New Approvals Help Fill Unmet Need in Treating Chronic GVHD

Oncology Live®Vol. 23/No. 14
Volume 23
Issue 14

A panel of hematology experts discuss use of steroids in the first-line setting as well as several subsequent-line treatments that have recently received FDA approval for patients with steroid-refractory chronic GVHD, which affects up to 50% of patients.

Yi-Bin Chen, MD

Yi-Bin Chen, MD

Despite significant advances in donor selection, conditioning regimens, and supportive care, graft-vs-host disease (GVHD) continues to afflict 30% to 50% of patients who undergo allogeneic hematopoietic cell transplantation (AHCT).1

GVHD occurs when immunocompetent T lymphocytes in the graft attack immunodeficient tissues of the AHCT recipient within 100 days of transplantation because of histocompatibility differences, leading to tissue damage and significant transplant- related morbidity and mortality.1,2

There is a significant unmet need in effectively treating chronic GVHD. “Unfortunately, when we see patients with chronic GVHD in the clinic, we still are treating them with steroids in the first line, just like in the acute setting.…That treatment strategy hasn’t changed in a couple of decades,” Yi-Bin Chen, MD, said during a recent OncLive Peer Exchange®.

Chen was joined by a panel of hematology experts who discussed use of steroids in the first-line setting as well as several subsequent-line treatments that have recently received FDA approval for patients with steroid-refractory chronic GVHD, which affects up to 50% of patients.3 They provided an overview of the clinical trial data that led to these agents’ approval and shared how they sequence these agents at their institutions.

Steroids for First-Line Treatment of Chronic GVHD

The initial choice for treating chronic GVHD is a systemic steroid, frequently prednisone, administered at a dose between 0.5 and 1 mg/ kg daily. This can be difficult on patients, Chen said. “Some [patients] have been on steroids in the past for acute GVHD and adding steroids again at that juncture often creates a lot of morbidity...which can present as anything from infections to changes in bone health, hypertension, mood swings, and so forth,” he explained. Subsequently, there has been a push to improve steroid administration and identify alternative treatment options for patients with chronic GVHD.

One area of research involves using GVHD biomarkers to identify high-risk patients for intervention before they become symptomatic. “We need to do the same approach as we have done for acute GVHD, to get the response to treatment and get the samples after you start a treatment,” Sophie Paczesny, MD, PhD, said. The panelists noted that several ongoing studies are seeking to identify predictive biomarkers and encouraged clinicians to commit any available samples from patients to such research. GVHD is a heterogeneous disease affecting a wide range of organ systems; a broad range of biomarkers is likely to have prognostic, diagnostic, or predictive value. Another important issue the panelists discussed is knowing when to initiate a secondline therapy. Nelson J. Chao, MD, said clinical f indings are sometimes not obvious or particularly remarkable; quality of life and performance status are key components of knowing when additional treatment is necessary. “Usually, the patient will tell you…they’re probably the best markers,” Chao said. Nevertheless, tools are available to help identify early symptoms, such as the National Institutes of Health consensus criteria measurements and the modified Lee Symptom Scale.4,5

Newly Approved Treatments for Steroid-Refractory Chronic GVHD

Since 2017, 3 agents have received FDA approval to treat chronic GVHD, including ruxolitinib (Jakafi), belumosudil (Rezurock), and ibrutinib (Imbruvica), each of which has a unique mechanism of action and drug profile (Table).6-11

Table. Overview of Most Recent FDA-Approved Treatments for Steroid-Refractory Chronic GVHD6-11

Table. Overview of Most Recent FDA-Approved Treatments for Steroid-Refractory Chronic GVHD6-11


Ruxolitinib is a JAK inhibitor that selectively inhibits JAK1 and JAK2, mediating the signaling of the JAK-STAT pathways that play a role in regulating the development, proliferation, and activation of several immune cell types important for GVHD pathogenesis (eg, inflammatory cytokines).9 The approval of ruxolitinib was based on data from the phase 3, open-label REACH3 trial (NCT03112603), which randomly assigned 329 patients aged at least 12 years with moderate or severe glucocorticoid-refractory or glucocorticoid-dependent chronic GVHD 1:1 to receive ruxolitinib 10 mg twice daily (n = 165) or best available therapy (BAT; n = 164).12

“BAT in this case was an investigator’s choice of 10 commonly used immunosuppressive or chronic GVHD therapies, which for the most part was ECP [extracorporeal photopheresis], mycophenolate, and ibrutinib, but also included infliximab [Remicade], pentostatin [Nipent], and others,” Hannah Choe, MD, said. She noted that the patients in the trial were not heavily pretreated. “Most of the patients had only received corticosteroids or calcineurin inhibition. Only roughly 14% to 15% had received an additional systemic therapy on top of that,” she said.

