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Belumosudil and ruxolitinib combination for treatment of refractory chronic graft-versus-host disease

Bone Marrow Transplantation volume 59, pages 282–284 (2024)Cite this article

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Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation [1]. High dose corticosteroids remain the mainstay for first-line treatment of cGvHD, but only 40–50% of patients (pts) respond adequately to corticosteroids and the rest become steroid-refractory or -dependent (SR/SD), requiring further lines of therapy (LOT) [2, 3]. Ruxolitinib and belumosudil are FDA-approved agents for the treatment of refractory cGvHD after failure of 1 or 2 prior LOT, respectively. Encouraging responses have been reported with both agents, with the best overall response rate (ORR) above 70% [4, 5]. However, complete and long-lasting responses are relatively rare, and a significant number of pts needs subsequent immunosuppressive therapies (IST). One potential approach to overcome the resistance to a single agent and improve outcomes might be to combine agents with different mechanisms of action. Ruxolitinib is an oral selective inhibitor of Janus kinase 1 and 2 (JAK1/2). JAKs are intracellular signaling components that play a critical role in the development and functioning of immune cells and downstream activation of many cytokines implicated in cGvHD pathogenesis [6, 7]. Belumosudil, an oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5 [8]. ROCK2 signaling plays an important role in fibrotic pathways leading to the activation of profibrotic gene expression and increased production of collagen [9]. Since the FDA approval of belumosudil for cGvHD in July 2021, it has been an occasional practice at our institutions to add belumosudil to pts with an unsatisfactory response to ruxolitinib. We conducted a multi-institutional retrospective study evaluating the safety, tolerability and clinical response of adding belumosudil to pts already on ruxolitinib (B + R) for SR/SD cGvHD, from June 2021 to October 2022. Treatment response was determined according to the investigator’s opinion, using the 2014 NIH Criteria for cGvHD as guidelines [10]. Results are reported descriptively. The trial was approved by the Institutional Review Board at each participating institution.

A cohort of 14 pts with SR/SD cGvHD who were concomitantly treated with ruxolitinib and belumosudil was evaluated (Table 1). Pts received a median of 3 (range, 2–5) LOT before initiating ruxolitinib. Four pts already on ruxolitinib, received an additional LOT prior to starting belumosudil. The median time from cGvHD diagnosis to B + R was 58 mo (range, 6–200). The median time on ruxolitinib prior to adding belumosudil was 37 mo (range, 6–69). The majority of pts had severe cGvHD at the time of adding belumosudil. The median number of organs affected by cGvHD at the time of initiating B + R was 4 (range, 1–6), and the most commonly affected organs were skin (n = 10; sclerotic skin n = 7), eyes (n = 10), mouth (n = 9), joint/fascia (n = 7) and lung (n = 5). At the initiation of B + R, pts were on a median of 1.5 (range, 0–3) additional IST, including prednisone (n = 9), sirolimus (n = 5), tacrolimus (n = 3), mycophenolate mofetil (MMF; n = 4), and extracorporeal photopheresis (n = 1). Belumosudil was initiated at 200 mg daily (n = 8) and 200 mg twice daily (n = 6) for pts on a proton pump inhibitor. At belumosudil initiation, the ruxolitinib dose was 10 mg twice daily in 8 pts, 5 mg twice daily in 5 pts, and 5 mg daily in 1 patient. The ruxolitinib dose was reduced by 50% in 8 pts, and eventually discontinued in 4 pts. Belumosudil was dose-reduced in 4 pts for worsening renal function, fatigue, and rash, and prednisone was successfully reduced in 4 of 9 pts due to clinical response. At a median follow-up of 10.7 mo (range, 1–13) after starting B + R, 6 pts had partial response (PR), 7 had stable disease, and 1 progressed. For 6 pts with PR, the median time to PR from B + R start was 2.6 mo (range, 1–4.3). In pts with PR, responding organs were skin (n = 3), mouth (n = 3), eyes (n = 2), joint/fascia (n = 2), and lungs (n = 1). Of the 7 pts with stable disease, 4 were on prednisone, and 2 of these 4 pts had prednisone dose reduced. Overall, B + R was well tolerated. Grade 3 anemia (n = 2) resolved with a ruxolitinib dose-reduction. There were no grade 3 or 4 neutropenia, thrombocytopenia, or transaminitis. One patient had grade 3 creatinine elevation that resolved after stopping sirolimus, and reducing MMF and ruxolitinib doses. Documented bacterial infections (n = 6) occurred in 3 pts, and respiratory viral infections (n = 9) and disseminated zoster (n = 1) in 5 pts. There were no cases of cytomegalovirus reactivation or fungal infection. Other grade 3 adverse events included nausea, fatigue, skin blisters and pulmonary embolism. There was no malignancy relapse. One patient with PR died at home from an unclear cause.

Table 1 Patient characteristics.
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Authors and Affiliations

  1. Washington University School of Medicine, Division of Oncology, St. Louis, MO, USA

    Iskra Pusic, Chelsea Minor & John F. DiPersio

  2. Fred Hutchinson Cancer Center, Clinical Research Division, Seattle, WA, USA

    Catherine Lee

  3. University of Arkansas for Medical Sciences, Department of Hematology and Medical Oncology, Little Rock, AR, USA

    Muthu Veeraputhiran

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Contributions

Contribution: IP, CL, MV, and CM conceptualized the study, designed the research, contributed data, analyzed the data and wrote the manuscript, JFD contributed data and reviewed the final manuscript.

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Correspondence to Iskra Pusic.

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IP is on the Advisory Board and receives research funding from for Incyte and Syndax; MV is on Speaker Bureau for KITE and has done the Advisory Board and Consulting for KITE, ADC therapeutics and Sanofi; CL is on the Advisory Board and Consulting for Incyte and Sanofi, she has received research funding form Incyte and is on Incyte Clinical Trial Steering Committee; CM has nothing to declare; JFD received research funding from Incyte, Mallinckrodt Pharmaceutical and he is on the Scientific Advisory Board for Magenta Therapeutics.

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Pusic, I., Lee, C., Veeraputhiran, M. et al. Belumosudil and ruxolitinib combination for treatment of refractory chronic graft-versus-host disease. Bone Marrow Transplant 59, 282–284 (2024). https://doi.org/10.1038/s41409-023-02165-3

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