In this issue of Blood, Zhao et al report excellent overall responses and acceptable safety of a first-in-class JAK/ROCK inhibitor in a prospective phase 1b/2a study in patients with glucocorticoid-refractory or -dependent chronic graft-versus-host disease (GVHD).1
Allogeneic stem cell transplantation (allo-SCT) is a curative treatment option for most malignant and nonmalignant hematological disorders. Chronic GVHD (cGVHD) affects approximately half of allogeneic hematopoietic cell transplant recipients and remains a major cause of morbidity and mortality despite significant improvements in prevention and treatment over the past decade.
The pathophysiology of cGVHD includes activation of T cells, B cells, and plasma cells; defective tolerance induction and immune regulation; and activation of macrophages, fibroblasts, and profibrotic factors.2 Clinical manifestations most often involve skin, eyes, oral mucosa, liver, musculoskeletal tissues, genital tract, lungs, hair, and nails but may involve almost any organ, mimicking autoimmune disease with variable severity graded according to National Institutes of Health criteria.3 Immunosuppressive systemic treatment is recommended for moderate or severe manifestations, with glucocorticoid remaining the mainstay of first-line therapy.4 With the US Food and Drug Administration approval of ibutinib,5 ruxolitinib,6 belumosudil,7 and axatilimab8 (see table), the available options for the treatment of patients who have failed one or more systemic therapies are increasing, and it has become clear to the pharmaceutical industry that GVHD is no longer the “place where drugs go to die.”
Despite these positive developments, the median failure-free survival of 18.6 months for second-line ruxolitinib and 12-month failure-free survival rates of 56% for belumosudil and 64% for axatilimab are still far from satisfactory. Novel therapies capable of preventing or reversing established cGVHD symptoms, reducing the patient’s symptom burden and thereby improving the overall outcome of allo-SCT, remain a priority.
Based on the known efficacy and safety of JAK inhibitors such as ruxolitinib and ROCK inhibitors such as belumosudil, dual JAK/ROCK inhibitors are currently being investigated in diseases associated with inflammation and fibrosis such as myelofibrosis (NCT04339400/NCT05020652), rheumatoid arthritis (NCT05374785), and cGVHD (NCT06682169) (https://clinicaltrials.gov).
Zhao et al are to be commended for conducting and reporting on this prospective study of a first-in-class JAK/ROCK inhibitor in patients with steroid-refractory or steroid-dependent cGVHD.
An obvious but relevant question is whether the combined JAK/ROCK inhibition improves efficacy without safety concerns compared with alternative treatment. The results are therefore best appreciated and interpreted in the context of the pivotal trials that led to the recent approvals (see table). Overall response rates of around 50% were reported in patients treated with the combination of ruxolitinib and belumosudil, and adverse events were consistent with those expected in patients with cGVHD receiving multiple lines of immunosuppression.9,10
The study population reported by Zhao et al included patients aged 12 years and older, similar to the REACH3 and ROCKstar trials, but other relevant patient characteristics such as steroid-refractory vs steroid-dependent cGVHD, lung involvement, or type and number of lines of prior therapies and definition of end points varied considerably between the studies (see table). This heterogeneity must be considered when attempting to make comparisons between studies and underlines the need for prospective randomized trials.
Responses with rovadicitinib were rapid, with a best overall response (BOR) rate of 86.4% until week 24, which translated to a failure-free survival of 85.2% at 12 months. Importantly, BOR was also high (77.8%) in patients with prior exposure to ruxolitinib. The relatively high reported incidence of Epstein-Barr viremia (36.36%) may not necessarily reflect overall immunosuppression, as cytomegalovirus and other viruses were not of similar concern. Although the COVID-19 pandemic may have contributed to the overall high incidence of pneumonia (25%), caution is still warranted, and future studies are needed to determine the impact of the dual JAK/ROCK inhibition on the risk of infection. Overall, rovadicitinib was well tolerated with only 4 adverse events (AEs) (9%) leading to discontinuation, none of which were considered drug related. As a result, patients could be treated for longer, allowing for late responses in otherwise vulnerable organs such as the lung, where the response rate increased from 6 of 26 (23%) before week 24 to 11 of 26 (42%) at 12 months. As in the pivotal studies, clinically meaningful improvements in the Lee cGVHD Symptom Scale were reported in the majority of patients. These results are encouraging and indicate that sustained treatment can improve lung function of a significant proportion of patients. This will require keeping these patients alive long enough with supportive care and combinations of targeted therapies that enable tissue regeneration without increasing the risk of debilitating and often fatal infections.
Building on our knowledge of the pathophysiology of cGVHD and recent successes, future research will lead to the development of even more novel targeted therapies. Increased efforts will need to be directed toward the use of these agents in earlier lines of treatment, preemptively or even included as prophylaxis of GVHD. As none of these agents have been shown to induce tolerance, their success in these earlier lines is uncertain. Attention will also need to be focused on how best to combine and sequence these therapies. In this regard, biomarkers that predict response to specific treatments or serve as surrogates for long-term outcomes will need to be incorporated into well-designed clinical trials.
Conflict-of-interest disclosures: F.A.A. declares honoraria from Celgene/BMS, Gilead, Janssen, Mallinckrodt/Therakos, Miltenyi Biomedicine, Takeda, Medac, Abbvie, and Novartis, and research funding from Mallinckrodt/Therakos.
