Non-myeloablative Allogeneic Haematopoietic Stem Cell Transplantation for Myelofibrosis. A Population-Based Study from Eastern Denmark.

Abstract

Background: Myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) regimens are both used before allogeneic haematopoietic stem cell transplantation (allo-HCT) for myelofibrosis (MF). The median age of patients with MF treated with allo-HCT is increasing and a high non-relapse mortality (NRM), especially to MAC, has increased utilisation of lesser intense non-myeloablative (NMA) regimens. NMA is used as the standard conditioning regimen before allo-HCT for MF at all transplantation centres in Denmark.

Objectives: To describe the outcomes of a highly homogenously treated, population derived cohort of MF-patients who received NMA conditioning prior to allo-HCT, and identify factors associated to transplantation outcomes.

Study design: The study is a retrospective cohort study of MF-patients treated with NMA prior to allo-HCT at Copenhagen University Hospital, Rigshospitalet from 2007 to 2023.

Results: Of 70 patients with MF who were treated with allo-HCT for MF from 2007 to 2023, 67 patients received NMA conditioning with fludarabine 90 mg/m² and total body irradiation of 2-4 Gray. These 67 patients had a median age of 61.1 years, 22 patients (33%) had a Karnofsky performance status below 90, and 28 patients (44%) had a haematopoietic-stem-cell-transplantation comorbidity index (HCT-CI) above 2. With a median follow-up time of 3.4 years (range 0.16-15.58 years), 39 patients (58%) were still alive. Eighteen patients (27%) relapsed and of the 28 patients (42%) that died during the study period, 12 (43%) died from relapse, and 16 (57%) from NRM. Median time to neutrophil engraftment, transfusion independency and platelet engraftment was 21 days (range 11 - 119 days), 69 days (range 0 - 470 days) and 17 days (range 0 - 308 days) respectively with primary graft failure identified in 13 patients (19.7%). Overall survival (OS) after 1, 3, and 5 years was 77%, 68%; 61% %, whereas the NRM was 15%, 15% and 21%. The cumulative incidence of relapse (CIR) was 24% after 1 year, 28 % after 3 years and 28% after 5 years. Multivariable analysis showed that male sex (HR= 5.43, p<0.001), graft from unrelated donor (HR= 3.58, p=0.018) and HCT-CI above 2 (HR= 2.5, p=0.025) remained associated to OS, whereas for progression-free survival, only NRAS mutations remained as an independent factor (HR= 5.88, p=0.013). Both male sex (HR= 8.41, p=0.037) and graft from unrelated donor (HR= 3.15, p=0.043) were associated to NRM in multivariable analysis.

Conclusion: NMA conditioning in the form of low dose TBI and fludarabine before allo-HCT for MF is feasible. Patients show low 1-year NRM but a relatively high 1-year CIR. Differentiated conditioning with more intensive RIC regiments for younger and fit patients could be considered to reduce the early relapse rate without increasing NRM. In survival analysis, donor-patient relation, patient comorbidity burden and patient sex were independently associated to OS.