BLOG: Therapeutic landscape for steroid-refractory chronic GVHD continues to evolve
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Chronic graft-versus-host disease continues to be a leading cause of late morbidity and mortality, complicating approximately 35% to 50% of allogeneic transplantations.
It results in significant impairment of patients’ quality of life and functionality.
Frontline therapy for moderate to severe chronic GVHD remains systemic corticosteroids at 1 mg/kg of prednisone equivalent. About 40% to 50% of patients respond adequately to steroids but more than 50% become steroid-resistant or -dependent, requiring second-line therapy.
Patients with steroid-refractory chronic GVHD have a very poor prognosis.
In the past 5 years, the FDA approved three drugs for steroid-refractory GVHD: ibrutinib (Imbruvica; Pharmacyclics, Janssen), belumosudil (Rezurock, Kadmon/Sanofi) and ruxolitinib (Jakafi, Incyte).
Ibrutinib
Ibrutinib irreversibly inhibits Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK). This results in impairment of B-cell survival and T-cell activation, which play crucial roles in the pathophysiology of chronic GVHD.
In August 2017, ibrutinib became the first FDA-approved drug for chronic GVHD. The agency based approval on results of a phase 1b/phase 2 multicenter single-arm study of 42 patients with steroid-refractory chronic GVHD who had received one to three prior lines of therapy.
Chronic GVHD response according to 2005 NIH consensus criteria served as the primary endpoint.
At median follow-up of 13.9 months, researchers reported best overall response of 67% (complete response, 21%; partial response, 45%), with multiorgan responses seen.
Among responding patients, investigators noted a reduction in corticosteroid dose.
Based on this trial, the FDA approved ibrutinib for adults with chronic GVHD after failure of at least one line of systemic therapy.
The phase 1/phase 2 iMAGINE study was a dose-finding, safety and efficacy study of ibrutinib that included 59 pediatric patients (median age, 13 years) with chronic GVHD.
Results showed plasma concentration-time profiles for ibrutinib 240 mg/m2 comparable to those observed among adults with chronic GVHD at a dose of 420 mg/day. At median follow-up of 20 months, researchers reported a 78% ORR, once again with multiorgan responses.
The findings of this study led to FDA approval of ibrutinib in August 2022 for pediatric patients with chronic GVHD, including a new oral suspension.
Belumosudil
Belumosudil is an oral first-in-class selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2).
It works by downregulation of signal transducer and activator of transcription 3 (STAT3), which reduces type 17 and follicular T helper cells and upregulates signal transducer and activator of transcription 5 (STAT5), which enhances regulatory T cells. This results in amelioration of chronic GVHD.
The FDA approved belumosudil based on the multicenter randomized phase 2 ROCKstar trial, which evaluated the agent at doses of 200 mg daily or 200 mg twice daily for 65 patients with chronic GVHD who had received two to five prior lines of therapy.
Best overall response served as the primary endpoint. Secondary endpoints included duration of response, change in Lee Symptom Score, failure-free survival, corticosteroid dose reductions and OS.
At median follow-up of 14 months, researchers reported best ORR of 74% for the once-daily dose and 77% for the twice-daily dose. Investigators observed responses in all affected organs.
Median time to response was 5 weeks. Median duration of response was 54 weeks, with 44% remaining on treatment for 1 year or longer.
Researchers observed responses among patients who had previously been treated with ruxolitinib and ibrutinib.
In July 2021, the FDA approved belumosudil for adults and children aged 12 years or older with chronic GHVD after failure of at least two prior lines of systemic therapy.
Ruxolitinib
Janus kinase 1 and 2 (JAK1/JAK2) signaling plays an important role in the steps leading to inflammation and tissue damage in acute and chronic GVHD.
Ruxolitinib is a JAK1/JAK2 inhibitor approved for the management of steroid-refractory acute or chronic GVHD.
The FDA based the approval — granted in February 2021 — on results of the randomized phase 3 REACH3 study, which included 329 patients with moderate to severe steroid-refractory chronic GVHD.
Researchers randomly assigned patients to ruxolitinib 10 mg twice daily or investigator’s choice of best available therapy (control group).
Overall response at 24 weeks served as the primary endpoint.
Results showed a significantly higher overall response at 24 weeks in the ruxolitinib group than the control group (49.7% vs. 25.6%), with higher overall responses seen in all involved organs in the ruxolitinib group.
In addition, treatment with ruxolitinib appeared associated with longer median failure-free survival (> 18.6 months vs. 5.7 months), significant symptom improvement (24.2% vs. 11%) and higher best overall response at any time up to week 24 (76.4% vs. 60.4%).
Future directions
Further studies are needed to determine the sequencing of these agents, the efficacy of combination therapy, and whether incorporating these agents in the upfront setting will further improve response rates and survival for adults and pediatric patients with chronic GVHD.
References:
- Carpenter PA, et al. Transplant Cell Ther. 2022;doi:10.1016/j.jtct.2022.08.021.
- Cutler C, et al Blood. 2021;doi:10.1182/blood.2021012021.
- Holtzman NG, et al. Br J Haematol. 2022;doi:10.1111/bjh.17835.
- Miklos D, et al. Blood. 2017;doi:10.1182/blood-2017-07-793786.
- Zeiser R, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2033122.
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