Impact of Donor Type on Outcomes after Allogeneic Hematopoietic Cell Transplantation in Myelofibrosis

Introduction: Historically, myelofibrosis (MF) patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) from a matched sibling donor (MSD) had better overall survival (OS) than those receiving grafts from a matched unrelated donor (MUD) or mismatched unrelated donor (MMUD). MMUD in particular associated with higher non-relapse mortality (NRM) rates. Limited data was available evaluating outcomes using haploidentical donors (HD) for MF, but activity is increasing, accounting for around 10% of allo-HCTs across Europe. We compare outcomes after allo-HCT based on donor type in a contemporary series of MF patients from the European Society for Blood and Marrow Transplantation (EBMT) registry.

Methods: This is a registry-based study approved by the Chronic Malignancies Working Party (CMWP) of EBMT. Inclusion criteria were adult primary and secondary MF patients undergoing first allo-HCT between 2015-2021. Patients transplanted from cord blood or with leukemic transformation were excluded. HD was defined as a family donor mismatched by 2 or more HLA loci; MUD as matched at allele level for HLA-A, -B, -C, -DRB1, and -DQB1; MMUD as unrelated with at least one mismatch. Study outcomes were OS, progression-free survival (PFS), NRM, relapse, engraftment, and acute and chronic graft-versus-host disease (GVHD). Factors associated with these outcomes were analyzed by multivariable methods.

Results: 2809 MF patients were included, 62.4% were male. Four transplant cohorts were compared: MSD (n=742, 26.4%), MUD (n=1401, 49.9%), MMUD (n=379, 13.5%) and HD (n=287, 10.2%). Key differences were younger patient age and older donor age, higher frequency of female donor to male recipient, and lower frequency of CMV patient+/donor- in MSD; more splenectomized patients in MMUD and HD; more ATG use in MUD and MMUD; longer period from diagnosis-transplant, worse performance status, and more frequent use of myeloablative conditioning and bone marrow graft source in HD. All HD transplants received post-transplant cyclophosphamide (PT-Cy). After a median follow-up of 33.5 months from transplant, univariate 3-year estimated OS rates were 65.8% (95% Confidence Interval [CI]: 62.1-69.6) for MSD, 61.5% (95% CI: 58.7-64.3) for MUD, 53.2% (95% CI: 47.6-58.7) for MMUD, and 57.7% (95% CI: 51.6-63.7) for HD. The 3-year PFS rates were 54.0% (95% CI: 50.0-57.9) for MSD, 53.5% (95% CI: 50.6-56.3) for MUD, 45.6% (95% CI: 40.0-51.2) for MMUD, and 51.1% (95% CI: 44.9-57.3) for HD. The 3-year NRM rate were 23.9% (95% CI: 20.6-27.2) for MSD, 27.3% (95% CI: 24.8-29.8) for MUD, 34.1% (95% CI: 29.0-39.3) for MMUD, and 32.3% (95% CI: 26.8-37.9) for HD. The 3-year relapse/progression rate were 22.1% (95% CI: 18.8-25.4) for MSD, 19.2% (95% CI: 17.0-21.4) for MUD, 20.3% (95% CI: 15.8-24.7) for MMUD, and 16.5% (95% CI: 11.8-21.2) for HD. Multivariable analyses adjusting for confounding factors (MSD as reference) showed that MMUD and HD had significantly reduced OS (Hazard Risk [HR]: 1.63, 95% CI: 1.33-2.00 for MMUD; HR: 1.42, 95% CI: 1.12-1.80 for HD), MMUD had worse PFS (HR: 1.38, 95% CI: 1.15-1.65), and MMUD and HD had increased NRM (HR: 1.73, 95% CI: 1.36-2.20 for MMUD; HR: 1.47, 95% CI: 1.11-1.94 for HD). The differences between HD and MSD tended to decrease over time.Donor type was not significantly associated with relapse risk, but, of note, the lowest risk was observed with HD (HR: 0.76, 95% CI: 0.53-1.08). MMUD (HR: 0.72, 95% CI: 0.63-0.83) and HD (HR: 0.40, 95% CI: 0.34-0.48) were associated with a lower probability of engraftment. MUD (HR: 1.50, 95% CI: 1.23-1.83), MMUD (HR: 1.69, 95% CI: 1.31-2.18), and HD (HR: 1.48, 95% CI: 1.10-2.00) were associated with a higher risk of grade 2-4 acute GVHD, while MUD (HR: 0.77, 95% CI: 0.63-0.94) and HD (HR: 0.66, 95% CI: 0.46-0.96) had a lower risk of extensive chronic GVHD. Finally, when MMUD transplants using PT-Cy (n=75) were compared with HD transplants no significant differences were observed in any of the study outcomes.

Conclusion: These data indicate that, with current practices, comparable results are achieved in MF patients transplanted from MSD and MUD. Worse OS and NRM are observed with HD and MMUD. However, HD shows comparable PFS to MSD due to a lower, though not significantly reduced, relapse risk. Although MMUD transplants had a higher risk of grade 2-4 acute GVHD and extensive chronic GVHD compared to HD, these differences were not found in the subgroup of MMUD who received PT-Cy.