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

Myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) regimens are both used before allogeneic hematopoietic 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 utilization of lesser intense non-myeloablative (NMA) regimens. The NMA regimen is used as the standard conditioning regimen before allo-HCT for MF at all transplantation centers in Denmark. We describe the outcomes of a highly homogenously treated, population-derived cohort of patients with MF who received NMA conditioning prior to allo-HCT and identify factors associated to transplantation outcomes. The study is a retrospective cohort study of patients with MF treated with an NMA regimen prior to allo-HCT at Copenhagen University Hospital, Rigshospitalet from 2007 to 2023. 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 to 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 hematopoietic 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%) who 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), 96 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%, and 61%, respectively, whereas the NRM was 15%, 15%, and 21%, respectively. 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 (hazard ratio (HR) = 5.43, P < .001), graft from unrelated donor (HR = 3.58, P = .018) and HCT-CI above 2 (HR = 2.5, P = .025) remained associated to OS, whereas for progression-free survival, only NRAS mutations remained as an independent factor (HR = 5.88, P = .013). Both male sex (HR = 8.41, P = .037) and graft from unrelated donor (HR = 3.15, P = .043) were associated to NRM in multivariable analysis. Our analysis shows that NMA conditioning in the form of low dose total body irradiation 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.