Allogeneic stem cell transplantation for CGD is becoming more common and reflects increased overall transplant success. Survival has increased from approximately 85% prior to 2000 to 90–95%, based on recently reported outcomes and our own results, even with the use of unrelated donors. In fact, outcomes with perfectly HLA matched unrelated donors appear to approach if not equal those using HLA sibling donors. This suggests that donor availability should not be limiting for transplant of CGD patients.
Even for those without a matched unrelated donor, cord blood products are proving to be a reasonable alternative, and are being used more frequently. Even in adults, double cord products have had good engraftment rates, at least in the setting of leukemia. 80
In one study, the non-relapse mortality was slightly higher for recipients of double cord products compared to those receiving matched unrelated or matched related donor products. Studies will be needed in CGD to determine if a double cord transplant is preferable to an unrelated donor transplant.81
Although one published case used a haploidentical donor, the patient rejected requiring a second transplant.54
Both peripheral blood stem cells and marrow have been used successfully, and the choice for CGD patients currently depends on donor and center preferences. Data from transplants in aplastic anemia suggest that bone marrow products result in less GvHD; however cell dose can be a limiting factor.82
Older patients with CGD often have splenomegaly and/or hepatomegaly, thereby requiring a larger cell dose. Although T cell depletion of products has been used in transplants for patients with CGD, the incidence of GvHD with donor lymphocyte infusion is significant, as seen in the first NIH series.69 In vivo
or in vitro
T-cell depletion with alemtuzumab appears to result in less GvHD without significantly affecting engraftment, although the need for viral monitoring is prolonged.
Some transplant centers prefer myeloablative transplant regimens.65
Although graft rejection is more likely with a reduced intensity conditioning regimen, the risk of GvHD, particularly acute GvHD, and regimen related toxicity, appears to be reduced with the non-myeloablative regimens. 83–85
This type of conditioning also allows transplantation during ongoing infection, with fewer infection related deaths. Further, those who have rejected after receiving reduced intensity conditioning have for the most part gone on to successful second transplants. On the other hand, patients with McLeod syndrome, (Kell antigen deficiency due to contiguous gene deletion of XK which is found next to the CYBB gene), who have red cell antigen sensitization should be considered for a myeloablative regimen, or at least pretreatment with rituximab, to limit red cell incompatibility as the availability of McLeod matched blood is extremely limited. Elimination of B cells with anti-CD 20 therapy prior to transplant diminishes the risk of transfusion reactions and makes red cell management easier during the transplant period prior to conversion to donor blood type.51
Those without preexisting red cell antibodies however, have successfully undergone non-myeloablative transplant.64
Most successful regimens in CGD patients appear to include busulfan. Some consider fludarabine necessary as well; however, the experience at NIH does not support this.
The question remains of which CGD patient to transplant? Given the current success rates, some favour transplanting all CGD patients who have an appropriate donor at the earliest opportunity. The recent data from Kuhns et al, showed that patients with very low superoxide production had worse long term survival than those with higher levels of NADPH oxidase activity suggesting that these patients might be considered appropriate candidates for early transplantation, particularly if a sibling matched donor is available. 3
However, even within this subgroup, there are patients who do relatively well for prolonged periods. Elevated alkaline phosphatase, a history of liver abscesses, and decline in platelet count reflecting portal hypertension are adverse prognostic indicators.86
These patients may also be considered for early transplantation.
Even with improved survival and longevity due to better infection and inflammation management, complications and their consequences can accumulate over time. However, transplant outcomes are probably better before infectious and inflammatory damage accumulate. Transplant has reversed some of the inflammatory and autoimmune complications associated with CGD and may prevent their development.65
Therefore, patients with significant inflammatory or autoimmune disease should also be at least evaluated for transplant, preferably at a center with experience in CGD transplantation. Those who have an active infection should not be summarily excluded, as non-myeloablative regimens have been successful even in this setting. Additionally, granulocyte transfusions may be helpful during the transplant period for those with active infections and do not appear to impact on engraftment. 87
For those with a prior history of infections, including fungal infections but no active infection, the necessity to use granulocytes is not clear. Patients who are being considered for transplant should not receive granulocytes prior to transplant (as opposed to during) so as to avoid the development of HLA alloimmunization.
While overall CGD life expectancy is still less than the general population even with the best current care, the strides in infection and inflammation management over the last decades have been significant. Allogeneic hematopoietic transplantation may have unanticipated consequences, and even the reduced intensity regimens may pose unknown long-term risks. Although there has been strong interest and progress in gene based therapies, it has not been shown to be curative at this point and has been reviewed elsewhere.88
Further, even ex vivo gene therapy appears to require some form of conditioning, so cytoreductive agents may still be needed.89–91
However, allogeneic transplantation has also improved dramatically over the last decade, due to improved conditioning regimens and GvHD prophylaxis, high resolution sequence based matching, and improved pre-, peri- and post- transplant management. It has become a successful and sensible option for many patients with CGD, that will likely treat and prevent both infectious and inflammatory complications. While further studies will be required to determine optimal timing, donor selection, and long-term efficacy in these patients, hematopoietic stem cell transplant is finally coming of age as a curative treatment of CGD.