Belumosudil Induces Responses in Refractory Chronic Graft-Versus-Host Disease

Belumosudil, a selective Rho-associated coiled-coil–containing protein kinase-2 (ROCK2) inhibitor, was associated with organ responses in heavily pretreated patients with chronic graft-versus-host disease (cGVHD) that was refractory to ibrutinib and ruxolitinib. These findings were recently published in Blood.

In July 2021, the U.S. Food and Drug Administration (FDA) approved belumosudil for adults and children ages 12 years and older with cGVHD after disease progression following at least two previous lines of treatment. “This study adds a third agent to the armamentarium against steroid-refractory cGVHD – with ibrutinib currently approved and an anticipated approval of ruxolitinib occurring in the near future,” said senior study author Corey Cutler, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

Most patients who undergo allogeneic hematopoietic cell transplantation develop cGVHD. In a substantial proportion of these patients, the disease involves four or more organs at diagnosis and, in many cases, progresses further.

While first-line therapy for moderate-to-severe cGVHD may initially be helpful, many patients require additional lines of therapy. Currently, there is a need for more targeted and better-tolerated therapies that address inflammation and fibrosis in cGVHD without compromising patient immunity.

Dr. Cutler and colleagues investigated the tolerability and potential efficacy of belumosudil in a phase II study of patients with heavily pretreated cGVHD. All patients were on a stable corticosteroid therapy for two weeks before screening.

Patients were randomly assigned to receive either of the following:

  • belumosudil 200 mg once daily (n=66)
  • belumosudil 200 mg twice daily (n=66)

The primary endpoint of the study was the overall response rate (ORR).

The median age of the overall cohort was 56 years, and the overall median time between cGVHD diagnosis and study enrollment was 28 months. Approximately 31% of patients and 67% of patients had moderate and severe disease, respectively. More than half of patients (52%) had involvement in four or more organs.

Patients in the U.S.-based multicenter study had previously received a median of three prior lines of therapy (range = 2-5). The majority of patients (72%) had cGVHD refractory to their last line of therapy. A total of 45 patients had previously received ibrutinib and 38 had received ruxolitinib.

Over the median follow-up period of 14 months, ORR was 74% (range = 62-84%) for belumosudil 200 mg once daily and 77% (65-87%) for 200 mg twice daily. The efficacy of the ROCK2 inhibitor was maintained over follow-up irrespective of prior treatment with either ibrutinib or ruxolitinib.

Organ-specific analyses in the intention-to-treat population found a best ORR of 42% in the eyes, 37% in the skin, 39% in the liver, 55% in the mouth, 71% in the joints/fascia, 26% in the lungs, 52% in the upper gastrointestinal (GI) tract and 69% in the lower GI tract, as well as 45% in the esophagus. A CR was observed in all affected organs of seven patients.

Overall, the median time to response was five weeks. Most responses (91%) occurred within a six-month period of treatment, while the remaining occurred between six and 12 months. Responses were maintained for 20 weeks or longer in 59% of responders.

Among patients who responded to treatment, the median duration of response was 54 weeks, with 44% of patients remaining on treatment for one year or longer. Approximately 59% of patients in the belumosudil 200 mg once daily group and 62% of patients in the 200 mg twice daily group experienced symptom reduction during treatment.

A total of 16 patients (12%) discontinued the study drug due to possible treatment-related adverse events (AEs). Overall, however, AEs were deemed consistent with those expected in the cGVHD population managed with corticosteroids and immunosuppressants.

The primary limitation of this study was its lack of a control group. As such, future research may need to compare belumosudil with placebo or another third-line approach to further evaluate its efficacy in cGVHD.

“Naturally, identifying a compound with this impressive activity in later stages of cGVHD makes us wonder how well it would perform in earlier steroid-refractory disease, in steroid-naïve patients, or even as a cGVHD prophylactic agent,” Dr. Cutler added.

The authors report conflicts of interest with Kadmon Corporation, which funded the study.


Cutler CS, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease (cGVHD) after 2 or more prior lines of therapy: the ROCKstar study [published online ahead of print, 2021 Jul 15]. Blood. doi: 10.1182/blood.2021012021.