Controversies and expectations for the prevention of GVHD: A biological and clinical perspective

Abstract

Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Historically, cord blood and matched sibling transplantation has been associated with the lowest rates of GVHD. Newer methods have modified the lymphocyte components to minimize alloimmunity, including: anti-thymocyte globulin, post-transplant cyclophosphamide, alpha/beta T cell depletion, and abatacept. These agents have shown promise in reducing severe GVHD, however, can be associated with increased risks of relapse, graft failure, infections, and delayed immune reconstitution. Nonetheless, these GVHD prophylaxis strategies have permitted expansion of donor sources, especially critical for those of non-Caucasian decent who previously lacked transplant options. This review will focus on the biologic mechanisms driving GVHD, the method by which each agent impacts these activated pathways, and the clinical consequences of these modern prophylaxis approaches. In addition, emerging novel targeted strategies will be described. These GVHD prophylaxis approaches have revolutionized our ability to increase access to transplant and have provided important insights into the biology of GVHD and immune reconstitution.

Keywords: GVHD; GVHD biology; GVHD prophylaxis; GVHD therapies; controversy.

Figure 1

Mechanisms of aGVHD Schema of the contributions to acute GVHD after hematopoietic cell transplantation The pink donor and blue recipient represent the gender mismatch (female to male); <8/8 match= not fully HLA matched donor/recipient pair, PBSC, peripheral blood stem cell source; T cell dose, higher T cell doses are linked to more disease. For the host, chemo/XRT, chemotherapy/radiation with increased preparative regimen intensity linked to increased risk of aGVHD and the microbiome potentially playing a role. The key contributing T cell populations are shown (T Eff-Th, T effector helper cell; DAMPS, danger-associated molecular patterns; PAMPS, pathogen-associated molecular patterns. The figures were generated by the authors using BioRender.com.

Figure 2

Mechanisms of cGVHD Schema of the contributions to chronic GVHD after hematopoietic cell transplantation The pink donor and blue recipient represent the gender mismatch (female to male); <8/8 match= not fully HLA matched donor/recipient pair, PBSCT= peripheral blood stem cell source, dec. if cord= decreased if cord blood source used, T cell dose= higher T cell doses and B cells are linked to more cGVHD. For the host, the microbiome may potentially play a role in addition to pre-HCT organ injury. The key contributing T cell populations are shown (T Eff-Th, T effector helper cell), Treg, T regulatory cell; RTE, recent thymic emigrants; DAMPS, danger-associated molecular patterns; alt. act. Macrophages, alternatively activated macrophages. The figures were generated by the authors using BioRender.com.

Figure 3

Personalized approach to GVHD prophylaxis. Variables to consider for the personalized approach to GVHD prophylaxis. The figures were generated by the authors using BioRender.com.