Advancements in cGVHD Yield New and Anticipated Treatment Options


Chronic graft-versus-host disease management has continued to advance in recent years, with new and anticipated treatment options for its treatment landscape.

Advancements in cGVHD Yield New and Anticipated Treatment Options

Advancements in cGVHD Yield New and Anticipated Treatment Options

Chronic graft-versus- host disease (cGVHD) management has advanced greatly in recent years. Not only have experts gained valuable insight into the pathophysiology of the disease, but new treatment modalities continue to be better understood, explained Daniel R. Couriel, MD, MS, in a presentation as part of the 2021 Society of Hematologic Oncology (SOHO) Annual Meeting.1

Couriel showed that there are options for patients with cGVHD through to the second line of therapy.

Frontline Therapy for cGVHD

Therapies for primary treatment of cGVHD have an average objective response rate of 50% which are achieved over 2 to 3 years of treatment. After 6 months of treatment, research shows <40% of patients are still alive, on lower doses of steroids, and do not require additional steroid of cGVHD therapy. This status of treatment in the field has come long way since the studies of historical agents, Couriel explained.

Multiple studies of historic agents used for the frontline treatment of cGVHD failed to show a survival benefit. Instead, these studies demonstrated decreased survival, limited benefit, unacceptable toxicity, or no benefit at all.

The most recent study highlighted during Couriel‘s presentation was the phase 3 BMT CTN 0801 clinical trial (NCT01106833) of sirolimus (Rapamune) plus prednisone with or without a calcineurin inhibitor. In 138 evaluable patients, the study showed that failure-free survival and overall survival were similar regardless of inclusion of a calcineurin inhibitor. There was all no difference in response rate between the 2 treatment arms, leading investigators of the study to conclude that the results were insufficient to warrant a randomized controlled trial, and the study was terminated early.

According to Couriel, BMT CTN 0801 and other studies of frontline treatment for cGVHD are no longer relevant because the agents are not widely used in the space. Further, if effective primary treatment does not bring patients into remission, there is opportunity to treat these patients in later-line settings.

Treating Steroid-Refractory Disease

Everyday treatment of steroid-refractory cGVHD can include off-label use of agents that are not FDA approved for the treatment of this patient population. This is because after failure on corticosteroids, agents like rituximab (Rituxan), mycophenolate mofetil, sirolimus, and others have shown the ability to induce high response rates in retrospective and prospective studies.

“Traditionally, we've used these treatments for steroid-refractory chronic GVHD. These modalities are not FDA approved, but we're still using them. For instance, in my case, especially Rituxan, and then the list continues with mTOR inhibitors, specifically sirolimus, more than everolimus [Afinitor] in the case of our patients. The overall response rate is around 60% to 70%, with the exception of modalities that seem to be on the lower end of the range, like imatinib,” Couriel stated during his presentation.

The challenge with these agents, according to Couriel, is that the study results are difficult to understand because the study designs are not always curated in a way that can translate to clinical practice. Further, oncologists select treatment based on experience, ease of use, need for monitoring, and risk of toxicity.

Treatment with rituximab is FDA approved for the treatment of steroid-refractory acute GVHD and was considered a potential option for steroid-refractory cGVHD following results from a phase1/2 study.2,3 In the study, 21 patients received 38 cycles of rituximab and the objective response rate achieved was 70%. Responses included 2 complete responses. In terms of toxicity, the treatment was well-tolerated. There were 9 grade 3/4 adverse events observed. AEs included infectious toxicity like hepatitis B reactivation in 1 patients and septic arthritis in a clinically uninvolved hip joint in 1 patient, infectious diarrhea in 3 patients, and viral conjunctivitis in 1 patient. Non-infectious AEs included gastrointestinal hemorrhage, nephrolithiasis with acute renal colic in, and acute infusion reaction to rituximab in 1 patient each.3

One agent is now making progress with the FDA for the potential treatment of steroid-refractory cGVHD; ruxolitinib (Jakafi). A new drug application for the agent was granted priority review by the FDA in February 2021 based on data from the phase 3 REACH-3 clinical trial (NCT03112603). Ruxolitinib led to a higher response rate of 49.7% compared with 25.6% in the best available therapy arm and showed a trend toward improvement in FFS. The FDA plans to make a decision on the potential approval at the end of September 2021.4,5

Further progress in the armamentarium of cGVHD has been shown with second-line therapies, explained Couriel.

