Reduced Intensity Allogeneic Stem Cell Transplantation for Younger Patients with Myelofibrosis
Authors: Mannina Daniele , Wolschke Christine , Zabelina Tatjana , Zeck Gaby , von Pein Ute-Marie , Ayuk Francis Ayuketang , Kroeger Nicolaus 
Published: October 2019

Abstract
INTRODUCTION Allogeneic stem cell transplantation (alloSCT) is the only curative procedure for primary and secondary myelofibrosis (PMF, SMF). Elderly people are mainly affected, limiting the feasibility of intensive myeloablative chemotherapy regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible and effective for old patients. Nevertheless, the incidence of PMF and SMF is not negligible in young patients, theoretically able to tolerate also high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in the particular setting of young-aged MF patients.
PATIENTS AND METHODS This study includes 56consecutive Myelofibrosis young patients (age <55y) who received alloSCT allogeneic stem cell procedure between 2002 and 2016 at the University Hospital Hamburg/Germany treated in UK-Eppendorf, Hamburg. Only 4 patients were previously splenectomized. Patients mostly fall into intermediate risk groups according to DIPSS model (int-1: 22; int-2: 24; high: 3). Four patients belonged to the high-risk triple-negative category (JAK2/CALR/MPL-). ASXL1 additional mutation was tested in 50 patients (, and positive: in 17) cases. In 96% graft source was peripheral blood stem cells, 2 patients received bone marrow stem cell. Only 30% of patients had a 10/10 HLA-matched sibling donor, the others were transplanted from fully-matched (36%) or partially-matched (34%) unrelated donor. All transplants were conditioned according the EBMT protocol with Busulfan (10 mg/Kg PO or 8 mg/Kg IV), Fludarabine (150 mg/m2), ATLG (Grafalon® Neovii, Germany) administered in 3 days at a dose of 20 mg/Kg die for MUD, 10 mg/Kg die for MRD transplants, followed by Cylosporin A, and Mycophenolate in the first 28 days was added only in MUD/MMUD transplants.
RESULTS Engraftment rate was 98%, with a median neutrophil engraftment time of 15 days. Platelet engraftment was reached by 51 patients (91%) in a median time of 19 days. Four patients (7%) developed poor graft function, successfully treated with CD34+ selected PBSC boost. After a median follow up of 8.6 y estimated 5y PFS and OS was 68% and 82% respectively. DIPSS risk and donor HLA-matching resulted the only significant impacting factors on OS. Neither cytogenetic nor molecular abnormalities (included ASXL1) were significantly related to OS. Twenty-five patients (44%) experienced acute GVHD grade >1. Chronic GVHD was observed in 34 patients (65%), mostly (82%) beginning in the first 300 days after transplantation. Cumulative incidence of TRM was 7% at 1 year, with a plateau after the first year (5y TRM = 12%). TRM was observed only in patients with maximal grade (3) of marrow fibrosis (p=0.00). Furthermore, TRM never occurred in previously splenectomized patients (p=0.00), but no significant impact from splenectomy on OS was observed (p=0.32). After transplant, 11 patients (20%) relapsed: 1 died without any treatment because of infection, 9 received DLI with durable recovery of complete remission in 3 cases, 7 patients (6 after DLI) underwent a second alloSCT, with long-term survival in 5 cases.
CONCLUSION Reduced intensity conditioning followed by allogeneic SCT is a curative treatment approach for younger patients with myelofibrosis with a low NRM. The most important outcome-determining factor is donor HLA-matching. Interestingly, marrow high grade fibrosis showed to significantly impact TRM. Biological markers such as ASXL1 mutation and cytogenetics, largely known as highly predictive for poor prognosis in the disease natural course, did not show any impact on survival, suggesting that patients harboring these abnormalities could get the greatest benefit from alloSCT. According to these data, RIC-alloSCT ensures optimal engraftment and low relapse rate, being able to lead also younger MF patients to cure. Further data collection, and a prospective randomized trial are needed to confirm our conclusion.

Disclosures
No relevant conflicts of interest to declare.