ABSTRACT
Introduction
Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is the main cause of late non-relapse mortality (NRM). Three new agents are now approved to treat cGVHD, of which belumosudil has a unique and dual mechanism of action of i) targeting the Rho-GTPase-associated coiled-coil kinase 2 (ROCK2) in T helper follicular cells (TFH) and TH17 cells, this results in downregulation of proinflammatory cytokines (interleukin −21 and 17), the former in a STAT3-dependent mechanism, ii) inhibition of tissue fibrosis by targeting stress-induced polymerization of G-actin fibrils by inhibiting the Rho-ROCK-MRTF pathway.
Areas covered
In this review we describe the epidemiology of cGVHD, its cardinal symptoms, preventive and therapeutic options, including second-line approved therapies in the United States (US). Clinical trial data that led to approval of belumosudil is discussed, in addition to the clinical scenarios in which the approved drugs may be most applicable.
Expert opinion
Belumosudil is approved for treatment of adult and pediatric patients ≥ 12 years with cGVHD after failing two lines of therapy based on results of the ROCKstar study that showed high overall response rates (ORR), favorable adverse effect profiles, and low rates of severe infections. With the availability of three new agents for treatment of cGVHD, treating physicians have more therapeutic options for patients and have additional options of development new clinical trials using a combination of recently approved drugs.
KEYWORDS:
Article highlights
The incidence of cGVHD remains high in survivors of HCT highlighting the limitations of current prophylactic strategies in patients undergoing allo-HCT. We discuss the pathophysiology of development of cGVHD in allo-HCT patients.
The Rho-GTPase pathway is critical for T cell receptor (TCR) signaling and activation of this pathway leads to downstream phosphorylation events mediated by ROCK1/2 kinases followed by secretion of proinflammatory cytokines secreted by TFH (IL-21) and TH17 (IL-17) cells.
Pharmacologic inhibition of the ROCK2 pathway results in a decrease in STAT3 phosphorylation in TFH cells and reduction of proinflammatory cytokine IL-21. ROCK2 inhibition also decreases stress fiber formation which is useful in treating sclerotic manifestations of cGVHD.
Belumosudil was studied in a phase 2a, dose-finding, open-label study (NCT028411995) based on preclinical activity showing inhibition of ROCK2. Clinical efficacy and safety were noted at all three dose levels studied. In the pivotal phase 2 ROCKstar multicenter study (NCT03640481), the ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% and 77%, respectively, with a median duration of response of 52 weeks. Based on this promising activity in a heavily pretreated patient population with multiorgan involvement, it is now approved for use in cGVHD.
Declaration of interest
A Salhotra Received research funding from Bristol-Myers Squibb and Jazz pharmaceuticals. On advisory board of Kadmon, Syros Pharma, ATARA biotherapeutics and Jazz. R Nakamura declares: advisory board: Merck, Magenta therapeutics, Kadmon Napajen pharma; consultancy: Viracor. H Ali declares: research support and advisory board of Incyte. B Modi is a consultant for Kadmon Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Kadmon provided a scientific accuracy review at the request of the journal editor.