Higher Allele Level HLA Matching Improves Prognostication after Double Umbilical Cord Blood (dUCB) Transplantation for Hematological Malignancies
Authors: Oran Betul , Cao Kai , Saliba Rima M. , Hosing Chitra M. , Popat Uday R. , de Lima Marcos , Carmazzi Yudith , Alousi Amin , Kebriaei Partow , Nieto Yago , Rondon Gabriela , Willis Dana , Shah Nina , Parmar Simrit , Olson Amanda , Moore Brandt , Champlin Richard E. , Rezvani Katayoun , Shpall Elizabeth J 
Published: October 2019

Abstract
Cord blood (CB) as a hematopoietic stem cell source has the advantage of decreased stringency of human leukocyte antigen (HLA) matching requirements. However, recent studies showed better outcomes in single CB transplant (CBT) with improved allele-level matching for 4 HLA loci (-A, -B, -C, and -DRB1).
We retrospectively analyzed 146 patients with hematological malignancies who engrafted after dCBT between 2003 through 2013 to compare the prognostic value of the current standard HLA matching criteria (intermediate resolution HLA typing at A and B and allele-level typing at DRB1) versus that of allele level matching at –A, -B, -DRB1 (6/6 allele) and at -A, -B, -C, and -DRB1 (8/8 allele). The effect of HLA match was based on the HLA type of the predominant long term engrafting unit. The primary endpoint was 1-year transplant related mortality (TRM).
In this cohort, median age was 43 (range; 1 –73). Disease diagnoses were AML in 56%, ALL in 21%, other hematological malignancies in the rest of the group. Disease status at dCBT was first or second complete remission in 55% and third remission or active disease in 45% of the patients. Conditioning was myeloablative in 62% of the patients consisting of mostly thiotepa, fludarabine and melphalan (86%). Reduced intensity conditioning was given to older and/or frail patients (38%) and consisted of cytoxan, fludarabine and TBI 200 cGy in 64% and melphalan with fludarabine in 36% of the patients. Immunosuppressive were mycophenolate mofetil (MMF) with tacrolimus and all patients received ATG as a part of the conditioning. Per protocol requirements over the years, 63% of the patients had ex-vivo expansion of one of the CB units with mesenchymal-cell coculture and 2% had one of the CB unit fucoylated. Median cell dose infused was 2.2 x 10e7 TNC/kg (range 0.5-291).
Of 146 patients, 54% had 4/6, 40% 5/6 and only 6% 6/6 matched CB units by the current standard HLA matching criteria. Patients who had 6/6 matched units have the lowest TRM compared with 4/6 group but this did not reach statistical significance (p=0.2). By 6/6 allele-level matching criteria; 20% of the patients had ≤3/6; 51% 4/6 and 29% were 5-6/6 matched CB units. Per this criteria, patients with 5-6/6 allele-level matched units had lower TRM compared with ≤4/6 allele-level matched unit recipients (HR=0.4, p=0.04). More importantly, of 65 patients with 5-6/6 matched units by standard criteria, 37% were found to have ≤4/6 allele-level matched units that would lead to high TRM. By 8/8 allele-level matching criteria; 26% of the patients had 3-4/8; 39% 5/8, 26% 6/8 and 10% 7-8/8 matched CB units. Based on this criteria, 3 different groups emerged; 7-8/8, 5-6/8, and ≤4/8. Recipients of 7-8/8 allele-level matched units did not experience TRM at one year. Patients with 5-6/8 allele-level matched units also had less TRM compared with ≤4/8 matched recipients (HR=0.5, p=0.02).
Among other variables analyzed; including age, disease, disease status, conditioning regimen, CB unit modification, unit TNC dose; only age >30 was a poor risk factor for 1-year TRM (HR=2.5, p=0.03). When we simultaneously accounted for age and 8/8 allele-level matching, we were able to identify 3 distinct risk groups for 1-year TRM (Table and Figure): 1) Low risk; 7-8/8 allele-level matched unit recipients with 1 year TRM of 0%. 2) High risk; age>30 and ≤4/8 allele-level matched CB units with 1-year TRM of 60% 3) Intermediate risk; all remaining patients with TRM of 30%. This risk stratification was independent of TNC cell dose infused. The respective 1-year cumulative incidence of TRM in the low-, high-, and intermediate-risk groups was 0%, 64% and 30% for patients who received TNC dose ≤ median (0.22X10e7); and 0%, 54% and 31% for patients who received TNC dose > median. Abstract 2532. Table 1TRMProgressionOSnHR95%CIpHR95%CIpHR95%CIpHigh risk27RefRefRefIntermediate risk930.40.1-0.70.0041.50.4-4.40.40.50.3-0.80.005Low risk13NE0.0032.30.6-8.50.20.40.1-0.90.04
Figure 1 Figure 1.
These results show that, compared with the current standard matching, allele-level matching for HLA -A, -B, -C, and –DR may have a stronger prognostic value as it identifies subgroups of patients likely to have very high or very low rate of TRM after dCBT. We suggest that allele-level matching for 4 HLA loci should be used for the selection of dCB units.

Disclosures
No relevant conflicts of interest to declare.