Recap: Earlier Detection May Be Key to Treatment Advances in Chronic GVHD


An expert in hematology/oncology, Dr Yi-Bin Chen, provides insight on chronic GvHD, with a focus on early detection of disease and therapeutic options for the management of steroid-refractory chronic GvHD.

Systemic management of chronic graft-versus-host disease (GVHD) can be an ongoing battle in patients with cancer, with the goals of approved treatments including improvement of quality of life.

In an OncViewTM conversation with CancerNetwork®, Yi-Bin Chen, MD, director of the Blood & Marrow Transplant Program at Massachusetts General Hospital, Cara J. Rogers Endowed Scholar, and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, discussed GVHD diagnosis and recent advances in treating the disease.

“The diagnosis of chronic graft-versus-host disease remains a wholly clinical diagnosis,” Chen explained. “There is no gold standard, [no] noninvasive blood tests or imaging. There are a lot of supportive tests that we can do depending on the organs involved, but it’s a clinical diagnosis.”

Once a patient receives a diagnosis, it needs to be determined if they are refractory to treatment with steroids, Chen explained.

“Identifying patients with steroid-refractory chronic GVHD can be challenging,” Chen said. “There’s a subset of patients [who] clearly don’t respond and there’s a subset of patients [who] get better. It’s the patients in the middle [for whom it’s] difficult to figure out if they’re truly steroid refractory or not.”

FDA-Approved Treatment Options

Chen discussed treatment options for chronic GVHD, focusing on 3 FDA-approved options: ibrutinib (Imbruvica), belumosudil (Rezurock), and ruxolitinib (Jakafi).1-3

“Our standard [of care] right now is ruxolitinib,” Chen explained. “It’s been that way even before approval because of how well tolerated ruxolitinib was and how well it was working. I would guess at least three-[fourths] of the patients I’ve started on ruxolitinib for chronic GVHD see a benefit.”

Chen revisited the 2017 approval of the oral Bruton tyrosine kinase inhibitor ibrutinib for patients with chronic GVHD who failed 1 or more prior lines of therapy. The single-center, phase PCYC-1129-CA 1b/2 study (NCT02195869) that supported the approval included 42 patients with chronic GVHD and produced a best overall response rate (ORR) of 69%, with 31% of patients with complete response (CR) and 38% with partial responses (PR), after a median follow-up of 26 months.4

“[The research] showed some durable responses and some complete responses. Complete response is an end point that we rarely [see achieved] in patients with GVHD, so it’s difficult to ignore those results,” Chen explained.

While emphasizing the presence of CRs in this research, Chen said to use caution when interpreting these results given that ibrutinib has been slightly less efficacious in the real-world setting.

“Given that this disease is a bit subjective and heterogeneous in how we judge response, one has to be somewhat skeptical,” Chen explained. “That‘s not to knock the trial, but it is a small trial without a control arm. Nevertheless, it was approved and became an option for our patients.”

Next, the ρ-associated coiled coil–containing kinase 2 inhibitor belumosudil received approval from the FDA for adult and pediatric patients 12 years and older with chronic GVHD after failure of at least 2 prior lines of therapy based on results of the phase 2 ROCKstar trial (NCT03640481).

In patients taking belumosudil once daily (n = 66), the ORR was 74%
(95% CI, 62%-84%) through the first day of cycle 7. Six percent of patients reached a CR and 68% had PRs.5

“The findings in the ROCKstar trial were impressive. [We saw higher than] 70% overall response rates, but again that was a trial where all patients were treated with [belumosudil], so it’s tough to know in a blinded control trial what that [response rate] would look like,” Chen explained.

Regarding ruxolitinib, Chen offered that care providers have been using it for steroid-refractory chronic GVHD because of prior efficacious experience, also stating that it’s a familiar agent due to use in myeloproliferative disease.

Ruxolitinib received FDA approval in 2021 for adult and pediatric patients 12 years and older with chronic GVHD after failure of 1 or 2 prior lines of systemic therapy. The approval is based on results from the multicenter, phase 3 REACH3 study (NCT03112603).6

REACH3 included 329 patients randomized to 10 mg of ruxolitinib twice daily (n = 165) or investigator’s choice of therapy (n = 164). The primary end point was ORR at 24 weeks, and a key secondary end point was failure-free survival.

ORR at 24 weeks was 49.7% for patients receiving ruxolitinib compared with 25.6% for the control group (odds ratio, 2.99; P < .001). Median failure-free survival in the ruxolitinib arm was more than 18.6 months compared with the control arm at 5.7 months (HR, 0.37; P < .001).

Common grade 3 or higher adverse effects included thrombocytopenia (15.2% vs 10.1%) and anemia (12.7% vs 7.6%) in the ruxolitinib and control groups, respectively.

“The data from REACH3, [although] not surprising, validate what we were doing in our clinical practice over the past few years. At this point, ruxolitinib is the standard for second-line therapy for chronic GVHD in patients for whom either steroids are not efficacious or who need to be spared exposure to some steroids because of certain comorbidities,” Chen said.

Unmet Needs and Future Investments

Chen emphasized that research in GVHD has come a long way over the past couple of decades. “We’ve managed to generate investment by industry and interest. We have 3 approved agents and hopefully more on the way with ongoing clinical trials that we…hope will ultimately improve outcomes,” he explained.

Regardless, Chen acknowledged that work remains to be done. Specifically, he cited the need for deeper and more durable responses in patients with chronic GVHD.

“Looking at the trials that got these agents approved, one can see that the majority of clinical responses are partial and not complete responses,” Chen said. “Partial responses can be life changing or partial responses can make no difference.”

Looking ahead, Chen was excited about the prospects of prevention and even preemptive treatment to ultimately improve outcomes for patients earlier.

“There are obvious needs in prevention and maybe even preemptive [care], meaning we should launch trials that focus on finding populations in real time that are at high risk of chronic GVHD after transplant with earlier intervention to prevent that fixed-organ damage,” Chen said. “I’m excited for the next 10 years because this will be a really active area of research that will help our patients going forward.”


  1. FDA expands ibrutinib indications to chronic GVHD. News release. FDA. August 2, 2017. Accessed March 23, 2022.
  2. FDA approves belumosudil for chronic graft-versus-host disease. News release. FDA. Updated February 1, 2022. Accessed March 23, 2022.
  3. FDA approves ruxolitinib for chronic graft-versus-host disease. News release. FDA. September 22, 2021. Accessed March 23, 2022.
  4. Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant. 2019;25(10):2002-2007. doi:10.1016/j.bbmt.2019.06.023
  5. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar study. Blood. 2021;138(22):2278-2289. doi:10.1182/blood.2021012021
  6. Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228-238. doi:10.1056/NEJMoa2033122
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