Acute GVHD Suppression Using Costimulation Blockade to Expand Non-malignant Transplant

Many serious non-malignant hematologic diseases (NMHD) affecting children, including severe aplastic anemia (SAA), Fanconi anemia (FA), sickle cell disease (SCD), and thalassemia can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). While the best results are achieved with HSCT from human leukocyte antigen (HLA)-matched siblings, most children lack such donors, and many children with NMHD are therefore transplanted with grafts from an adult unrelated donor (URD). Because URD grafts are less histocompatible, they are more likely to cause GVHD, a process driven by the reaction of donor T cells against incompatible host tissues. Despite the routine administration of immune suppression for GVHD prophylaxis, GVHD claims the lives of many and plagues others with incapacitating chronic illness. For NMHD, the threat of GVHD limits the use of URD HSCT to only the most severely affected children. In African-Americans and other ethnic minorities, the situation is compounded by the fact that most of these children lack fully matched URD and typically receive mismatched and matched grafts, which carry an increased risk for graft rejection. A more effective form of GVHD prophylaxis that does not compromise engraftment is urgently needed, both to improve outcomes for those children undergoing HSCT as well as to allow expansion of this curative therapy to the many children with NMHD who forego transplantation because of the risk for GVHD.

The researchers have investigated the use of the co-stimulation blocking agent CTLA4-Ig (abatacept) to prevent GVHD. Study results to date indicate that abatacept strongly inhibits allo-reactive donor T cells and is clinically safe and effective. The clinical experience has included a variety of recipients: children and adults, peripheral blood stem cells (PBSC) and bone marrow (BM) grafts, as well as mismatched and matched unrelated and matched related donors; all have involved the administration of four IV doses of abatacept, on days -1, +5, +14, and +28, in combination with standard calcineurin inhibitor-based GVHD prophylaxis. Collectively, the results to date suggest that this combination, including abatacept, very effectively prevents acute GVHD. However, these results also suggest that protection against chronic GVHD is more limited. In this current trial, the researchers will attempt to more effectively prevent chronic GVHD by extending the administration of abatacept, giving eight doses (additional doses days +56, +84, +112, and +150). This trial will test the hypothesis that extended abatacept administration (combined with a standard regimen of tacrolimus and mycophenolate mofetil) will effectively prevent acute and chronic GVHD in children and adolescents receiving URD HSCT, without compromising their engraftment or reconstitution of protective immunity to infection.