Allogeneic STEM CELL Transplants for Patients with Myelofibrosis: Changes in the Transplant Platform and Improved the Outcome

Introduction. Allogeneic stem cell transplantation remains the only curative therapy for patients with myelofibrosis, but is associated with relevant morbidity and mortality, possiby due to the specific nature of the disease. The outcome is significantly worse when alternative donor transplants are compared to matched siblings (MSD): in a recent cooperative study, TRM was 22% in MSD vs 59% in patients receiving unrelated donor grafts (UD) (Blood 2014 124:1183).

Aim of the study. This is a retrospective analysis of 95 patients with myelofibrosis (MF) allografted in our Unit between 2001 and 2014. The aim of the study was to assess whether (a) the outcome of alternative donor grafts has improved with time and (b) how this compares with the outcome of identical sibling grafts.

Patients were studied in two time intervals-2000-2010 (n=58) and 2011-2014 (n=37). The DIPSS score was comparable in the two time periods, but differences in the most recent group included older age (58 vs 53 years, p=0.004), more family haploidentical donors (54% vs 5%, p<0.0001), and the introduction of the thiotepa- fludarabine- busulfan conditioning regimen (70% of patients vs 2%, p<0.0001). Reduced intensity regimens were used mainly in the first transplant period (85% vs 30% in the most recent period).

All patients received unmanipulated grafts (86% bone marrow). GvHD prophylaxis for sibling donor grafts was cyclosporin methotrexate (CsA+MTX), with the addition of ATG for unrelated transplants. Haploidentical grafts were performed with high dose cyclophosphamide post-transplant (PT-CY), CsA and mycophenolate.

Results. Acute and chronic GvHD were comparable in the two time periods. Full donor chimerism was >90% in both periods in sibling transplants; on the other hand, in alternative donor transplants it improved from 69% to 95% in the most recent period (p=0.02). The 3 year transplant related mortality (TRM), in the 2011-2014 vs the 2000-2010 period, is 16% vs 38% (p=0.08), the relapse rate 19% vs 43% (p=0.01) and actuarial survival 70% vs 39% (p=0.08). Improved survival was most pronounced in alternative donor grafts (69% vs 21%, p=0.02), as compared to matched sibling grafts (72% vs 45%, p=0.4). The actuarial 3 year survival for high risk DIPSS was 8% in the 2000-2010 period, and it is currently 57% (p<0.01). In multivariate Cox analysis, DIPSS (p=0.001) and transplant score (transfusion requirement and spleen size) (p=0.03) were independent predictor of survival. Donor type was not predictive in multivariate analysis.

Conclusions. The outcome of allografts for myelofibrosis has improved in recent years, due to a reduction of both TRM and relapse, despite comparable DIPSS and older age in the more recent group of patients. Improved survival has been more pronounced for alternative donor transplants, such that 3 year survival is currently superimposable to sibling donor grafts. There have been significant changes in the transplant platform, including conditioning regimen, donor type and GvHD prophylaxis, mainly with the introduction of PT-CY. All of our MF patients now receive the thiotepa, busulfan fludarabin conditioning, and, for patients lacking a matched sibling, a family haploidentical donor seems to be an interesting alternative.