Prospective Evaluation of Cord Blood (CB) & Haplo-Identical Donor Availability Reveals Compromised Donor Access for Both Graft Types in Minorities and High Rates of Failure to Clear Haplo Donors in Adult Patients
Authors: Kosuri Satyajit , Wolff Tara F. , Byam Courtney , Lauer Emily , Yoo Yeon , Perales Miguel-Angel , Giralt Sergio A. , Scaradavou Andromachi , Ponce Doris M , Barker Juliet N. 
Published: October 2019

Abstract
Background: Many patients in need of hematopoietic allografts without matched siblings do not have any 8/8 HLA-matched unrelated volunteer donors (URD). This is especially true in patients of non-European & mixed ancestries & this applies to 50% of patients undergoing URD searches at our center. While unrelated donor CB & haploidentical (haplo) related donors offer alternative graft sources their availability in all patient populations is not established.
Methods: We prospectively evaluated the availability of CB & haplo grafts 9/2012 - 7/2015 in a phase II clinical trial of double unit CBT (dCBT) supplemented by haplo CD34+ cells in patients with hematologic malignancies lacking an 8/8 HLA-matched URD. CB units required a cryopreserved TNC dose ≥ 1.5 x 107 /kg/unit, were ≥ 4/6 HLA-A,-B antigen, -DRB1 allele matched, & high resolution 8 HLA-allele match & CD34+ cell dose were also considered. Standard criteria were used to define donor eligibility for haplo PBSC collection. Reasons for failure of haplo donor clearance were classified as either medical ineligibility or psychosocial (including financial inability to relocate to our transplant center, international donors unable to come to the US, donor refusal or withdrawal of consent during workup, donor imprisonment, or patient refusal to approach the donor for collection).
Results: 89 patients [median age 50 years (range 15-68)] were evaluated. Diagnoses included 58 acute leukemias, 10 MDS/ myeloproliferative disorders, & 21 NHL/ Hodgkins lymphomas. Evaluation of CB graft &/or haplo donor availability revealed 3 patient groups. Group 1 (59/89, 66% of the total) had both suitable CB grafts & haplo donors and underwent dCBT-haplo CD34+ transplants. 33% were non-European & their median weight was 78 kg (range 33-133). The CB grafts had a median infused TNC of 2.4 (larger unit) & 1.9 (smaller unit) x 107/kg with a median 5/8 (range 2-7/8) donor-recipient HLA-match whereas the 59 haplos (median age 36 years, range 15-71) included 17 siblings, 9 parents, 27 children, & 6 extended family. In Group 1, the first haplo chosen was cleared for donation in 52/59 (88%) patients whereas 6/59 (10%) required work-up of 2-4 haplos/ patient for a total of 16 donors who failed clearance for medical or psychosocial reasons. The remaining patient had pan-donor specific HLA antibodies to 5 haplos & subsequently a 7/8 HLA-matched nephew was secured. Group 2 (17/89, 19% of the total) received only dCB grafts due to failure to identify a suitable haplo donor. Group 2 patients were more likely to be non-European (65%) but had a similar weight (median 78 kg, range 55-118) as Group 1. The CB grafts were also similar to Group 1 (median infused TNC 2.2 & 1.5 x 107/kg & median donor-recipient HLA-match 5/8, range 3-8/8). Of these 17 dCBT only patients, 6 had no eligible haplos identified within their extended family whereas in 8 patients 1-4 haplos/ patient failed to clear for medical reasons, combinations of medical & psychosocial reasons, or pursuit of haplos failed due to a combination of medical failure & subsequent transplant urgency. Of the remaining patients, 2 had haplos who failed for purely psychosocial reasons, & in 1 the transplant was too urgent to delay to complete donor clearance. In this group a total of 19 haplos failed to clear. Finally, Group 3 (13/89, 15% of the total) had no dCB grafts + no haplo grafts. They were nearly all (85%) non-European including 7 patients of African ancestry & they had a higher weight (median 95 kg, range 52-143). One of these patients received a haplo transplant, 3 had no haplos identified, & in 9 patients clearance of potential haplos was not determined to date, or they pursued alternative therapy, were lost to follow-up, or their disease progressed.
Conclusions: In this study, 15% of patients had no CB grafts & these patients were predominantly non-European with a high weight. Additionally, over 20% of patients had no haplo grafts & compromised haplo donor availability was common especially in minority patients. This data demonstrates that even in patients with identified haplos, donor clearance cannot be assumed & the need for workup of multiple haplos/ patient can delay admission & substantially add to transplant costs. These observations support continued investment in public CB inventories to provide a readily available graft especially for minority patients who are at increased risk for inability to identify a CB &/or haplo donor.

Disclosures
Perales: National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Scaradavou:National Cord Blood Program- New York Blood Center: Employment.