Transplantation Following Myeloablative Cytoreduction Results in Excellent Survival, Long-Term Engraftment, and Donor Chimerism in Children with Chronic Granulomatous Disease Across Donor and Graft Sources.

The curative potential of hematopoietic stem cell transplantation (HSCT) in chronic granulomatous disease (CGD) is dependant upon achievement and maintenance of long-term donor chimerism and availability of suitable donor for every patient.

Ten children with clinically severe CGD (x-linked recessive, n=6; autosomal recessive, n=4) received HSCT following myeloablative conditioning at Duke University Medical Center between August 1997 and July 2009. Diagnoses were made by respiratory burst assays +/− mutation analyses. Prior to transplant, patients had a median of 3 (range, 2-9) serious bacterial or fungal infections. One patient had an active invasive aspergillous infection of the chest wall and lung at the time of transplant. The patients were transplanted at a median age of 64.5 months (range, 8-140), weighed a median of 19.6 kg (range, 9.6-60), and had a performance status of 80 to 100 (Lansky). One patient was referred to Duke for second transplant after he developed primary graft failure following a reduced intensity transplant at another center. Graft sources were matched sibling bone marrow (SibBM) in 5, unrelated donor cord blood (UCB) in 4, and sibling cord blood (SibCB) in 1 patient. SibBM and SibCB donors were 6 of 6 HLA matched. UCB units matched at 4/6 (n=1) or 5/6 (n=3) and contained a median precyropreservation total nucleated cell dose of 3.8×10—7 per kg. SibBM patients were cytoreduced with Busulfan (Bu) and Cyclophosphamide (Cy) with or without ATG. Use of Bu/Cy/ATG in the first UCB recipient resulted in primary graft failure. All subsequent CB recipients were cytoreduced with Fludarabine(Flu)/Bu/Cy/ATG. Five patients were given irradiated granulocyte transfusions from family donors during the neutropenic period. Engraftment, chimerism, graft versus host disease (GvHD), and survival were evaluated using descriptive statistics.

All patients are alive and disease free with a median follow-up of 55 (range, 1-144) months. Neutrophil engraftment occurred in a median of 16 days (range, 11-20) in BM and 29 (range, 16-43) in CB recipients. Platelet engraftment occurred in a median of 41 days (range, 33-45) in BM and 123 days (range, 29-169) in CB recipients. Two UCB recipients who had primary graft failure were successfully retransplanted using Flu/Cy with either TBI (200cGy) or Campath. At the most recent follow up (range, 1-84 months post transplant) chimerism was all donor in 8 patients and 94% in one patient. All patients have normal respiratory burst assays, are free of new infections, and are doing well with a Lansky score of 80-100 at their last follow up. Acute grades III/IV GvHD developed in 2 patients and extensive chronic GvHD occurred in only 1 patient.

Myeloablative hematopoietic stem cell transplant leads to correction of neutrophil dysfunction, durable high-level chimerism, excellent survival, and low incidence of GvHD. Patients transplanted with UBC had equivalent outcomes to those transplanted with HLA-matched sibling donors.

No relevant conflicts of interest to declare.