Excellent Outcomes for Pediatric Non-Malignant Diseases Using Umbilical Cord Blood Transplantation (UCBT) Conditioned without Serotherapy in the Absence of a Matched Related Donor

Introduction There is no consensus about the best donor for children with non-malignant disorders in the absence of a matched related donor (MRD). Objectives Evaluate UCBT as an attractive option for these patients because of prompt availability, lower risk of GvHD, and increased cell dose at young ages. Methods From 2008-2017, we performed UCBT in 42 children, median age 5 mo. (range, 2–108 mo.) with: SCID (30), IPEX (2), LAD (1), WAS (1), CGD (1), metabolic disorders (3), HLH (1), and other hematologic disorders (3). 26 patients had persistent infections prior to transplant: PJP (5), fungal (1), RSV (4), Parainfluenza 3 (4), VZV (1), Norovirus (1), CMV (4), Rhinovirus (2), bacterial (4); with 9 patients having pneumonia (20%), and 7 (17%) patients requiring mechanical ventilation prior to transplantation. Thirty-four percent of patients were 6/6 HLA antigen matched, and 66% were one HLA antigen mismatched. All patients were enrolled on a prospective clinical trial using fully ablative busulfan, cyclophosphamide, and fludarabine without serotherapy. The median TNC was 15 × 10 7 kg (range, 5.1 – 26.4). Results The median time to neutrophil and platelet recovery were 18 days (range,6-30d) and 35 days (range,22-85d), respectively. All but one evaluable patient achieved full donor chimerism (defined as > 95% donor cells in peripheral blood by day +42). The overall survival (OS) at 2 years was 90% (95% CI:77-96%) with a median follow up of 4 years (range: 0.5 – 8.5yr). The OS for patients with SCID was 93.3% (28/30) at 2 years with engraftment of all lineages. Four patients died, from severe GvHD (n=2) and MOF (n=2). The cumulative incidence of aGvHD grade II-IV by day 100 was 16% (n=7) with only 2 (IV). No cGvHD has been seen. All but three patients developed engraftment syndrome at a median time of 19 days, (range: 6-46) successfully treated with steroids. All patients with viral infections at the time of transplant cleared infection at a median time of 54 days (range, 44-91). ELISpot analysis after resolution of infections showed T cell responses against the pertinent viruses. The median absolute CD3 (x10^6/L) counts by day 42 and 60 were 361 and 733; respectively. The median absolute CD3CD4 counts by day 42 and 60, were 296, and 506; respectively. The median absolute CD3CD8 absolute count by day 42 and 60, were 71 and 114; respectively. IVIg was discontinued at a median 138 days; (range: 52-769d). Median time to begin immunizations was 11 months, (range: 8-26). All evaluable patients have had correction of their immune or metabolic defect including adequate B cell function in SCID patients. Conclusion We conclude that in the absence of a MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in children with non-malignant disorders, producing rapid engraftment, prompt functional immune-reconstitution, and a low incidence of GvHD.