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.
Authors: Tewari Priti , Wood Susan , Martin Paul L , Parikh Suhag H , Szabolcs Paul , Page Kristin M , Driscoll Timothy , Kurtzberg Joanne , Prasad Vinod K. 
Published: October 2019

Abstract
Abstract 3398
Poster Board III-286

Background:
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.

Methods:
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.

Results:
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.

Conclusions:
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.

Disclosures:
No relevant conflicts of interest to declare.