Ruxolitinib Plus Post-Transplant Cyclophosphamide Controls GVHD in Myelofibrosis


“In this study, we evaluated ruxolitinib as a bridge, relapse, and GVHD prevention agent in patients with myelofibrosis. The regimen was well tolerated, with an acceptable rate of organ toxicity."

Ruxolitinib (Jakafi) and post-transplant cyclophosphamide (PTCy) as treatment of graft-versus-host-disease (GVHD) prophylaxis induced good control of both acute and chronic GVHD and was deemed well-tolerated in patients with myelofibrosis (MF), according to results from a prospective pilot study.

“In this study, we evaluated ruxolitinib as a bridge, relapse, and GVHD prevention agent in patients with MF. The regimen was well tolerated, with an acceptable rate of organ toxicity,” the study authors led by Elena V. Morozova, MD of Pavlov First Saint Petersburg State Medical University wrote. “CMV [cytomegalovirus] reactivation was documented in 30% of cases, which is similar to previous data with PTCy and tacrolimus-based prophylaxis.”

Seventeen patients had documented primary engraftment, and the median time to neutrophil engraftment was 27 days (range, 18-44). The median time to platelet engraftment was 38 days (range, 15-219), and the median time to achievement of red blood cell transfusion independence was 59 days (range, 20-540). Prior to engraftment, two patients succumbed to severe pseudomonas aeruginosa sepsis and gastrointestinal bleeding, and 1 patient died at day 115 due to thrombotic microangiopathy and infectious complications after cyclosporine A and steroid therapy due to grade 3 acute GVHD. One patient who experienced primary graft failure (PGF) is alive and in remission at 1 year following a second transplant.

Overall, 55% of patients had experienced severe poor graft function (SPGF; n = 11), and this was resolved in 2 patients without dose modifications of ruxolitinib. Eight patients had a dose reduction from 15 mg/day to 10 mg/day to control SPGF, and 1 of these patients had SPGF resolved at day 77. Another 1 of these 8 patients had SPGF resolved after treatment discontinuation at day 100. A total of 3 patients also required CD34+ boost administration, and 3 also required donor lymphocyte infusion to treat the SPGF.

One patient had mild veno-occlusive disease, and 7 patients had sepsis. One patient also had invasive mycosis, and 9 had a viral reactivation or infection, which included CMV reactivation, HHV type 6, HHV type ½, BK, and parvovirus B19. Hemorrhagic cystitis was observed in 3 patients.

Grades 2 to 4 acute GVHD were observed in 5 patients (25%), and severe disease of grade 3 to 4 was observed in 3 patients (15%). The overall rate of chronic GVHD was 40%, moderate GVHD was 20%, and mild GVHD was 20%. Calcineurin inhibition was used to treat 6 patients in the first-line setting, and 2 patients required systemic steroid therapy. One patient experienced GVHD-related mortality.

Hematological and molecular remission, as well as splenomegaly regression, was achieved in all engrafted patients. Additionally, 65% achieved near-complete bone marrow fibrosis resolution at day 398 (range, 131-748). One patient had a molecular and hematological relapse at day 665.

The rate of 2-year non-relapse mortality was 15% (95% CI, 4%-34%). Two-year overall survival (OS) rate was 85% (95% CI, 60%-93%), and 2-year event-free survival (EFS) rate was 72% (95% CI, 45%-87%). In contrast, the 2-year OS rate without peri-transplant ruxolitinib administration was only 40% to 50%.

Investigators also observed heightened cytokine levels after graft transfusion with a subsequent decline after PTCy and ruxolitinib initiation. Levels of interleukin (IL)-8, however, were increased after engraftment with no post-infusion peak. There was a positive correlation between ruxolitinib concentration and levels of IL-8 (R=.242; P =.041) and IL-1β (R =.246; P =.039).

The primary end point of this study was the incidence of acute GVHD grades 2-4 and chronic moderate and sever GVHD. Secondary end points included OS, EFS, the incidence of relapse, PGF, and SPGF. Patients with primary MF, post-essential thrombocytopenia (ET) MF, and post-polycythemia vera (PV) MF were enrolled in the study at Pavlov First Saint Petersburg State Medical University. All patients had received pre-transplant ruxolitinib for a median of 7.4 months (range, 2.6-22.3) and continued this treatment at 45 mg/day from day 7 to day 2.

The median age of patients was 51 years (range, 32-64) and there was an equal number of males versus females in the study (n = 10 each). Fourteen patients (70%) had primary MF, 3 (15%) had post-PV-MF, and 3 (15%) had post-ET-MF. According to DIPSS Plus, 2 patients (10%) were intermediate-1 risk, 14 (70%) were intermediate-2 risk, and 4 (20%) were high-risk.

Allogeneic hematopoietic stem cell transplantation remains the only treatment available with curative potential for patients with either primary or secondary MF, but this treatment is associated with relatively high rates of non-relapse mortality, early relapse, and PGF. The most common cause of death with this treatment is progression of disease or relapse, acute/chronic GVHD, infections, and organ toxicities. The calcineurin inhibitor-free regimen of ruxolitinib plus PTCy was associated with both a lower relapse incidence and a low toxicity profile among patients with MF.

“The favorable toxicity profile and absence of early relapses prompted the initiation of a multicenter randomized phase 2 trial,” the study Morozova et al concluded. “The study will commence in the first quarter of 2020 and compare PTCy plus ruxolitinib versus conventional PTCy in combination with tacrolimus and mycophenolate mofetil prophylaxis in acute leukemia patients undergoing unrelated and haploidentical transplantation.”


Morozova EV, Barabanshikova MV, Moiseev IS, et al. A Prospective Pilot Study of Graft-versus-Host Disease Prophylacix with Post-Transplantation Cyclophosphamide and Ruxolitinib in Patients with Myelofibrosis [Published Online April 23, 2020]. Acta Haematol. doi: 10.1159/000506758

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