Allele Level HLA Matching On Outcomes After Double Umbilical Cord Blood (dUCB) Transplantation for Hematological Malignancies: Stronger Graft Vs. Leukemia with HLA Mismatch
Authors: Brunstein Claudio G , Defor Todd E. , Noreen Harriet , Maurer David , MacMillan Margaret L. , Verneris Michael R. , McGlave Phillip , Weisdorf Daniel , Wagner John E. 
Published: October 2019

Abstract
Abstract 1976
Multiple single center and registry reports have documented the critical impact of donor-recipient HLA match on engraftment, transplant-related mortality (TRM) and survival after umbilical cord blood (UCB) transplantation. However, nearly all reports have only considered HLA A and B at antigen level and HLA DRB1 at allele level typing without consideration of HLA C or DQ. Therefore, we retrospectively performed allele level HLA typing for HLA-A, B, C, DRB1, DQB1 for UCB donor-recipient pairs in order to assess the importance of high resolution HLA typing on transplant outcomes. After 2002, most patients received a dUCB transplant in order to achieve the desired cell doses of ≥3, ≥4 and ≥5 × 10e7 NC/kg for grafts that were HLA 6/6, 5/6 and 4/6 matched by original typing resolution, respectively. Therefore, the analysis was limited to 275 recipients of dUCBT for hematological malignancy and whom DNA from both units was available. The effect of HLA match was based on the HLA type of the predominant long term engrafting unit. The median recipient age and weight was 44 years (range, 0.6–69) and 76.9 kg (range, 7.1–148), respectively. Conditioning was myeloablative (40%) consisting of cyclophosphamide (CY) 120 mg/kg, fludarabine (FLU) 75 mg/m2 and total body irradiation (TBI) 1320 cGy, or non-myeloablative (60%) consisting of CY 50 mg/kg, FLU 200 mg/m2, TBI 200 cGy with 95% receiving cyclosporine A (CsA) and mycophenolate mofetil (MMF) immunosuppression. Patients had acute leukemia (62%), standard risk disease (62%), cytomegalovirus seropositive (59%), and received at least one UCB unit that was sex mismatched to the recipient (78%). Results reported are based on the long-term predominant UCB unit. Notably, survival was not adversely affected by HLA mismatch. The probability of survival at 5 years was 46% (95%CI, 33–58%), 47% (95%CI, 38–54%) and 29% (95%CI, 13–47%) in patients engrafting with a 3–5/10, 6–8/10 and 9–10/10 HLA-matched UCB grafts, respectively (p=.47). In multivariable analysis after adjusting for disease risk, CMV serostatus, and KPS, there was similar risk of overall mortality for all groups regardless of HLA matching level. All other transplant outcomes including the incidence of acute and chronic GVHD were similar for all HLA-matching groups (data not shown). In the subset with acute leukemia (n=174), however, greater HLA mismatch was associated with a significantly lower risk of relapse without a deleterious effect on risk of TRM, resulting in a benefit in LFS (inverse of treatment failure) as shown below.
Transplant Outcome for Acute Leukemia HLA 3–5/10 match (n=84) RR (95%CI), p-value HLA 6–8/10 match (n=168) RR (95%CI), p-value HLA 9–10/10 match (n=34) RR (95%CI), p-value TRM at 2 years 1.0 1.1 (0.6–2.4)  P=.73 1.1 (0.6–2.4)  P=.73 Leukemia Relapse 1.0 1.9 (0.9–4.3)  P=.11 3.5 (1.3–9.5)  P=.01 Treatment failure 1.0 1.4 (0.8–2.4)  P=.19 2.2 (1.1–4.2)  P=.02
Together these data indicate that UCB units with greater HLA mismatch may confer greater GVL effect without greater TRM compared to HLA better-matched UCB grafts. These results suggest importance of evaluating allele level HLA typing in the setting of dUCB transplantation. If confirmed, these results could have major implications not only on graft selection (ie avoidance of HLA matched units), but also the target size of the international UCB banking inventory.

Disclosures:
No relevant conflicts of interest to declare.