Genetic factors rather than blast reduction determine outcomes of allogeneic HCT in BCR-ABL–negative MPN in blast phase

Abstract

There is a limited understanding of the clinical and molecular factors associated with outcomes of hematopoietic cell transplantation (HCT) in patients with BCR-ABL–negative myeloproliferative neoplasms in blast phase (MPN-BP). Using the Center for International Blood and Marrow Transplant Research database, we evaluated HCT outcomes in 177 patients with MPN-BP. Ninety-five (54%) had sufficient DNA for targeted next-generation sequencing of 49 genes clinically relevant in hematologic malignancies. At 5 years, overall survival (OS), cumulative incidence of relapse, and nonrelapse mortality of the study cohort was 18%, 61%, and 25%, respectively. In a multivariable model, poor-risk cytogenetics was associated with inferior OS (hazard ratio [HR], 1.71; 95% CI, 1.21-2.41) due to increased relapse (HR, 1.93; 95% CI, 1.32-2.82). Transplants using mobilized peripheral blood (PB) were associated with better OS (HR, 0.60; 95% CI, 0.38-0.96). No difference in outcomes was observed in patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Among the 95 patients with molecular data, mutation of TP53, present in 23%, was the only genetic alteration associated with outcomes. In a multivariate model, TP53-mutant patients had inferior OS (HR, 1.99; 95% CI, 1.14-3.49) and increased incidence of relapse (HR, 2.59; 95% CI, 1.41-4.74). There were no differences in the spectrum of gene mutations, number of mutations, or variant allele frequency between patients undergoing HCT with PB/BM blasts <5% vs those with active leukemia. Genetic factors, namely cytogenetic alterations and TP53 mutation status, rather than degree of cytoreduction predict outcomes of HCT in MPN-BP. No meaningful benefit of conventional HCT was observed in patients with MPN-BP and mutated TP53.

Impact of molecular profiling on the management of patients with myelofibrosis

“…Conflicting results have been published regarding the impact of molecular abnormalities on transplantation outcomes (Table 3). In some European series, CALR-mutated patients had better survival than those with other genotypes [13,64,89], and ASXL1-mutated patients had higher relapse incidence [64,89], but these findings have not been confirmed in other studies [90][91][92] In a series of 95 patients with post-MPN AML, detection of TP53 gene mutations by NGS at the time of allo-HCT was associated with a higher risk of relapse and worse survival, suggesting that the adverse impact of these mutations could not be overcome by transplantation [93].…”

Acute Myeloid Leukemia Evolving from Myeloproliferative Neoplasms: Many Sides of a Challenging Disease

“…That prompts one to rethink the timing of HSCT in this clinical context. A recent report by CIBMTR highlighted how the disease genotype can overcome the prognostic impact of disease status at transplant, in particular, a TP53 -mutated status was correlated with dismal outcome regardless of the achievement of a response before HSCT [ 36 ]. Indeed, the immunologic effect by HSCT appears to be largely ineffective in this subgroup, possibly, also due to an immunosuppressive phenotype conferred by the TP53 mutant [ 37 ].…”

Novel therapies vs hematopoietic cell transplantation in myelofibrosis: who, when, how?

“…There is no one-size-fits-all approach in patients with MF; how ever, we strongly rec om mend against waiting for dis ease to prog ress to AP/BP as out comes after the HCT are poor and many patients never make it to the trans plant stage. [11][12][13] Our goal in the begin ning is to under stand the nat u ral history of the dis ease based on best avail able infor ma tion on clin i cal and genetic risk fac tors. This infor ma tion helps in understand ing the expected sur vival and the like li hood of response and the dura bil ity of nontransplant ther apy.…”