In the past 10 years, perhaps no greater advance has been made in hematopoietic stem cell transplantation (HSCT) than in the prevention and therapy of chronic graft-versus-host disease (cGVHD). Chronic GVHD, the clinical syndrome of donor-mediated rejection of host tissues following both matched and mismatched allogeneic transplantation, historically occurred in 30-50% of HSCT recipients. Chronic GVHD remains the major cause of long-term morbidity and mortality following transplantation and is responsible for serious reductions in quality-of-life among long-term HSCT survivors.
Therapy of chronic graft-versus-host disease (cGVHD) traditionally relied heavily on systemic corticosteroids for newly diagnosed patients requiring systemic therapy, followed by older immunosuppressive agents used around the time of transplantation, such as tacrolimus, sirolimus, or mycophenolate mofetil. However, three novel agents have now been approved in the management of cGVHD, all of which appear to be active and associated with quality-of-life benefits in the management of cGVHD. Ibrutinib, a BTK inhibitor, was the first agent approved for the management of steroid-refractory cGVHD in 2017. In an open label, phase II trial in patients with inflammatory manifestations of cGVHD, a response rate of nearly 70% was noted. The drug is reasonably well tolerated, although diarrhea, fatigue, and the risk of cardiac conduction abnormalities are the prominent side effects of this compound. Belumosudil, a novel ROCK2 inhibitor developed specifically for the treatment of advanced GVHD, was the second compound approved in 2021 based on the ROCKstar study, which demonstrated a response rate between 74-77% in patients dosed once or twice daily, respectively. Belumosudil is approved for patients who have failed two or more prior lines of therapy, is extremely well tolerated, and is being tested in the initial management of cGVHD in an ongoing randomized, placebo-controlled study. Finally, ruxolitinib, a JAK2 inhibitor previously approved for the management of steroid-refractory acute GVHD, was approved in late 2021 based on the randomized REACH3 trial, which demonstrated a significant improvement in the cGVHD response rate 24 weeks after randomization, in comparison to investigator-chosen best supportive care. The important toxicities include cytopenias and an increased risk of some infections. Looking ahead, axatilimab, a monoclonal antibody directed against the CSF1 receptor found on monocyte/macrophage lineage cells, is likely to become the fourth approved agent for the management of cGVHD. In a plenary presentation of the AGAVE-201 trial presented at the American Society of Hematology (ASH) Annual Meeting in 2023, axatilimab demonstrated impressive response and low toxicity rates when given at a dose of 0.3 mg/kg every two weeks.
While advances in therapy of advanced disease is critical, prevention of chronic graft-versus-host disease (cGVHD) might be even more important. Here, a novel strategy of GVHD prevention using modest doses of cyclophosphamide following transplantation to control the expansion of alloreactive T cells following hematopoietic stem cell transplantation (HSCT) has been developed. This post-transplantation cyclophosphamide (PTCy) regimen has now been widely instituted in several settings. In the haploidentical setting, the development of PTCy has spurred the massive expansion of haploidentical stem cell transplantation, making HSCT a feasible approach for individuals (and in particular ethnic minorities) who do not have suitable donors in the unrelated donor registries. In the matched related and unrelated donor settings, the use of PTCy was noted to be significantly better than the traditional combination of tacrolimus and methotrexate in the reduced-intensity setting in the BMT CTN 1703 trial and has now become the standard of care (Figure). Other strategies to reduce the risk of cGVHD that are currently being evaluated include the use of the costimulation blockade agent, abatacept, sophisticated graft manipulation strategies, and prophylactic B cell depletion, a strategy most recently demonstrated to be effective in a randomized trial performed at Dana-Farber.
