Excellent Outcomes in Children and Young Adults Using Reduced-Intensity Conditioning for Patients with Inborn Errors of Immunity, Hematopoiesis, and Metabolism with Single-Unit Cord Blood or Bone Marrow
Authors: Vander Lugt Mark , Chong Hey Jin , Chen Xiaohua , Windreich Randy M. , Goyal Rakesh , Escolar Maria , Szabolcs Paul 
Published: October 2019

Abstract
Reduced-intensity conditioning (RIC) regimens have been shown to decrease transplant-related morbidity and mortality; however, this comes with an increased risk of graft failure and morbidity and mortality secondary to infections following intense serotherapy. Here we report a novel RIC regimen for chemotherapy-naïve patients. (Trial: NCT01852370).
Between 2012 and 2015, 28 patients with non-malignant conditions underwent first hematopoietic cell transplantation (HCT) using either single-unit umbilical cord blood (UCB; n=23) or bone marrow (4 unrelated, 1 mismatched maternal donor) at the Children's Hospital of Pittsburgh of UPMC. Patients received alemtuzumab (0.7-2.2 mg/kg), hydroxyurea (30 mg/kg/day), fludarabine (150 mg/m2), melphalan (140 mg/m2), and thiotepa (200 mg/m2) with tacrolimus and mycophenolate mofetil as GVHD prophylaxis. Patient and graft characteristics are shown in the table.
Neutrophil engraftment occurred in all patients at a median of 14 days post-HCT. Platelet engraftment (>20K) occurred at a median of 35 days post-HCT in 24 of 25 evaluable patients. 1 patient developed graft failure prior to platelet engraftment, and 3 patients were not evaluable due to mucosal bleeding requiring prolonged transfusion (Table). 27 of 28 patients had >98% donor whole blood chimerism at first measurement, performed at a median of 28 days post-HCT. The median chimerism was 100% in whole blood (range: 50-100%; n=20) and T cell fraction (range: 0-100%; n=18) at 6 months post-HCT, and 100% (range: 83-100%; n=16) in whole blood and 100% (range: 71-100%; n=13) in the T cell fraction at 12 months. 1 patient had graft failure at day +38 and after autologous reconstitution, underwent a successful second single-unit umbilical cord blood transplant. No patient developed VOD, IPS, hemorrhagic cystitis, or pericardial effusion requiring drainage.
T cell reconstitution commenced between 100-180 days post-HCT (Fig. 1A), and in some, TREC numbers and TCR Vβ repertoire achieved pre-transplant values by 9 months post-HCT. Fifteen patients developed viremia with CMV (n=7), EBV (n=6), adenovirus (n=5), or HHV-6 (n=5); however, only two developed serious viral disease. The incidence of acute GVHD was low, with 7 patients developing grade II-IV acute GVHD, and only 1 developing grade III-IV acute GVHD (Fig. 1B). All patients responded to therapy. None of the 24 patients who are beyond Day 180 post-UCBT have developed extensive chronic GVHD. 13 of 18 patients evaluable at 1 year post-HCT are completely off systemic immunosuppression, and 12 of 18 no longer require IgG supplementation. Two patients died after day +100 post-transplant, one from cardiopulmonary complications of viruses acquired pre-transplant (CMV, adenovirus, and parainfluenza), and one from disease progression. Twenty-six patients (92%) are alive with a median follow-up of 22 months (range 1.5-47 months) (Fig. 1C).
In conclusion, this novel RIC regimen allows for rapid engraftment of donor cells and immune reconstitution in chemotherapy-naive patients with acceptable rates of viral reactivation and GVHD despite the use of single-unit UCB grafts in most cases. High rates of survival and improved quality of life was associated with a low incidence of end-organ toxicity and absence of extensive cGVHD.
Table. Characteristic N=28 Age (years) - median (range) 1.6 (0.5-33.0) Gender - no. (%) Male 12 (43%) Diagnosis - no. (%) Krabbe 7 (25%) Metachromatic Leukodystrophy 5 (18%) MHC II Deficiency 2 (7%) Diamond-Blackfan Anemia 2 (7%) Cartilage-Hair Hypoplasia 1 (4%) Combined Immunodeficiency (CID) 1 (4%) CID with Intestinal Atresias 1 (4%) DiGeorge Syndrome 1 (4%) Gaucher Disease 1 (4%) HLH 1 (4%) Hunter Syndrome 1 (4%) Severe Congenital Neutropenia 1 (4%) Tay-Sachs Disease 1 (4%) X-linked Adrenoleukodystrophy 1 (4%) XLP2 1 (4%) Osteopetrosis 1 (4%) Stem Cell Source UCB 23 (82%) Marrow 5 (18%) Cell dose (E+07; TNC/kg) - median (range) UCB 10.2 (3.8-22.5) Marrow 31.4 (11.8-86.0) Cell dose (E+05; CD34/kg) - median (range) UCB 3.33 (1.55-9.00) Marrow 22.4 (44.2-91.4) Match (UCB) - no. (%) 6/6 9 (39%) 5/6 7 (30%) 4/6 7 (30%) Match (Marrow) - no. (%) 8/8 4 (80%) 7/8 1 (20%) ABO mismatch - no. (%) 19 (68%) Neutrophil engraftment (days) - median (range) 14 (9-33) Platelet >20K (days; N=24) - median (range) 35 (17-56) Platelets >50K (days; N=25) - median (range) 37 (18-105)

Disclosures
No relevant conflicts of interest to declare.