Mechanistic approaches for the prevention and treatment of chronic GVHD

Abstract

Clinical outcomes for patients undergoing allogeneic hematopoietic stem cell transplantation continue to improve, but chronic graft-versus-host disease (GVHD) remains a common toxicity and major cause of nonrelapse morbidity and mortality. Treatment of chronic GVHD has previously relied primarily on corticosteroids and other broadly immune suppressive agents. However, conventional immune suppressive agents have limited clinical efficacy in chronic GVHD, and prolonged immune suppressive treatments result in additional toxicities that further limit clinical recovery from transplant and return to normal daily function. Recent advances in our understanding of the immune pathology of chronic GVHD offer the possibility that new therapeutic approaches can be directed in more precise ways to target specific immunologic mechanisms and pathways. In this review, we briefly summarize current standard treatment options and present new therapeutic approaches that are supported by preclinical studies and early-phase clinical trials suggesting that these approaches may have clinical utility for treatment or prevention of chronic GVHD. Further evaluation of these new therapeutic options in well-designed prospective multicenter trials are needed to identify the most effective new agents and improve outcomes for patients with chronic GVHD.

Introduction to a review series on chronic GVHD: from pathogenic B-cell receptor signaling to novel therapeutic targets

“…2 These findings are consistent with the central role of autoreactive B cells for cGVHD maintenance, forming the basis for phase 3 testing that is currently underway.…”

“…In this review series, leading authors in the field present and discuss novel findings in basic T-and B-cell biology research that have led to novel therapeutic targets in cGVHD, 1 mechanistic approaches for prevention and treatment of cGVHD, 2 and a summary of the National Institutes of Health (NIH) Consensus Development Projects on Criteria for Clinical Trials in cGVHD; they then put these concepts into the clinical context. 3 The articles in this review series, "Chronic graft-versus-host disease," include the following:…”

“…Articles in this review series explore the biology of B cells that produce antibodies to polymorphic recipient antigens or nonpolymorphic antigens common to both recipient and donor. 1,2 Of the different antigens recognized by B cells, H-Y antigens were found in male recipients of female hematopoietic cells. 4 Control mechanisms that counteract abnormal B-cell activation, such as interleukin-10 (IL-10)-producing regulatory B cells, 5 appear to be impaired under conditions of cGVHD.…”

“…Consistently, murine cGVHD and human cGVHD responded to JAK1/2 inhibition by ruxolitinib. 14 Besides these approaches, multiple mechanistic interventions for cGVHD are summarized in elegant fashion in the review by Cutler et al 2 These approaches include stem cell graft engineering, inhibition of T-cell signaling, regulatory T cell (Treg)-related therapies (Treg sparing, Treg transfer, and in vivo Treg expansion), and depletion or inhibition of B cells. 2 The authors highlight studies focused on in vivo Treg expansion showing that low-dose IL-2 increases Treg numbers in patients with cGVHD, which opens a new therapeutic option besides adoptive Treg transfer.…”

Developing role of B cells in the pathogenesis and treatment of chronic GVHD

“…Compared with B‐cell signalling, inhibiting IKT on T cells is less effective. Previous research showed that blocking IKT leads to CD8 + T cell‐mediated GVL effects, but extensive inhibition of T‐cell activation prevents both GVHD and GVL effects (Cutler et al , ). A phase 2 study with ibrutinib in steroid refractory cGVHD has reported encouraging results, with a 67% overall response rate and a 71% sustained response rate >20 weeks using a daily dose of 420 mg. After a 13.9‐month follow‐up, 75% of responders had corticosteroid doses <0.15 mg/kg/day, and the median patient‐assessed overall cGVHD score decreased, from 7 ( n = 42) to 4 ( n = 14), at week 49.…”