Second-line Therapy for cGVHD

Based on findings from a multicenter, open-label, phase 2 study (PCYC-1129-CA; NCT02195869), ibrutinib (Imbruvica) was granted FDA approval for the treatment cGVHD after failure of first-line corticosteroid therapy and requiring additional therapy in 2017.6

Regarding the study, Couriel said: “It was well designed and included steroid refractory chronic GVHD patients, and the primary endpoint was response using the chronic GVHD response criteria. There was a documented 60 something response rate. This was in 28 patients, 9 of whom had complete remission, and 7 patients had stable disease.”

Of the 42 patients envaulted on oral ibrutinib 420 mg once daily, the 67% responded to therapy (95% CI, 51%-80%). Notably, 88% of the patient population had 2 organs involved at baseline. Responses were observed in all involved areas, which included the mouth, skin, gastrointestinal tract, and liver. The median time to response was 12.3 weeks (range, 4.1-42.1 weeks).

More than 20% of patients in the study experienced AEs. The most common AE observed with second-line ibrutinib in patients with cGVHD included fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia.

Since, 2017, 1 additional therapy was granted FDA approval for the second-line treatment f cGVHD which is belumosudil (Rezurock) for the treatment of adult and pediatric patients 12 years and older with cGVHD after failure of at least two prior lines of systemic therapy.

Approval was granted based on results from the ROCKstar study (NCT03640481) during which the ORR was assessed as the primary end point, and the key secondary end points evaluated were duration of response, change in Lee Symptom Scale Score, OS, FFS, and change in GVHD severity.

ROCKstar showed a 75% ORR with belumosudil (95% CI, 63%-85%). Response included CRs in 6% of patients and partial responses in 69%. The treatment was also determined to be well-tolerate and consistent with prior reports of the agent in patients with cGVHD.

Now that the treatment landscape for cGVHD appears to be well-populating with treatment options, Couriel explains that questions about sequencing linger.

“We still need to establish a more or less standard algorithm in terms of how we position them in in the middle of the traditional therapies. And the treatment choices are still based on physician experience, ease of use need for monitoring, risk of toxicity, and now with new agents’ cost. FDA-approved agents are 2 factors that I would include in the equation,” Couriel stated.

In the pipeline for cGVHD, JAK-1/JAK2 inhibition is very promising, Couriel stated, and oncologists await the FDA decision on whether to approve ruxolitinib for cGVHD indications.


  1. Couriel, DR. Chronic GVHD - New Therapies. Presented at: 2021 Society of Hematology Oncology Annual Meeting September 8-11, 2021; virtual.
  2. Carpenter PA, Logan BR, Lee SJ, et al. A phase II/III randomized, multicenter trial of prednisone/sirolimus versus prednisone/ sirolimus/calcineurin inhibitor for the treatment of chronic graft-versus-host disease: BMT CTN 0801. Haematologica.2018;103(11). Doi: 10.3324/haematol.2018.195123
  3. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2016;108(2):756-762. doi: 10.1182/blood-2006-01-0233
  4. Incyte announces acceptance and Priority Review of sNDA for Jakafi® (ruxolitinib) as a treatment for patients with chronic graft-versus-host disease, News release. Incyte. February 22, 2021. Accessed September 8, 2021.
  5. Incyte announces U.S. FDA has extended the sNDA review period for ruxolitinib (Jakafi®) in chronic graft-versus-host disease (GVHD). News release. Incyte. June 8, 2021. September 8, 2021.
  6. FDA expands ibrutinib indications to chronic GVHD. News release. FDA. August 2, 2017. Accessed September 8, 2021.
  7. US FDA grants full approval of REZUROCK (TM) (belumosudil) for the treatment of patients with chronic graft-versus-host disease (cGVHD). News release. Kadmon Holdings, Inc. July 16, 2021. Accessed September 8. 2021.
  8. 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. Blood. 2020;136(suppl 1). doi: 10.1182/blood.2021012021
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