At week 24, the overall response rate (ORR) was 49.7% in the ruxolitinib arm and 25.6% in the BAT arm (odds ratio [OR], 2.99; P < .001).12 Most responses were partial responses (PRs); however, 11 patients (6.7%) in the ruxolitinib arm had a complete response (CR) vs 5 (3.0%) patients in the BAT arm. A higher ORR was observed with ruxolitinib than BAT regardless of the organs involved. Ruxolitinib vs BAT led to a median failure-free survival (FFS) of 18.6 and 5.7 months, respectively (HR, 0.37; P < .001), and a higher symptom response rate of 24.2% vs 11.0%, respectively (OR, 2.62; P = .001). “It was the first big step for chronic GVHD to finally get phase 3–level support for FDA approval,” Choe said. Based on the REACH-3 data, Chen said ruxolitinib has become the standard second-line treatment at his institution for patients with chronic GVHD.

More recent reports have shown additional benefits with ruxolitinib. Data from a presentation at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition in 2021 showed that ruxolitinib resulted in substantial improvements in patient-reported outcomes vs BAT. Categories included continued symptom improvement and benefits across chronic GVHD–specific modified Lee symptom subscales.13 Additionally, patients reported greater improvements in organ-specific symptoms with ruxolitinib, a finding consistent with physician-assessed objective organ responses, which also favored ruxolitinib. More recent reports have shown additional benefits with ruxolitinib.

Unlike belumosudil and ibrutinib, ruxolitinib has also been approved by the FDA for the treatment of steroid-refractory acute GVHD.9 A presentation at the European Hematology Association 2021 Virtual Congress reported high response rates with ruxolitinib among the patients with steroid-refractory acute GVHD in the REACH2 trial (NCT02913261) who crossed over from BAT to ruxolitinib (n = 49/309).14 At day 28 after crossover, ORR was 67.3% (95% CI, 52.5%-80.1%), with 23 (46.9%) CRs and 10 (20.4%) PRs. At day 56 after crossover, durable ORR was 42.9% (95% CI, 28.8%57.8%), with 19 (38.8%) CRs and 2 (4.1%) PRs. These findings were consistent with observations in the ruxolitinib arm at the primary analysis. Collectively, these data in combination with the REACH3 data in patients with chronic GVHD lend support for using ruxolitinib in patients with steroid-refractory GVHD who previously failed treatment with other systemic therapies.


Belumosudil stems profibrotic activity by inhibiting ROCK2—rho-associated, coiled-coil containing protein kinase 2—thereby controlling inflammatory T helper 17 (Th17) cells while enhancing regulatory T cells. Because of its mechanism of action, belumosudil is expected to control chronic GVHD without significantly increasing immunosuppression.15

Belumosudil was approved based on data from the phase 2 ROCKstar study (NCT03640481). This open-label, dose-ranging trial included 66 patients with chronic GVHD treated with belumosudil 200 mg once daily, which became the FDA-approved dose, and 66 patients treated with 200 mg twice daily.15 “The study was well designed but it wasn’t a randomized trial. The investigators didn’t feel it could be randomized because these patients had failed at least 2 different lines of therapy,” Chao said.

ROCKstar’s primary end point was best ORR, which was 74% for belumosudil 200 mg daily (95% CI, 62%-84%) and 77% for belumosudil 200 mg twice daily (95% CI, 65%-87%), with high response rates observed in all subgroups. The median duration of response was 54 weeks, with 44% of patients on therapy for at least 1 year. Symptom reduction was reported in 59% of patients treated with the once-daily dose vs 62% of those treated with the twice-daily dose.

“What was most interesting to me was the toxicity profile, which was quite impressive. It was well tolerated. As with ibrutinib, we must see what it’s going to look like in the real world as [patients] start to use it,” Chao said.

In ROCKstar, the median relative dose intensity (RDI), used as a surrogate measure of drug tolerability, was 99.7%, with 81% of patients receiving an RDI greater than 95%. RDI was defined as actual dose intensity/planned dose intensity, with dose intensity being the cumulative dose/duration of exposure (mg/d).

Although the 200-mg twice-daily dose was associated with higher responses in certain organs, including the skin, and slightly fewer adverse effects (AEs), the difference in safety and efficacy was not deemed significant. Subsequently, the lower dose of 200 mg once daily was chosen as the recommended dosage.

