Ruxolitinib during Peritransplant Period for Myelofibrosis Patients Undergoing Allogeneic Stem Cell Transplantation Reduces Acute Graft-Versus-Host Disease

Introduction

Allogeneic stem cell transplantation is a curative treatment approach for patients with myelofibrosis, but associated with a high risk of therapy related complications such as graft versus host disease (GvHD). Ruxolitinib is the first approved drug for treatment of myelofibrosis. Major effects are reduction in spleen size and improvement of constitutional symptoms, which may be useful in order to reduce transplant related complications. Therefore, the EBMT/ELN guidelines recommend to administer Ruxolitinib prior to allogeneic stem cell transplantation (Leukemia 2015). Because of the immunosuppressive properties, Ruxolitinib has been shown to be active in steroid refractory graft versus host disease (GvHD). While in transplant setting Ruxolitinib is usually stopped at time of conditioning, data of Ruxolitinib during peritransplant period are lacking.

Patients and methods

From 171 myelofibrosis patients(pts) who underwent allogeneic stem cell transplantation 58 pts (34%) received Ruxolitinib at any time point prior to ASCT and 12 did not stop Ruxolitinib at start of conditioning, but continued during Busulfan based reduced conditioning and after stem cell transplantation until stable engraftment. For those 12 pts (male n=6, female n=6), the median age was 63 years (range 43-71 years) and disease status according DIPSS was intermediate 1 (n=1), intermediate 2 (n=9) and high risk (n=2). Nine patients were JAK2V617F positive, 4 were CALR positive and 1 was triple negative. The median duration of Ruxolitinib was 163 days (range 61-1268 days) and all patients showed at least improvement in spleen size and constitutional symptoms. CMV serostatus was positive in 6 patients. Pts received peripheral blood stem cells from HLA-identical sibling (n=2), matched (n=8) or mismatched (n=2) unrelated donors. The dose of Ruxolitinib during condition therapy was 2 x 5mg and continued until stable engraftment, then tapered and stopped around day 28 post transplantation. GvHD prophylaxis consisted of cyclosporine A from day -1 and MMF from day +1 until day 28. All patients received anti-lymphocyte globulin (ATG Neovii®) at dose of 30mg for related and 60mg/kg for unrelated stem cell grafts.

Results

No major toxicity was observed during conditioning therapy. ATG treatment was well tolerated without any SIRS syndrome. We observed no graft failure. Leukocyte engraftment was achieved after a median of 12 days (r., 11-18). Overall, only 1 patients experienced acute GvHD grade III , resulting in an incidence of aGvHD grade II-IV and of 8%. Complete donor cell chimerism was achieved in 11 patients after a median of 40 days and molecular clearance was noted in 10 patients after a median of 32 days. CMV reactivation in the CMV positive patients was seen in 67% (n= 4) and one of them has CMV colitis as well. The onset of CMV reactivation is earlier as observed in a historical non Ruxolitinib treated cohort (median 22 vs 54 days, respectively). In two patients, Ruxolitinib was discontinued on day 17 and 18 after ASCT due to cytopenia after engraftment. After a short median follow up of 112 days (range 42-191) all patients are alive, with one progessing disease and no NRM. One patients developed fever of unknown origin after discontinuation of Ruxolitinib , otherwise no case of withdrawal syndrome was observed.

Conclusions

These results suggest that Ruxolitinib given during peritransplant period in patients with myelofibrosis is well tolerated and ensure safe and fast engraftment and leads to a low incidence of acute GvHD. Ruxolitinib should be further investigated as GvHD prophylaxis.