Updates in chronic graft-versus-host disease: novel treatments and best practices in the current era

Abstract

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic hematopoietic cell transplant. The development of cGVHD involves a complex, multistep process that is characterized by early inflammation and tissue injury, followed by chronic inflammation, aberrant tissue repair, and fibrosis. Systemic corticosteroids remain the first line of treatment for cGVHD. New treatments for patients with cGVHD for whom treatment has failed or who develop steroid-dependent cGVHD are now available; these include ibrutinib, ruxolitinib, and belumosudil. Treatment selection may be based on the patient's individual needs, graft-versus-host disease organ involvement, and comorbidities. However, as therapeutic options for patients without a treatment response or with only a partial response remain an unmet need, new agents are under investigation. Furthermore, patients with cGVHD can develop multiorgan involvement and frequently require specialized care. A multidisciplinary team approach that focuses on the individual's needs and quality of life is strongly encouraged.

Fig. 1:. Pathophysiology of chronic graft-versus-host disease.

Chronic GVHD involves 3 phases: early inflammation and tissue injury, chronic inflammation and dysregulated immunity, and fibrosis and improper repair. α-SMA alpha smooth muscle actin, Ag antigen, Allo allogeneic, APC antigen-presenting cell, BAFF B-cell activating factor, BCR B-cell receptor, CTGF connective tissue growth factor, DAMP damage-associated molecular pattern, HCT hematopoietic cell transplant, PAMP pathogen-associated molecular pattern, PDGF platelet-derived growth factor, PDGFR-α platelet-derived growth factor receptor alpha, Tfh T follicular helper, TGF-β tumor growth factor beta, Th T helper.

Fig. 2:. Mechanism of action of ibrutinib, ruxolitinib, and belumosudil in chronic graft-versus-host disease.

Ibrutinib inhibits Bruton tyrosine kinase–dependent and immune thrombocytopenia–dependent processes. Ruxolitinib inhibits Janusassociated kinase 1/2–dependent processes. Belumosudil inhibits the rho-associated coiled-coil–containing protein kinase 2–dependent pathway. α-SMA alpha smooth muscle actin, Ag antigen, APC antigen-presenting cell, BCR B-cell receptor, BEL belumosudil, BLNK B-cell linker protein, BTK Bruton tyrosine kinase, cGVHD chronic graft-versus-host disease, CTGF connective tissue growth factor, FDA Federal Drug Administration, GDP guanosine diphosphate, GEF guaninine nucleotide exchange factor, GTP guanosine triphosphate, IBR ibrutinib, ITK interleukin-2–inducible T-cell kinase, ITP immune thrombocytopenia, JAK Janus-associated kinase, LAT linker for the activation of T-cells, LcK lymphocyte-specific protein tyrosine kinase, LYN Lck/Yes novel tyrosine kinase, MRTF myocardin-related transcription factor, PDGFR-α platelet-derived growth factor receptor alpha, PLC phospholipase C, ROCK2 rhoassociated coiled-coil–containing protein kinase 2, RUX ruxolitinib, SLP-76 SH2-domain–containing leukocyte protein of 76kDa, STAT signal transducer and activator of transcription, SYK spleen tyrosine kinase, TCR T-cell receptor, Tfh T follicular helper, TGF-β tumor growth factor beta, Th17 T helper cell 17, Treg cell T regulatory cell, ZAP-70 zeta-chain–associated protein kinase 70.