In a presentation at the 63rd ASH Annual Meeting and Exposition, treatment with belumosudil resulted in high FFS rates vs historic benchmarks in chronic GVHD after failure of 1 to 3 lines of systemic therapy.16 The median FFS for all doses was 14 months. Among patients who received the recommended 200-mg belumosudil dose once daily, the Kaplan-Meier estimate of FFS was 75% at 6 months (95% CI, 64%-83%), 56% at 12 months (95% CI, 45%-66%), and 37% at 24 months (95% CI, 23%-52%).


Ibrutinib inhibits inducible T-cell kinase (ITK) and Bruton tyrosine kinase (BTK). “Basically, ITK is on the T cell and BTK is on the B cell,” Paczesny said.

Approval of ibrutinib as a treatment for chronic GVHD was based on the phase 1b/2 PCYC1129-CA study (NCT02195869), an open-label, multicenter, single-arm clinical trial enrolling 42 patients with chronic GVHD who required additional therapy after failure of first-line corticosteroid therapy.17 “[Ibrutinib] was the first FDA approval based on a small clinical trial, with some efficacy in the second line. That was the first improvement in the first FDA-approved drug in the field, even before acute GVHD,” Paczesny said.

All patients in PCYC-1129-CA were treated with ibrutinib 420 mg daily until GVHD progression. The primary end point was chronic GVHD response based on the 2005 National Institutes of Health criteria.

After a median follow-up of 13.9 months, the best overall response was 67%. Among responders, 71% had a sustained response lasting at least 20 weeks. All organs assessed showed response, and most patients with chronic GVHD affecting multiple organs showed multiorgan response. At week 49, the median corticosteroid dose in responders decreased from 0.29 mg/kg daily at baseline to 0.12 mg/kg daily, with 5 responders discontinuing corticosteroids.

“[Ibrutinib is] maybe a little more difficult to give, and there’s some toxicity, so it seems that ruxolitinib is better tolerated and [individuals] will go more often to ruxolitinib rather than ibrutinib. In pediatrics, ibrutinib is still used and can help some patients,” Paczesny said.

In 2019, the 1-year update of PCYC-1129-CA was published, reaffirming the clinically meaningful benefit of ibrutinib and its acceptable safety profile.18 At a median follow-up of 26 months, the best ORR was 69% (29 of 42 patients), with 31% (n = 13) achieving a CR and 38% (n = 16) achieving a PR. Sustained responses were seen in 69% of patients (n = 20) for at least 20 weeks, 62% (n = 18) for at least 32 weeks, and in 55% (n = 16) for at least 44 weeks. Among the patients with multiorgan involvement, 73% (19 of 26) with at least 2 organs affected showed responses in 2 or more organs and 60% (6 of 10) with 3 or more organs affected showed responses in at least 3 organs. Additionally, 61% (11 of 18) of patients with sclerosis at baseline showed a sclerotic response, 39% with a CR and 22% with a PR. Reductions in corticosteroid dose to less than 0.15 mg/kg daily were observed in 64% of all study patients (N = 42), with 8 discontinuing corticosteroid treatment and remaining off corticosteroids at study closure.

Sequencing Treatment for Steroid-Refractory GVHD

“We’ve been excited about the fact that we have ruxolitinib and belumosudil as options for patients. They have decently durable responses and give patients an improvement in quality of life,” Choe said. She noted that belumosudil’s favorable response rate even in patients who experienced treatment failure with ruxolitinib is encouraging; the expectation has been that failure of one therapy usually leads to a lower response rate with subsequent treatments.

“In this case, we can give ruxolitinib first. We have more experience with it because it’s been used off-label for much longer. Then we can transition to belumosudil in case of failure or intolerance [and] can still potentially get another year of response with belumosudil with a response rate of 68%. It’s nice to have that in our armamentarium for these patients,” she said.

Chen and Chao agreed with this approach; however, Chao said in patients with skin involvement, his institution (Duke Cancer Institute) primarily uses ECP. In contrast, Choe said her institution (The Ohio State University Comprehensive Cancer Center) places belumosudil before ECP. She also emphasized the importance of considering the AE profile when selecting between the FDA-approved agents. “Ruxolitinib and belumosudil are very well tolerated, but the cytopenias with ruxolitinib can be difficult,” she said.

Subsequently, if she is concerned about cytopenias in patients, she will select belumosudil over ruxolitinib.

The panelists said they are eagerly anticipating real-world data to help guide treatment decision-making, including optimal treatment sequencing, use of combination treatments, and how and when to taper patients off treatments. “Not only do we not know how long we use these agents for—it’s usually guided by how our patients are doing—but when we transition, we also don’t know whether to stop or decrease. If we’re tapering, we don’t know how long to taper. Hopefully real-world experience will shed some more light on it,” Chen said.


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  10. Rezurock. Prescribing information. Kadmon Pharmaceuticals; 2021. Accessed June 14, 2022.
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