High Molecular and Cytogenetic Risk in Myelofibrosis Does Not Benefit From Higher Intensity Conditioning Before Hematopoietic Cell Transplantation: An International Collaborative Analysis

Abstract

There is no direct evidence to recommend specific conditioning intensities in myelofibrosis undergoing allogeneic hematopoietic cell transplantation, especially in the molecular era. We aimed to compare outcomes of reduced intensity (RIC) or myeloablative conditioning (MAC) transplantation in myelofibrosis with molecular information. The study included 645 genetically annotated patients (with at least driver mutation status available), of whom 414 received RIC and 231 patients received MAC. The median follow-up time from transplantation was 6.0 years for RIC and 9.4 years for MAC. The 6-year overall survival rates for RIC and MAC were 63% (95% confidence interval [CI], 58%-68%) and 59% (95% CI, 52%-66%; P = 0.34) and progression-free survival was 52% (95% CI, 47%-57%) and 52% (95% CI, 45%-59%; P = 0.64). The 2-year cumulative incidence of nonrelapse mortality was 26% (95% CI, 21%-31%) for RIC and 29% (95% CI, 23%-34%) for MAC (P = 0.51). In terms of progression/relapse, the 2-year cumulative incidence was 10% (95% CI, 5%-19%) for RIC and 9% (95% CI, 4%-14%) for MAC (P = 0.46). Higher intensity conditioning did not seem to improve outcomes for higher-risk disease, according to mutational, cytogenetic, and clinical profile. In contrast, patients with reduced performance status, matched unrelated donors, and ASXL1 mutations appeared to benefit from RIC in terms of overall survival.

Figure 1.

Overall survival according to driver mutation status and high molecular risk status within both conditioning intensity groups. In the RIC group: 6-year overall survival (A) was 81% for CALR, 58% for JAK2, 83% for MPL, and 55% for triple negative patients. No significant difference in outcome was observed for CALR-type 1 versus CALR-type 2 mutations (P = 0.59) nor for presence of HMR versus absence of HMR (B). In the MAC group: 6-year overall survival (C) was 72% for CALR, 55% for JAK2, 100% for MPL, and 55% for triple negative patients. No significant difference in outcome was observed for presence of HMR versus absence of HMR (D). HMR = high molecular risk (as defined by Vannucchi et al includes ASXL1, SRSF2, IDH1/2, EZH2); MAC = myeloablative conditioning; RIC = reduced intensity conditioning.

Figure 2.

Posttransplant outcomes according to conditioning intensity. The 6-year overall survival (A) rates for RIC and MAC were 63% and 59% (P = 0.34). In terms of progression-free survival (B), 6-year rates were 52% for RIC and 52% for MAC (P = 0.64). The 2-year cumulative incidence of nonrelapse mortality (C) was 26% for RIC and 29% for MAC (P = 0.51). In terms of progression/relapse (D), the 2-year cumulative incidence was 10% for RIC and 9% for MAC (P = 0.46). MAC = myeloablative conditioning; RIC = reduced intensity conditioning.

Figure 3.

Forest plot and corresponding risk ratios of overall survival (A) and progression-free survival (B) in clinical and molecular subgroups. Risk ratio below 1.0 favors RIC and risk ratio above 1.0 favors MAC. DIPSS = Dynamic International Prognostic Scoring System; HMR = high molecular risk (as defined by Vannucchi et al includes ASXL1, SRSF2, IDH1/2, EZH2); KPS = Karnofsky performance status; MAC = myeloablative conditioning; MMRD = mismatched related donor; MMUD = mismatched unrelated donor; MRD = matched related donor; MUD = matched unrelated donor; PMF = primary myelofibrosis; RIC = reduced intensity conditioning; SMF = secondary myelofibrosis; VHR = very high risk according to cytogenetics (Tefferi et al).