Graft-Versus-Host Disease Prophylaxis with Posttransplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis

Introduction. Allogeneic stem cell transplantation (alloHSCT) is currently the only treatment modality with curative potential in patients with myelofibrosis (MF), although transplant-associated complications and relapses significantly reduce the application of this method. JAK1/JAK2 inhibitor ruxolitinib is effective in reducing symptomatic splenomegaly and myelofibrosis-related symptoms. At the same time it has significant immunomodulatory effect and is used for the treatment of steroid-refractory acute and chronic graft-versus-host disease (GVHD). This study evaluated calcineurin inhibitor free GVHD prophylaxis regimen with ruxolitinib in combination with posttransplant cyclophosphamide (PTCy).

Patients and methods. Pilot prospective study (NCT02806375) so far enrolled 13 patients with primary or secondary MF. One patient had post-essential thrombocythemia MF, 3 -post-polycythemia vera MF, 9 - primary MF. 11 patients had intermediate-2 risk and 2 had high risk according to DIPSSplus. Median age was 50 years (range 32-64). Nine patients were JAK2V617F positive, 1 patient MPL -positive, 2 patients CALR -positive before alloHSCT. 5 patients had pre-transplant splenectomy. Reduced intensity conditioning was performed with fludarabine 180 mg/m² and busulfan 10 mg/kg (N Kröger et al., 2009). GVHD prophylaxis included PTCy 50 mg/kg at day +3, +4 and ruxolitinib 45 mg/day at days -7 to -2, and 15 mg/day at days +5 to +100. 4 patients were grafted from matched related donor, 6 from 10/10-matched unrelated donor, 1 from 9/10 matched unrelated donor and 2 from haploidentical donor. Peripheral blood stem cells were used as a graft source in 12/13 patients.

Results. Median folow-up was 192 days (range 49-676). Engraftment was documented in all patients. Median time to neutrophil engraftment was 25 days (range 16-57 days), to platelet engraftment - 42 days (15-345). In two cases stem cell "boost" was administered due to poor graft function. Dose reduction of ruxolitinib to 10 mg/day due to poor graft function was performed in all but two patients. 12/13 are alive and with full donor chimerism. One died of Pseudomonas aeruginosa sepsis. In 5 patients near complete bone marrow fibrosis resolution (grade 1-0) was observed. No hematologic relapses of MF were documented.

Two patients developed grade III acute GVHD and one grade II acute GVHD. 4/13 patients developed chronic GVHD, in two cases it was classified as moderate (NIH). In all but one patient, who required systemic steroids, GVHD was successfully treated with cyclosporine A.

The regimen was well tolerated. Grade 3-4 toxicities included only toxic hepatitis in 3 and sepsis in 3 patients. Mild veno-occlusive disease was observed in one patient. Viral reactivations were relatively frequent, including CMV in 62%, HSV type 1,2 in 100%, HSV type 6 in 8% and BK virus in 23% of patients. Moderate hemorrhagic cystitis developed in 2 patients.

Conclusion. GVHD prophylaxis with combination of PTCy and ruxolitinib is associated with good acute and chronic GVHD control and seems promising modality at least for MF patients. Further recruitment of patients and longer follow-up is required to draw more solid conclusions.