Allogeneic Hematopoietic Cell Transplantation For Patients With Primary and Secondary Myelofibrosis: Report Of a Single Center Experience
Authors: Dorn Christiane , Haen Sebastian P. , Faul Christoph , Vogel Wichard , Kanz Lothar , Bethge Wolfgang A 
Published: October 2019

Introduction
Myelofibrosis (MF) is a heterogenous myeloproliferative disorder arising at the level of pluripotent hematopoietic stem cells. It is characterized by reactive marrow fibrosis resulting in extramedullary hematopoeisis, cytopenias, hepatosplenomegaly and constitutional symptoms. The only curative treatment for MF patients is allogeneic hematopoietic cell transplantation (HCT). However, advanced age, comorbidities and disease-related complications are challenging factors for allogeneic HCT. Reduced intensity conditioning (RIC) regimens have lead to an increased frequency of allogeneic HCT for MF patients in recent years. We here report our own experience with allogeneic HCT in MF.

Methods
By searching our database of allogeneic HCT we identified a total of 55 patients with primary or secondary myelofibrosis that underwent allogeneic HCT from 1997 to 2012. Retrospective analysis of data and review of patient charts was performed.

Results
Among the 55 MF patients were 32 males and 23 females with a median age of 54 years (range 28-75). The median interval from diagnosis to HCT was 123 months (range 2-269). Conditioning regimens were either myeloablative (MAC, 18/55 patients (33%)) or RIC (37/55 patients (67%)). Median age was 58 years (range 45-75) for RIC und 47 years (range 28-60) for MAC. As graft source either peripheral blood stem cells (n= 46) or bone marrow (n= 9) was used from either matched related (MRD, n=17, 31%), matched unrelated (MUD, n=21, 38%) or mismatched unrelated donors (MMUD, n=17, 31%). The MAC regimen consisted of 12 Gy total body irradiation in combination with high-dose cyclophosphamide (TBI/Cy, 78%) or high-dose busulfan and cyclophosphamide (Bu/Cy, 22%). Fludarabine and busulfan were the most frequently applied drugs for RIC (Flu/Bu, n=31, 84%), in a few cases fludarabine in combination with TBI (n=1, 3%) or treosulfan-containing regimens (n=3, 8%) were used. Two patients with accelerated disease were treated with the FLAMSA-protocol, followed by busulfan and cyclophosphamide containing RIC. As graft versus host disease (GVHD) prophylaxis, a combination of calcineurine inhibitors and methotrexate or mycophenolate mofetil was used, in 80% (n=44) antithymocyte globuline was additionally applied.
Kaplan Meier estimated overall survival at 4 years was 62% for all patients and 62% after RIC compared to 58% with MAC (p= 0.42) with a median follow-up of patients alive of 49 months (range 9-151). Cumulative incidence of non relapse mortalitiy (NRM) overall and for MAC and RIC was 31%. The overall survival of patients with MRD, MUD and MMUD was 60%, 61% and 61%, respectively. NRM of patients with matched and unmatched donors was not significantly different (MRD 31% versus MUD 35% versus MMUD 33%). Engraftment of neutrophils (ANC>500/µL) was achieved at a median of 16 (range 9-31) days and 23 (range 13-60) days for patients in the MAC and the RIC-group, respectively (p= 0.0051). Platelet recovery (PLT>20.000/µL) occurred at a median of 24 (range 11-51) days after MAC and 21 (range 8-41) days after RIC (p= 0.2866). Despite the significantly delayed engraftment, the risk for severe or lethal infection was lower in the RIC- than in the MAC-group (n=3 versus n=1). Graft rejection occurred only in 3 patients after RIC.
Acute GVHD occurred in 31% (n=17) of the patients. As expected, patients with MAC, compared to RIC, had a higher risk of acute GVHD (71% (n=12) versus 29% (n=5), p< 0.0001). Chronic GVHD occured in 59% of the patients, with 44% extensive and 56% limited cases. Chronic GvHD was more frequent after RIC compared to MAC (59% versus 41%, p= 0.1462). Patients with an extensive GVHD only survived in 18%, whereas patients with a mild or limited GvHD survived in 39% (p= 0.2059). Overall the occurence of GVHD was associated with a poorer outcome.

Conclusion
Our retrospective single center study confirms existing data that allogeneic HCT following RIC may have a similar outcome compared to MAC although used in an older and more comorbid patient population. Allogeneic HCT even with MMUD thus is a potentially curative treatment option in up to 60% of patients with primary or secondary MF.

Disclosures:
No relevant conflicts of interest to declare.