). No difference in age at HSCT was noted in TP53^MT carriers as compared to wild type cases (median 56 vs 57 years, respectively). Cytogenetic risk (Tefferi et al. 2018) was favorable (n=248, 71%), unfavorable (n=79, 23%), and very high (n=22, 6%) with complex karyotype present in 36 patients (10%). Accordingly, when compared to wild type cases TP53^MT carriers were enriched in the unfavorable cytogenetic risk category (20% vs 39%, P=0.01) and, importantly, in patients with complex karyotype (7% vs 29%; P<0.001).

No significant difference was observed between both groups when accounting for ontogenesis of myelofibrosis (primary vs secondary), blood counts, constitutional symptoms, nontransplant (DIPSS) and transplant-specific risk stratification (MTSS), co-occurring mutations such as driver mutations (JAK2, CALR, MPL), high-risk mutations (ASXL1, SRSF2, IDH1/2, EZH2) and mutational burden.

With a median follow-up from HSCT of 5.8 years for the TP53^MT and 9.2 years for the non- TP53^MT group, the 6-year OS achieved 35% vs 64%, respectively (P<0.001). As a result, median OS was 1.5 years (95% confidence interval [CI], 0.3-2.8 years) for the TP53^MT vs 13.5 years (95% CI, 9.2-17.8) for the wild-type group. When stratified according to TP53 status and clonal burden (VAF), 6-year OS was 45% for monoallelic vs 24% for multi-hit TP53^MT carriers (P=0.25), and 46% vs 27% for VAF <20% and VAF >20%, respectively (P=0.21). Current cytogenetic risk stratification showed no discrete survival differences (P=0.59), whereas complex karyotype still impacted on post-HSCT outcomes, with a median OS of 1.9 years (95% CI, 0-4.2) in such setting vs 13.5 years in cases with other karyotypes (P<0.001). Of note, interaction test for TP53^MT and complex karyotype was not significant (P=0.25).

TP53^MTcarriers showed also significantly higher 6-year cumulative incidence of relapse (35% [95% CI, 21-49%] vs 17% [95% CI, 13-21%]; P=0.001) when compared to the non-TP53^MT group. A total of 19 TP53^MT patients (39%) experienced post-HSCT relapse with 10 (20%) presenting as leukemic transformation vs only 7 (2%) in the non-TP53 group. Importantly, nor the rate nor the time to leukemic transformation differed according to the TP53^MT type. Furthermore, nonrelapse mortality was not significantly different between the TP53^MTand wild-type group (P=0.22). In terms of cytogenetics, again the current risk stratification failed to separate patients with different relapse risks (P=0.73), whereas 6-year cumulative incidence of relapse achieved 31% in cases harboring complex karyotype as compared to 19% in patients with other cytogenetic configurations (P=0.03).

When adjusting in 2 models either for MTSS or DIPSS, TP53^MTand complex karyotype were independently associated with worse OS, showing HR of 1.76 (95% CI, 1.14-2.74) or 2.10 (95% CI, 1.34-3.31) and 1.64 (95% CI, 1.00-2.66) or 1.84 (95% CI, 1.10-3.08), respectively. While MTSS maintained its significant power (P<0.001), DIPSS was not significantly associated with OS (P=0.70). In terms of relapse, TP53^MT, complex karyotype, circulating blasts and increasing MTSS scores independently associated with post-HSCT outcomes.

ConclusionTP53 and complex karyotype represent a very high-risk group in myelofibrosis undergoing HSCT, informing prognostication for OS. Importantly, these features may also facilitate patient counseling regarding relapse after HSCT, together with current transplant-specific tools.

Salit:Incyte Corporation: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees. Heuser:PinotBio: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kura Oncology: Consultancy; Glycostem: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy; Agios: Consultancy, Research Funding; Takeda: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Eurocept: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Tolremo: Consultancy; Astellas: Research Funding; Bayer Pharma AG: Research Funding; BergenBio: Research Funding; Loxo Oncology: Research Funding. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion: Consultancy. Reinhardt:CDL Therapeutics GmbH: Other; Merck: Honoraria; Abbvie: Honoraria; Gilead: Research Funding. Scott:Alexion: Consultancy; Celgene: Consultancy, Honoraria, Other: Advisor Panel; Jazz Pharmaceuticals: Other: Advisory Panel; Novartis: Other: Advisory Panel, Research Funding; Nektar: Other: data and safety monitoring board; Incyte: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Other: Advisory Panel, Research Funding; Johnson and Johnson: Other: data and safety monitoring board.