Impact of High-Molecular-Risk Mutations on Transplantation Outcomes in Patients with Myelofibrosis

Abstract

Mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with myelofibrosis (MF). However, there is limited data regarding the prognostic utility of genetic profiling in MF patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We performed high-throughput sequencing of 585 genes on pre-transplant samples from 101 patients with MF who underwent allo-HCT and evaluated the association of mutations and clinical variables with transplantation outcomes. Overall survival (OS) at 5 years post-transplantation was 52%, and relapse-free survival (RFS) was 51.1 % for this cohort. Nonrelapse mortality (NRM) accounted for most deaths. Patient's age, donor's age, donor type, and Dynamic International Prognostic Scoring System score at diagnosis did not predict for outcomes. Mutations known to be associated with increased risk of disease progression, such as ASXL1, SRSF2, IDH1/2, EZH2, and TP53, did not impact OS or RFS. The presence of U2AF1 (P = .007) or DNMT3A (P = .034) mutations was associated with worse OS. A Mutation-Enhanced International Prognostic Scoring System 70 score was available for 80 patients (79%), and there were no differences in outcomes between patients with high risk scores and those with intermediate and low risk scores. Collectively, these data identify mutational predictors of outcome in MF patients undergoing allo-HCT. These genetic biomarkers in conjunction with clinical variables may have important utility in guiding transplantation decision making.

Keywords: Molecular mutations; Myelofibrosis; Stem cell transplantation.

Figure 1:. Summary of mutations and cytogenetic abnormalities detected in 101 patients with myelofibrosis.

Figure 1A: Spectrum and frequency of mutations. Mutations are grouped according to mechanism. Figure 1B: Number of mutations per sample Figure 1C: Summary of Cytogenetic data, which was available for 86 patients.

Figure 2:. Kaplan-Meier curves for the whole cohort.

(A) Overall survival, (B) Relapse-Free survival, (C) Non-relapse mortality and (D) Cumulative incidence of relapse

Figure 3:. Kaplan-Meier curves for overall survival (OS) by conditioning intensity, mutations and cytogenetic abnormalities.

OS (A) compared between myeloablative conditioning (MAC) and reduced intensity conditioning (RIC), (B) Presence or absence of high molecular risk (HMR) mutations (C) Presence or absence of U2AF1 mutations (D) Presence or absence of DNMT3A mutations (E) Favorable and unfavorable cytogenetic abnormalities and (F) The combined effect of conditioning intensity and presence or absence of U2AF1 and DNMT3A mutations.

Figure 4:. Multivariate analysis for overall survival shown by forest plot.

Figure 5:. Mutations analysis of cases of disease relapse post-transplant.

(A) Sequencing analysis of 6 paired pre-transplant and post-transplant relapse cases. (B) Trend over time of chimerism and recurrence of JAK2V617F mutation post-transplant.