Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades
Authors: Kurtzberg Joanne , Troy Jesse D , Page Kristin M. , Rafii-Elayoubi Hanadi , Volt Fernanda , Scigliuolo Graziana Maria , Cappelli Barbara , Rocha Vanderson , Ruggeri Annalisa , Gluckman Eliane 
Published: November 2021

Abstract
Four decades ago, Hal Broxmeyer demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al reported the first successful cord blood transplant (CBT) of a child with Fanconi Anemia using matched sibling CB. This patient survives and 35 years later still has durable hematopoiesis from the CB donor graft. In 1991, Rubinstein et al established an unrelated donor (UD) CB bank and in 1993 the first UD CBT was using a unit from this bank. Since that time, &gt;40,000 CBTs have been performed worldwide. We hypothesized that changes in cord blood banking (increased size, diversity, and quality of banked units enabling selection of units with higher cell doses and closer HLA matching) and in transplantation (less use of steroids, availability of newer therapies for prophylaxis and treatment of graft versus host disease [GVHD], improved antifungal and antiviral detection and therapeutics) have improved outcomes of CBT today.
To address this hypothesis, we performed a retrospective study combining data from Eurocord and Duke University in a large cohort of children transplanted with a single UD CB unit (CBU) from 1993-2019. Standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic GVHD, treatment related mortality [TRM], and relapse) and changes in outcomes over 3 time periods (1:&lt;2005, n=1297; 2:2005-2010, n=1735; and 3:&gt;2010, n=1802) were studied. Relative contributions of cell dose and HLA matching to transplant outcomes over time were assessed.
A total of 4834 patients (4015 from Eurocord and 819 from Duke) were analyzed. The majority of patients, (59%, n=2839) had malignant diagnoses including 1422 with ALL, 887 with AML and 167 with MDS. Of the 1995 with non-malignant diagnoses, 761 had inborn errors of metabolism, 644 had primary immunodeficiency, 325 had a bone marrow failure syndrome and 206 had a histiocytic disorder. Half of the patients had positive serologies for CMV prior to transplant. The median age of the cohort fell from 5.2 to 3.25 years over time. In patients with malignancies, use of total body irradiation decreased over time. The median total nucleated cell (TNC) and CD34+ cell doses administered were 8.07x10e7 and 6.17x10e5 cells/kg and increased over time. HLA matching and transplantation of patients in earlier disease states also increased over time, p&lt;0.001 for both. The probability of 5-year OS in the entire cohort was 53.48% and improved over time: 42%; 57.4%; and 60.4%, in periods 1,2,3 respectively (p&lt;0.0001). OS improved with closer HLA matching, higher cell dose, myeloablative conditioning, and negative pre-transplant CMV serologies. For patients with malignancies, DFS increased and TRM and acute GVHD decreased over time. In contrast, leukemic relapse did not change throughout the years. OS was higher in patients with inborn errors of metabolism and also improved over time with 57.8% surviving before 2005, 69.4% from 2005-2010, and 71% after 2010 (p=0.0141). Similar results were seen in the cohort with immune deficiencies. In the entire cohort, the median time to neutrophil engraftment decreased from 25 days (period 1) to 19 days (period 3). In multivariate analysis for engraftment, a higher TNC dose (p=0.001) up to but not beyond the median cell dose (8.07x10e7 cells/kg), total body irradiation, and the use of ATG improved engraftment. Acute GVHD decreased from 35% before 2005 to 27.1% after 2010 (p=0.0556) while the incidence of chronic GvHD was stable. The use of ATG reduced the risk of acute GVHD and closer HLA matching reduced the risk of both acute and chronic GVHD. In this population of patients receiving high cell doses, outcomes were predominantly influenced by HLA matching and increasing cell dose did not abrogate HLA mismatching.
In conclusion, we analyzed the largest cohort of pediatric patients undergoing CBT over the past 3 decades. OS, DFS and engraftment have improved over time accompanied by decreases in TRM and acute GVHD. Relapse and chronic GVHD were stable and remain low. These improvements are explained by the increased availability of high quality banked CBUs enabling selection of closer HLA matching and units with higher cell doses. The numbers of CBTs have decreased in the past decade, but these results support the ongoing use of CBT in children lacking matched related or unrelated donors.
Figure 1 Figure 1.

Disclosures
Kurtzberg: Neurogene: Consultancy; CryoCell: Patents & Royalties: Duke licensed IP, and data and regulatory packages for manufacturing and use of cord blood and cord tissue MSCs in the treatment of patients with hypoxic ischemic encephalopathy, cerebral palsy, autism, acute ischemic stroke, COVID-ARDS, and COVID-MIS-C. ; Sinocell: Patents & Royalties: Duke licensed IP, data, and regulatory packages for use of autologous and sibling cord blood to treat children with cerebral palsy.; Celularity: Current holder of stock options in a privately-held company. Troy: SinoCell: Patents & Royalties; CryoCell: Patents & Royalties; Bristol Myers Squibb: Research Funding; Synthetic Biologics: Honoraria; Gamida Cell: Consultancy; The EMMES Corporation: Consultancy; The Community Data Roundtable: Consultancy; AegisCN: Consultancy.