Umbilical Cord Blood Transplantation Conditioned without Serotherapy Is an Excellent Curative Alternative for Pediatric Non-Malignant Diseases

Stem cell transplantation for patients with non-malignant disorders is often challenging, with frequent failure to engraft. In the absence of an HLA-identical source, there is no consensus about the best alternative hemopoietic stem cell donor for patients who lack a matched sibling. Although cord blood transplant has been a recent option for these patients, an increased risk of viral infections and the potential for failed engraftment have remained problematic and associated with significant mortality.  We therefore studied 25 children who underwent UCBT transplant at our institution for non-malignant disorders between 2007 and 2014. Their median age was 8 months (range, 2–66 months) an their diagnoses were: SCID (n=17), IPEX (n=2), LAD (n=1), Wiskott-Aldrich syndrome (n=1), Krabbe (n=1), mannosidosis (n=1), HLH (n=1), and Diamond-Blackfan anemia (n=1).  Five patients had persistent viral infections prior to transplant: RSV (n=2), Parainfluenza 3 (n=1), VZV (n=1) and Norovirus (n=1), and 7 (30%) patients had required mechanical ventilation prior to transplantation. Eight of 25 patients were 6/6 HLA antigen matched with their cord stem cell donor, and 17 were one HLA antigen mismatched. All patients participated in a prospective trial consisting of myeloablative conditioning using busulfan, cyclophosphamide and fludarabine without the use of serotherapy. The median total nucleated cell dose in the transplant was 10x10⁷ TNC/kg (range, 5.9 – 25.4). The median time to neutrophil recovery was 19 days (range,8-30) and the median time to platelet recovery was 38 days (range, 26-127). All but one evaluable patient achieved full donor chimerism (defined as > 95% donor cells in peripheral blood) by day +42. The exception was a patient with Krabbe’s disease who is nonetheless 60% donor chimeric at 6 months post-transplant with normalization of enzyme levels. No severe aGVHD or cGvHD has occurred and only one patient developed grade II aGvHD (skin).  All except the patient with HLH (who died of multiorgan failure) are alive with a median follow up of 2 years (range, 10 days – 5 years) and a 3-Yr OS by Kaplan Meier analysis of 96% (95%CI: 73%-99%). All patients with viral infections at the time of transplant cleared the infection at a median time of 51 days (range, 44-54). ELISPOT analyses of peripheral blood at the time that infections responded showed significant T cell responses against the pertinent viruses.  All evaluable patients have normalization of their immune or metabolic defect including adequate B cell function in SCID patients. Hence, UCBT after full intensity conditioning without serotherapy for pediatric non-malignant diseases can produce rapid functional engraftment and immune-reconstitution in the absence of significant GvHD, leading to excellent overall survival.