Chronic graft-versus-host disease (cGVHD) is one of most common, yet severe, consequences of allogeneic hematopoietic stem cell transplantation. Occurring in up to 70% of patients, cGVHD is the leading cause of non-relapse mortality after allogeneic transplantation. Two new agents, belumosudil (Rezurock, Kadmon Pharmaceuticals, LLC) and ruxolitinib (Jafaki), have demonstrated efficacy in treating patients with steroid-refractory chronic GVHD (cGVHD).
Belumosudil is an oral selective rho-associated coiled-coil containing protein kinase-2 (ROCK2) inhibitor. Inhibition of the ROCK2 pathway reduces multi-organ fibrosis, one of the major complications of cGVHD. Belumosudil was FDA-approved in July 2021 for use in adult and pediatric patients aged 12 years and older with cGVHD following failure of at least two prior lines of systemic therapy.
Approval of belumosudil was based on the phase 2
Key points to consider when prescribing and administering belumosudil:
- : belumosudil 200 mg orally daily
- : cGVHD after failure of at least two prior lines of systemic therapy
- : increase belumosudil to 200 mg orally twice daily with strong CYP3A inducers and/or proton pump inhibitors; no dose adjustments needed for strong 3A4 inhibitors
- infections, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, asthenia
- : C and AUC increase following administration with a high-fat and high-calorie meal
- : females of child-bearing age should be advised of risk to fetus and encouraged to use contraception
Another agent, ruxolitinib (Jafaki, Novartis), recently showed promise in the treatment of cGVHD. Approved in 2019 for acute GVHD (aGVHD) based on results from the REACH1 trial, ruxolitinib is a JAK1-JAK2 inhibitor, halting a pathway that leads to inflammation and fibrosis in both aGVHD and cGVHD. In the phase 3 REACH3 trial, patients with steroid-refractory or -dependent cGVHD showed significantly improved outcomes while on ruxolitinib compared to best available therapy (BAT). This phase 3 multicenter trial randomized 329 patients to ruxolitinib at 10 mg orally twice daily or BAT from a list of ten common options.
Approximately 42.9% of patients had moderate cGVHD, 56.5% had severe cGVHD, 71.4% had glucocorticoid-refractory disease, and 28.6% had glucocorticoid-dependent disease. The primary endpoint was overall response rate (ORR), defined as complete or partial response, at cycle 7, day 1. Secondary endpoints included change in the modified Lee cGVHD symptom scale score at cycle 7, day 1, rate of failure-free survival (FFS) until 36 months, best overall response (BOR), duration of response (DOR), and overall survival.
Results demonstrated substantial improvement after 24 weeks, with an ORR of 49.7% in the ruxolitinib group versus 25.6% (OR 2.99, p < 0.001) in the BAT group. Additionally, the BOR at week 24 was seen in 76.4% of patients in the ruxolitinib arm versus 60.4% in the BAT arm (95% CI, OR 2.17). Results in other key secondary endpoints, such as FFS, were also clinically improved in the ruxolitinib group. Ruxolitinib showed improved outcomes regardless of the individual organs that were affected at baseline. The safety profile seen in REACH3 was similar to adverse effects observed in prior clinical trials including thrombocytopenia, anemia, neutropenia, and pneumonia.
Key points to consider when prescribing and administering ruxolitinib:
- : aGVHD- Starting dose of 5 mg po BID for aGVHD, then increase to10 mg PO BID after at least 3 days of treatment if the ANC and platelet counts have not decreased by ≥ 50% relative to the first day of dosing 10 mg orally twice daily. cGVHD- Starting dose of 10 mg po BID.
- : cGVHD, aGVHD, myelofibrosis, polycythemia vera
- : Reduce Jakafi dosage with fluconazole doses less than or equal to 200 mg to starting doses of 5 mg po daily for aGVHD amd 5 mg po BID for cGVHD
- anemia, thrombocytopenia, infections
The results of REACH3 demonstrating the benefit of ruxolitinib in the treatment of steroid-refractory cGVHD coupled with the recent approval of belumosudil is encouraging and allows for hope in treating this serious, life-threatening complication for this delicate patient population. Overall, the extended treatment options for patients experiencing cGVHD demonstrate great promise. Many patients ultimately require additional lines of therapy for cGVHD, which makes later lines of therapy such as belumosudil and ruxolitinib critical to improving the clinical outcomes for these patients.