New age GVHD prophylaxis regimens: what works for what donor and why

Allogeneic hematopoietic stem-cell transplantation is a curative modality for hematologic malignancies, bone marrow failure syndromes, hemoglobinopathies, and other nonmalignant disorders. Graft-versus-host disease (GVHD)-in its acute or chronic form-is an important transplant complication. The effective prevention of GVHD is crucial to the success of allotransplantation. Acute GVHD is mediated by the recognition of recipient antigens by donor T lymphocytes, with the subsequent activation and proliferation of T cells and establishment of an inflammatory cytokine cascade. Chronic GVHD is mediated by T-cell, B-cell, and macrophage activation with eventual inflammation and fibrosis. Standard approaches for GVHD prevention have been calcineurin-inhibitor (CNI) based, while newer approaches have focused on adding in-vivo T-cell modulation to a CNI backbone with antimetabolites such as posttransplant cyclophosphamide (PTCy), checkpoint blocking agents such as abatacept, or mammalian target of rapamycin (mTOR) inhibition with sirolimus. Still other approaches focus on blocking T-cell trafficking to target organs via integrin blockade (vedolizumab), cytokine blockade (JAK inhibitors), and B-cell blockade for chronic GVHD prevention. The use of PTCy and abatacept have improved allotransplantation safety and efficacy with human leukocyte antigen (HLA)-mismatched as well as HLA-matched donors, thus expanding the donor pool greatly for patients of all ancestries, and ushering in a new era in transplantation where donors are available for almost every patient.