Reduced Intensity (RI) Allogeneic Cord Blood Hematopoietic Cell Transplantation (Allo CBHCT) in Pediatric Patients with Malignant and Non-Malignant Diseases.
Authors: Del Toro Gustavo , Bradley M. B. , Satwani P. , Morris E. , van de Ven C. , Cheung Y.-K. , Yamashiro D. , Garvin J. , Bhatia M. , Roman E. , Schwartz J. , Militano O. , Cooney E. , Wolownik K. , Hawks R. , Foley S. , Cairo M. S. 
Published: April 2020

Abstract
We and others have demonstrated that cord blood hematopoietic cells can be used successfully as an alternative allogeneic progenitor cell source in pediatric and adult recipients with both malignant and non-malignant diseases (Cairo et al, Blood 1997). However, there is significant amount of morbidity and mortality following myeloablative CBHCT (Gluckman et al, NEJM 1997; Rubinstein et al, NEJM 1998). RI conditioning may potentially reduce the incidence of regimen-related mortality (RRM) and the late effects associated with myeloablative regimens without increasing the risk of graft failure or relapse in children and adolescents (Del Toro et al, BMT 2004). Successful engraftment has been demonstrated in adult recipients with advanced hematologic malignancies who received unrelated mismatched cord blood following RI conditioning regimens (Chao et al, BBMT 2004). We report the results in 22 pediatric recipients, 6F:16M, median age 6.5 years (0.4–21). Twenty-one received unrelated CBHC, the majority mismatched at 1–2 HLA-Loci, 4/6 (n=14), 5/6 (n=5), 6/6 (n=2); 1 sibling CBHC (6/6). Recipients were transplanted for malignant n=17, [HD (5), NHL (2), NB(4),AML (2), MDS(3),CML (1)] and non-malignant n=5, [b-thal (1), HLH (2), WAS (1), SCD(1)] diseases. Poor-risk disease was defined as induction failure, PD, SD, ≥CR3, and 2nd allo HCT (n=8). RI conditioning was fludarabine-based (150–180mg/m2) with either busulfan (8mg/kg) +/− rabbit ATG/alemtuzumab or cyclophosphamide +/− etoposide/etoposide phosphate +/− ATG and craniospinal radiation prophylaxis (n=1). Graft-vs.-host-disease (GHVD) prophylaxis: tacrolimus 0.03 mg/kg/day and mycophenolate mofetil 900mg/m2 q 6h (Osunkwo et al, BBMT 2004). Median total nucleated cell count was 3.8 x107/kg (0.92–10.82) and CD34 cell count was 2.2 x105/kg (0.34–6.95). The median day to neutrophil engraftment was 19.5 days (1–47) and to platelet engraftment was 40 days (6–170). Engraftment was 72.7%. There were 6 primary graft failures observed (1 CML, 1 b-Thal, 2 HLH, 1 MDS, and 1 AML). Within this subgroup of graft failures, 4 were regrafted with myeloablative conditioning followed by a second CBHCT and 100% engrafted. Of the 16 engrafted patients, 15 achieved 90% or greater mixed-donor chimerism by day 60. Five of 16 evaluable patients developed acute GVHD, with 3 of those 5 developing grade III/IV acute GVHD. One patient developed extensive chronic GVHD. There were 8 deaths (4 PD, 1RRM, 3 GVHD). The probability of 3-year overall survival (OS) in all patients was 61%. Despite a log less nucleated cells/kg with CB vs. PB or BM HCT, the 3-yr OS in standard-risk malignancy pts. was 90%. The 1-yr OS in poor-risk malignancy pts. was 21%. The 1-yr OS in non-malignant diseases was 75%.These preliminary results indicate that RI Allo CBHCT may result in more rapid hematopoietic reconstitution while decreasing RRM compared to myeloablative CBHCT and be associated with high-to-full mixed-donor chimerism. Patients with diseases such as CML, β-Thal, and HLH may require increased intensity of conditioning. Further follow-up is required to evaluate the difference, if any, in long-term effects following RI Allo CBHCT.