New and emerging therapies for acute and chronic graftversushost disease

Abstract

Graft versus host disease (GVHD) remains a major cause of morbidity and mortality following allogeneic hematopoietic stem-cell transplantation (HSCT). Despite the use of prophylactic GVHD regimens, a significant proportion of transplant recipients will develop acute or chronic GVHD following HSCT. Corticosteroids are standard first-line therapy, but are only effective in roughly half of all cases with ~50% of patients going on to develop steroidrefractory disease, which increases the risk of nonrelapse mortality. While progress has been made with improvements in survival outcomes over time, corticosteroids are associated with significant toxicities, and many currently available salvage therapies are associated with increased immunosuppression, infectious complications, and potential loss of the graft versus leukemia (GVL) effect. Thus, there is an unmet need for development of newer treatment strategies for both acute and chronic GVHD to improve long-term post-transplant outcomes and quality of life for HSCT recipients. Here, we provide a concise review of major emerging therapies currently being studied in the treatment of acute and chronic GVHD.

Clinical Use of Mesenchymal Stromal Cells in the Treatment of Acute Graft-versus-Host Disease

“…Calcineurin inhibitors (e.g., cyclosporine A, tacrolimus) and methotrexate are used in the majority of patients undergoing SCT as pharmacological GvHD prophylaxis [3]. In spite of prophylaxis, GvHD occurs and the first-line of treatment persists in the administration of corticosteroids [4]. Within a couple of days, 40–60% of the patients respond to treatment [4].…”

“…In spite of prophylaxis, GvHD occurs and the first-line of treatment persists in the administration of corticosteroids [4]. Within a couple of days, 40–60% of the patients respond to treatment [4]. Steroid-refractoriness is defined as a lack of response or progression after 3–7 days of systemic corticosteroid therapy.…”

“…Steroid-refractoriness is defined as a lack of response or progression after 3–7 days of systemic corticosteroid therapy. The long-term prognosis of steroid-refractory GvHD is poor, with an OS rate less than 30% at 1 year, attrition being due either to GvHD directly, or to sequelae of the aggressive immunosuppression to control GvHD, such as latent virus reactivation, sepsis, or relapse [2, 4, 5]. To date, there is no standard approach practiced as second-line therapy.…”

“…The development of superior treatment strategies is crucial for survival improvement following allo-SCT. A variety of agents are currently used in steroid-resistant GvHD, e.g., mycophenolate mofetil (MMF), mammalian target of rapamycin (mTOR) inhibitor (Sirolimus), JAK inhibitors, proteasome inhibitors, and monoclonal antibodies [4]. A promising alternative to immunosuppressants is mesenchymal stromal cell (MSC) infusion in corticosteroid-resistant GvHD.…”

Extracorporeal Photopheresis (ECP) and the Potential of Novel Biomarkers in Optimizing Management of Acute and Chronic Graft vs. Host Disease (GvHD)

“…Chronic GvHD is reported to affect 30-40% of patients receiving allogeneic HSCT (10). The pathophysiology of cGvHD comprises of complex pathways involving both T and B cells, the mechanisms of which are yet to be fully understood (11). The myriad clinical manifestations of cGvHD can make diagnosis and monitoring response to treatment challenging.…”