Posttransplant ruxolitinib combined with cyclophosphamide for graft versus host disease prophylaxis and relapse prevention in patients with myelofibrosis
Contact: Dr. Maria V. Barabanshikova
Accepted 20 September 2016
Myelofibrosis (MF) is a BCR-ABL–negative myeloproliferative disorder with progressive clinical course and usually poor prognosis. Allogeneic stem cell transplantation (alloHSCT) is currently the only treatment modality with curative potential in patients with MF. JAK1/JAK2 inhibitor ruxolitinib is effective in decreasing symptomatic splenomegaly and myelofibrosis-related symptoms. At the same time, it shows a significant immunomodulatory effect and is widely used for the treatment of acute and chronic GVHD. In our study, we administered ruxolitinib with posttransplant cyclophosphamide for GVHD prophylaxis and relapse prevention.
Patients and methods
We analyzed the results of alloHSCT in 4 patients aged 36-52 (median 41) years. One patient was diagnosed with post-essential thrombocythemia myelofibrosis, and three cases of primary myelofibrosis. By DIPSSplus, 2 patients had intermediate-2 and 2 patients had a high-risk disease. 3 patients were JAK2V617F positive, 1 patient was MPL-positive before alloHSCT. All the patients were treated with JAK1/2 inhibitors before alloHSCT, with median treatment duration of 6 months (3 to 18). Disease stabilization occurred in two cases, and two other patients achieved clinical improvement. In one patient, splenectomy was performed, due to poor spleen response. A reduced-intensity conditioning (Fludarabine 180 mg/m2 plus Busulfan 8-10 mg/kg) followed by alloHSCT from full-matched (3) and mismatched (HLA 9/10) (1) unrelated donor was performed. Graft-versus-host disease prophylaxis consisted of posttransplant cyclophosphamide 100 mg/kg at day +3, +4 and ruxolitinib (5 to 7,5 mg bid from day+5 until day +50 (2), and day +100 (2). G-CSF mobilized peripheral blood progenitor cells were used as a stem cell source. Median number of CD34+cells/kg was 6.7×106 (1.4 to 7.3). The trial is registered on clinicaltrials. gov, NCT02806375.
Primary engraftment was documented in 4 patients. Median time to the leukocyte engraftment was 34 (19-79) days, to platelets’ engraftment, 57 days (20-112). 2 patients developed cytomegalovirus reactivation and were successfully treated with Gancyclovir. 2 patients experienced polyomavirus infection. We did not document any severe episodes of toxicity during ruxolitinib therapy in early posttransplant period. Four patients achieved hematological remission (splenomegaly reduction and constitutional symptoms resolution), molecular remission and full donor chimerism. a near-complete resolution of bone marrow fibrosis was observed in two patients (from grade 3-2 down to grade 1-0) accompanied by molecular remission and full donor chimerism. Two patients developed acute GVHD grade II and moderate overlap GVHD with skin and liver involvement after ruxolitinib discontinuation. GVHD resolved completely after cyclosporine A administration. None of the patients required steroid therapy. All patients are alive without any signs of disease progression with median follow-up of 5 months.
AlloHSCT is an effective treatment modality for myelofibrosis. Post-transplant JAK1/2 inhibition in combination with post-transplant Cyclophosphamide seems a promising therapeutic option to prevent GVHD and relapse. The trial will continue to recruit patients.
Allogeneic hematopoietic stem cell transplantation, ruxolitinib, cyclophosphamide, myelofibrosis
Accepted 20 September 2016