Chronic Granulomatous Disease (CGD) is an inherited disorder resulting from a failure to produce nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, necessary for protection against a number of infectious organisms. Patients are subject to recurrent infections and inflammatory complications. The current management of these patients is limited to close surveillance for infections, administration of prophylactic antimicrobials, and rapid and aggressive treatment of suspected and documented infections with broad-spectrum antibiotics. Although often effective, these treatments can require long hospitalizations, impacting the overall quality of life significantly and leading to significant morbidity, such as renal failure and deafness. CGD patients have autoinflammation that may manifest as inflammatory bowel disease, hypoxic lung inflammation, and/or liver nodular regenerative hyperplasia with venopathy as examples.
Currently the only available cure for these disorders is bone marrow transplantation, which preferentially uses a human leukocyte antigen (HLA)-matched related sibling as the donor (allogeneic stem cell transplantation). However, as only 30% of participants in the general
population have an HLA-matched related sibling, allogeneic related transplantation is often not an option, resulting in the need for matched unrelated donor (MUD) transplantation. The National Marrow Donor Program (NMDP) serves as both a national registry of volunteers who are willing to donate progenitor cells to eligible recipients as well as a repository of cord blood products. Despite continued improvement in the use of transplantation schemas - including the development of nonmyeloablative regimens - there remain significant morbidity and mortality associated with transplantation, in particular graft versus host disease (GvHD) and graft rejection.
CGD with severe autoinflammation manifested as C-reactive protein (CRP) \>= 100 milligrams per milliliter (mg/mL) has been a significant risk factor for mortality due to severe engraftment syndrome, and thus patients with elevated CRPs have not been eligible for prior transplant protocols.
In addition, despite improving engraftment rates, there continues to be mixed chimerism and late graft loss in CGD participants despite a variety of conditioning regimens being used at various centers.
In our most recent protocol, we have continued to have a low incidence of graft versus host disease and improved engraftment, but still could see improvement in graft stability. Thus, in order to improve outcomes with participants with elevated CRPs as well as improve overall engraftment, we are building on our prior regimens by targeting the inflammatory cytokines that appear to be involved in graft failure and engraftment syndrome.
Participants with a CRP of less than 100 mg/mL will be pretreated with a dose of tocilizumab, an anti-IL6 monoclonal antibody. Participants with a CRP of greater than 100 mg/mL will be pretreated with 2 doses of tocilizumab as well as an inhibitor of interferon-gamma in order to decrease the inflammation that has been seen in these participants with engraftment. Otherwise, the conditioning regimen will be similar to maintain the low rates of GvHD that we have seen to date.
