Corey S. Cutler, MD, MPH, FRCPC, medical director, Adult Stem Cell Transplantation Program, director of Clinical Research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discusses the toxicity profile of belumosudil (KD025) in patients with chronic graft-versus-host disease (cGVHD).

Data from the ongoing phase 2 ROCKstar trial (NCT03640481), which were presented virtually during the 47th Annual Meeting of the EBMT, demonstrated an overall response rate of 73% with once-daily belumosudil vs 77% with twice-daily belumosudil in patients with cGVHD. 

Regarding safety, the adverse effects with belumosudil were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants, says Cutler. Overall, grade 3 or greater toxicities were infrequent and included pneumonia, hypertension, and hyperglycemia, Cutler explains. Eight patients died while on study because of aspiration pneumonia, hemoptysis, multiple organ dysfunction syndrome/septic shock, relapse acute myeloid leukemia, cardiac arrest, infection, and respiratory failure. However, few patients had to discontinue treatment because of toxicity, Cutler says. 

Despite the incidence of relapse AML, these findings do not suggest that belumosudil is immunosuppressive enough to cause a high rate of relapse among patients treated, concludes Cutler. 

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Corey S. Cutler, MD, MPH, FRCPC, discusses the toxicity profile of belumosudil in patients with chronic graft-versus-host disease.  



Dr. Cutler on the Toxicity Profile of Belumosudil in cGVHD 

Corey S. Cutler, MD, MPH, FRCPC, medical director, Adult Stem Cell Transplantation Program, director of Clinical Research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discusses ​the efficacy results of the ongoing phase 2 ROCKstar trial (NCT03640481) in patients with chronic graft-versus-host disease (cGVHD).

The ROCKstar study randomized patients with cGVHD who received at least 2 prior lines of systemic therapy to receive 200 mg of belumosudil (KD025), a ROCK2 inhibitor, once or twice daily. Findings from the study, which were presented virtually during the 47th Annual Meeting of the EBMT, demonstrated an overall response rate of 73% in the once daily arm and 77% in the twice weekly arm per the 2014 National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in cGVHD.

Additionally, complete responses (CRs) were observed in all affected organ systems, including the joints/fascia, lower and upper gastrointestinal tracts, mouth, esophagus, eyes, skin, liver, and lungs. Some organ systems responded more quickly or more completely compared with others, Cutler explains. For example, the 54% response rate observed in the mouth was comprised of CR and partial response (PR) rates of 43% and 11%, respectively. Conversely, the 67% response rate reported in the joints/fascia was comprised of CR and PR rates of 20% and 47%, respectively. Reversing fibrosis in the joints/fascia takes a long time and is often incomplete, which accounts for the low CR rate in this organ system, concludes Cutler. 

Corey S. Cutler, MD, MPH, FRCPC, discusses ​the efficacy results of the ongoing phase 2 ROCKstar trial in patients with chronic graft-versus-host disease.  



Dr. Cutler on the Efficacy Results of the ROCKstar Study in cGVHD

Corey S. Cutler, MD, MPH, FRCPC, medical director, Adult Stem Cell Transplantation Program, director of Clinical Research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discusses ​the results of the ROCKstar study in chronic graft-versus-host disease (cGVHD).

The open-label, randomized, multicenter, phase 2 ROCKstar study evaluated the efficacy of belumosudil (KD025)​, an investigational oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor, given at 200 mg once or twice daily in patients with cGVHD who received 2 to 5 prior lines of therapy.

Patients were stratified based on number of prior lines of therapy ​and number of ​involved organs, says Cutler. Notably, 67% of patients had severe cGVHD, ​and 52% ​of patients had 4 or more organs involved. ​Additionally, 72% ​of patients received ​at least 3 prior lines of therapy, and 73% were refractory to their last line of therapy.

At a median follow up of 8 months, the overall response rate (ORR) was 73% among patients who received 200 mg of belumosudil once daily and 74% in the patients who received 200 mg of belumosudil twice daily. In the 29% of patients who previously received ruxolitinib (Jakafi), the ORR​s with 200 mg of belumosudil once and twice daily were 65% and 72%​, respectively. Moreover, in the 35% of patients who previously received ibrutinib (Imbruvica), the ORR​s with 200 mg of belumosudil once and twice daily were 73% and 71%​, respectively.

Corey S. Cutler, MD, MPH, FRCPC, discusses ​the results of the ROCKstar study in chronic graft-versus-host disease. 

Dr. Cutler on the Results of the ROCKstar Study in cGVHD

Corey S. Cutler, MD, MPH, FRCPC, medical director, Adult Stem Cell Transplantation Program, director of Clinical Research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discusses remaining challenges in graft-versus-host disease (GVHD).

Early identification of patients with GVHD who are unlikely to respond well to corticosteroids remains a clinical need, says Cutler. Additionally, understanding which patients require augmented therapy up front compared with those who can receive de-escalated treatment require more study.

