High Cure Rate By Allogeneic Stem Cell Transplantation for Myelofibrosis Patients Aged 65 or Older
Authors: Daghia Giulia , Zabelina Tatjana , Zeck Gaby , von Pein Ute-Marie , Christopeit Maximilian , Wolschke Christine , Ayuk Francis Ayuketang , Kroeger Nicolaus 
Published: October 2019

Abstract
Introduction
Myelofibrosis (MF) is predominantly a disease of the elderly with a median age of 65 years at diagnosis. Allogeneic stem cell transplantation (ASCT), which is associated with substantial treatment-related morbidity and mortality, is the only potentially curative option so far. The development of reduced intensity conditioning (RIC) regimens has enabled transplant to be performed successfully in older patients. To evaluate the outcome of transplantation among elderly patients, we conducted a retrospective analysis of results in 46 patients, aged 65 years or older, who were transplanted between 2002 and 2018 at the University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
Patients and methods
Retrospective data from 46 patients with primary or secondary MF, who underwent ASCT, were collected. Median age at ASCT was 67 years (r: 65-74). 76% of patients were classified as MF-3 according to the WHO criteria. DIPSS risk status was intermediate-1 in 4% of patients, intermediate-2 in 61% and high in 33%. 70% of patients had mutation in JAK2, 17% in CALR and 9% in MPL. All patients received peripheral blood stem cell (PBSC) as graft source. Stem cell donor was related in 9% of patients, unrelated in 91%; 74% of patients had a completely HLA-matched donor, whereas 26% had at least 1 allele or antigen mismatch. 85% of patients received busulfan 10 mg/kg orally (or 8 mg/kg intravenously) plus fludarabine (150 mg/m2) reduced intensity conditioning regimen, whereas 15% received myeloablative conditioning with busulfan 16 mg/kg orally (or 12.8 mg/kg intravenously) plus fludarabine (150 mg/m2). 96% of the patients received anti-T-lymphocyte globulin (Grafalon®, Neovii, Germany) at a cumulative dose of 30 mg/kg for matched related donor (MRD) transplants and 60 mg/kg for matched/mismatched unrelated donor (MUD/MMUD) transplants. Further GVHD prophylaxis consisted of cyclosporine A and mycophenolate from day +1 to +28.
Results
Engraftment rate was 94%, with a median time to neutrophil engraftment of 13 days (r: 10-19). Two patients (4%) experienced primary graft failure (PGF), one received a second ASCT with successful engraftment, while the other had further PGF after second ASCT and died of infection after third ASCT. Platelet engraftment rate was 87% and was reached in a median time of 21 days (r: 10-293). Five patients (11%) developed secondary poor graft function and four received CD34+ selected PBSC boost, two achieving complete remission (CR) and one obtaining CR with incomplete platelet recovery (CRp).
52% of patients experienced acute GVHD grade I to IV, while the overall rate of chronic GVHD was 56%, which was moderate disease in 24% and severe disease in 13%.
After a median follow-up of 4 years, 6-year estimated progression-free survival (PFS) and overall survival (OS) were 60% (95% CI: 42-78) and 64% (95% CI: 48-80), respectively. In the univariate analysis, male donor sex was the only significant factor for improved OS and PFS at 6 years (P=.001 and P=.003, respectively). A positive impact on OS was observed for mutation in CALR (P=.05), as previously reported. Interestingly, survival was not significantly different in patients aged 65-70 years compared with those aged 71-74 years.
Cumulative incidence of non-relapse mortality (NRM) was 29% at 4 years (95% CI: 13-45). Major causes of death were infections (n=4) and GVHD (n=3). The only significant factor for lower NRM in the univariate analysis was male donor sex vs female (NRM 17% vs 58%, P=.004). No NRM occurred in CALR-mutated patients (p=0.00).
Cumulative incidence of relapse at 6 years was 10% (95% CI: 0-22): one patient durably restored molecular response after early tapering of cyclosporine, one died because of GVHD without any further treatment, one achieved a long-lasting CR after donor lymphocytes infusions (DLI), while two patients underwent a second ASCT after DLI alone in one case and DLI plus azacitidine in the other, with long-term CR in the former.
Conclusion
Our results show that RIC regimen followed by allogeneic stem cell transplantation in older patients with myelofibrosis is a curative treatment option. These results are encouraging for older MF patients with minimal comorbidities. In addition to Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), a comprehensive geriatric assessment could be a useful tool for a better selection of patients with the aim to further reduce NRM.

Disclosures
No relevant conflicts of interest to declare.