Steroid-refractory chronic graft-versus-host disease: treatment options and patient management

Abstract

Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.

Fig. 1. Biologic phases of c-GVHD with agents added targeting specific pathways (modified version derived from Cooke 2017 [24]).

CNI calcineurin inhibitors, cyclo. cyclophosphamide, ECP extracorporeal photopheresis, IL-2 interleukin-2, IL17 interleukin 17, imids immunomodulatory imide drugs, MMF mycophenolate mofetil, MSC mesenchymal stromal cells, mTOR-Inh. mechanistic target of rapamycin inhibitors, MTX methotrexate, PDGFα platelet-derived growth factor receptor alpha, TGFβ transforming growth factor β, TLR Toll-like receptor, TNFα tumor necrosis factor alpha, TNI total nodal irradiation. mTOR-Inh.: sirolimus, everolimus; imids: thalidomide, pomalidomide; proteosome inhibitors: bortezomib, ixazomib. It should be noted that listing of one target does not exclude additional targets in specific drugs (i.e. proteosome inhibitors target T cells, B cells, and plasma cells).