While biomarkers for chronic GVHD are less developed, biomarkers for acute GVHD (aGVHD) could aid in identifying these patients, explains Cutler.

The randomized phase 2 BMT CTN 1501 trial showed that single-agent sirolimus (Rapamune) is a viable option for patients with standard-risk aGVHD and is associated with reduced steroid exposure, greater immune suppression discontinuation, and improved quality of life compared with prednisone, concludes Cutler.

Corey S. Cutler, MD, MPH, FRCPC, discusses remaining challenges in graft-versus-host disease.

Dr. Cutler on Remaining Challenges in GVHD

Corey S. Cutler, MD, MPH, FRCPC, medical director of the Adult Stem Cell Transplantation Program; director of Clinical Research, Stem Cell Transplantation; director of the Stem Cell Transplantation Survivorship Program; and institute physician at Dana-Farber Cancer Institute; as well as an associate professor of medicine at Harvard Medical School, discusses some of the novel preventive strategies against graft-versus-host disease (GVHD).

A significant unmet need with regard to GVHD is prevention, says Cutler; however, ongoing research efforts are exploring novel preventive regimens. Specifically, investigators are developing ways to manipulate the stem cell graft, take out specific T-cell fractions, or modulate the graft to prevent GVHD, says Cutler.

Additionally, several post-transplant medical interventions are available. For example, the post-transplant cyclophosphamide regimen is growing in importance. Additionally, other immunosuppressive agents are available, such as abatacept (Orencia), which is a costimulatory blockade agent that can help prevent GVHD, concludes Cutler.

Corey S. Cutler, MD, MPH, FRCPC, discusses some of the novel preventive strategies against graft-versus-host disease.

Dr. Cutler on Novel Preventive Strategies Against GVHD

Corey S. Cutler, MD, MPH, FRCPC, medical director, Adult Stem Cell Transplantation Program, director of Clinical Research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discusses methods to optimize treatment for patients with acute and chronic graft-versus-host disease (GVHD).

Optimizing management of acute GVHD requires a lot of attention to supportive care measures that go along with the treatment of patients with severe acute GVHD, including bowel rest, total parenteral nutrition, or antibiotics for the prevention of infection, explains Cutler. Specialists in different departments can be consulted in the care of these patients. For example, colleagues working in dermatology or the burn unit can help with the management of patients with GVHD who are severely affected, and hepatology colleagues can help patients who have affected livers, suggests Cutler.

Patients with chronic GVHD have access to many more supportive care measures. Patients are offered local care of individually affected organs, such as topical care of the eye, mouth, skin, or the gastrointestinal tract, says Cutler. Addressing these local needs for chronic GVHD is just as important as the systemic therapies used to treat patients, concludes Cutler.

Corey S. Cutler, MD, MPH, FRCPC, discusses methods to optimize treatment for patients with acute and chronic graft-versus-host disease.

Dr. Cutler on Optimizing Treatment for Acute and Chronic GVHD

Corey S. Cutler, MD, MPH, FRCPC, medical director, Adult Stem Cell Transplantation Program, director of clinical research, Stem Cell Transplantation, director, Stem Cell Transplantation Survivorship Program, institute physician, Dana-Farber Cancer Institute, and associate professor of medicine, Harvard Medical School, discusses treatment options for patients with acute and chronic graft-versus-host disease (GVHD).

The standard treatment for patients who develop acute GVHD is corticosteroids. These drugs can induce a response rate of 50% to 75%, says Cutler.

In May 2019, the FDA approved ruxolitinib (Jakafi) for the treatment of adult and pediatric patients ≥12 years of age with steroid-refractory acute GVHD. The approval was based on data from the phase II REACH1 trial, in which ruxolitinib led to a 57% overall response rate (ORR). Other agents that may have utility after ruxolitinib are currently under investigation, explains Cutler.

Corticosteroids are the mainstay of treatment in chronic GVHD as well. However, 50% to 60% of patients with chronic GVHD become resistant to corticosteroids within the first year of therapy, says Cutler.

In those cases, ibrutinib (Imbruvica) can be considered. The BTK inhibitor was approved in August 2017 for the treatment of patients with chronic GVHD who progressed on ≥1 line of systemic therapy. The approval was based on data from the single-arm phase Ib/II PCYC-1129 trial, in which ibrutinib led to a 67% ORR.

There is no approved standard third-line therapy for patients with chronic GVHD, says Cutler. However, KD025, an experimental ROCK2 inhibitor, has shown encouraging data in this space. In the phase II ROCKstar trial (NCT03640481), KD025 led to a 64% ORR at a daily dose of 200mg in patients with chronic GVHD who received ≥2 prior systemic therapies.

Corey S. Cutler, MD, MPH, FRCPC, discusses treatment options for patients with acute and chronic graft-versus-host disease.



Corey S. Cutler, MD, MPH, FRCPC

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