Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for High Risk Chronic Granulomatous Disease (CGD) Patients

HSCT can cure CGD, but some patients may be deemed ineligible due to ongoing severe infection or inflammation. Paradoxically, HSCT may provide their only chance of survival. Here we report our experience using nonmyeloablative conditioning with unrelated HLA matched donors in a high risk CGD population. Amongst our cohort (34 total) 23 were high risk with either McLeod’s (2), ongoing infection (7), refractory inflammatory disease (ID)(7), or both infection and ID (8). One had McLeod’s and infection. High risk patients were 4 to 32 years old, where 20 had X-linked CGD, 2 had p40 CGD and 1 had p47 CGD. Infections were mostly fungal, (Aspergillus, Scedosporium, Geosmithia, and Phellinus) but also included Nocardia, Serratia, and Granulibacter, with antimicrobial therapy often for more than a year, plus surgical resection where applicable. Patients with ID were receiving high dose corticosteroids and/or biologics. Conditioning was TBI at 300cGy total, busulfan 5mg/kg over 2 days and Campath. Post transplant Graft versus Host disease (GvHD) prophylaxis was sirolimus initially. All patients received mobilized unmanipulated peripheral blood stem cells (PBSCs) except one who received bone marrow (BM). Donors all matched at 10/10 loci, except for 1 with A mismatch. Until evidence of neutrophil recovery, 7 of 16 with active infection received 3rd party granulocyte infusions (median 3.7 products/patient). All patients had engraftment by dihydrorhodamine assay by day 14. Timing of neutrophil recovery varied (median day 19.8) in those receiving mobilized PBSCs. Overall survival was 78%. The BM recipient had pre-existing renal impairment, delayed engraftment and eventually died of renal failure. Only one patient died of infection progression. One patient had late graft rejection and died after a third transplant due to GvHD. Two patients developed GvHD after stem cell boosts resulting in infection in one and transfusion associated lung injury after platelet transfusion in the other. Event free survival was 93% of all patients surviving more than one year. One patient with early graft rejection was highly HLA alloimmunized. Rates of acute GvHD were surprisingly low (21%) and relatively mild with only two patients dying indirectly as a result of GVHD Thus our results to date show that it is reasonable to offer high risk patients allogeneic HSC transplant as a possibly life-saving salvage procedure even in the face of persistent active infection or severe inflammatory bowel disease unresponsive to conventional therapies. Funding acknowledgement: This research was supported [in part] by the National Institute of Allergy and Infectious Diseases. This research also was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, funded by the NCI Contract No. HHSN261200800001E.