HLA-A, -B, -C and –DRB1 High Resolution Matching Can Improve Patient' Outcome After Double Umbilical Allogeneic Stem Cell Transplantation (allo-SCT)
Authors: Malard Florent , Gagne Katia , Chevallier Patrice , Devys Anne , Guillaume Thierry , Herry Patricia , Delaunay Jacques , Moreau Philippe , Mohty Mohamad , Cesbron Anne 
Published: October 2019

Abstract

Background
Unrelated umbilical cord blood cells (UCB) have emerged as an alternative stem cell source for allo-SCT for patients who lack a matched-related or unrelated donor. In BM or PBSC unrelated transplantation, high resolution (HR) matching at HLA-A, -B, -C and –DRB1 loci is crucial. Whereas, in UCB allo-SCT, HLA typing is usually performed at low resolution (LR) for HLA-A and -B loci and HR for HLA-DRB1 locus. Also in many centres, priority is often given to cell dose over donor-recipient HLA matching for UCB selection. Development of double UCB allo-SCT allows achieving higher cell doses. However, in the setting of double UCB allo-SCT, data regarding the effect of HR HLA matching between patient and UCB are scarcer. With this background, this retrospective analysis assessed whether HR matching at HLA-A, -B, -C and –DRB1 loci could be associated with improved outcome after allo-SCT using double UCB.

Patients and Methods
This analysis was performed in a series of 46 consecutive adult patients treated for hematological diseases. 25 patients were males (54%) and the median age at time of allo-SCT was 49 years (range, 16-68). Diagnoses included 20 AML (43%), è MDS/MPN (15%) 13 NHL (28%), 2 HD (4%), 4 ALL (9%) and 1 severe aplastic anaemia (2%). 9 patients (20%) had standard risk disease and 36 patients (78%) presented with high risk disease. 6 patients (13%) received a myeloablative conditioning (cyclophosphamide and high dose TBI) and 40 patients (87%) received a reduced intensity conditioning (fludarabine, cyclophosphamide and low dose TBI). 9 patients (20%) received ATG. HLA-A, -B, -C and -DRB1 HR typing was retrospectively performed by sequencing on both UCB units. We compared patient’ outcome according to the donor recipient HLA-A, -B, -C and -DRB1 HR matching. We defined 2 groups, a group of 27 patients with high HLA matching, group “high” (24 UCB-recipient pair were matched at 5/8 or higher for both UCB, 3 dUCB-recipient were matched at 4/8 for one UCB and at 6/8 or 7/8 for the second UCB) and a group of 19 patients with low HLA matching, group “low” (UCB-recipient pair were matched at 5/8 and 4/8 or less for both UCB).

Results
With a median follow-up of 30.0 months (range, 6.5-83.0), there is a trend towards improved better overall survival (OS) at 2 years in group “high” [69% (95%CI, 47-83%) versus 42% (95%CI, 18-64%) in group “low” P=0.07]. The estimate of progression-free survival (PFS) at 2 years was significantly higher in group “high” [62% (95%CI, 41-78%) versus 30% (95%CI, 11-51%) in group “low” P=0.02]. Also, there was a trend towards a lower cumulative incidence of NRM in group “high” [12%, versus 39% in group “low” P=0.06]. Grade 3-4 acute GVHD and extensive chronic GVHD incidences were 11% versus 10% (P=0.99), and 4% versus 15% (P=0.25), in group “high” versus group “low”, respectively. The cumulative incidence of relapse was 23% in the group high versus 37% in the group low (P=0.07). The cumulative incidence of neutrophil recovery at day 42 and platelet recovery at 6 months were 78% versus 89% (P=0.38) and 78% versus 84% (P=0.54) in group “high” versus group “low”, respectively. In multivariable analysis including the most important parameters associated with outcome (patient’s age at transplantation, patient’s gender, disease status, conditioning regimen, TNC), HLA matching (high versus low) was the only parameter with a significant impact on OS (HR=0.31 (95% CI, 0.12-0.80); P=0.02). Regarding impact of HLA matching at HLA-A,-B LR and –DRB1 HR, both UCB-recipient pairs were matched at 5/6 or higher in 22 cases and in 24 cases at least one UCB-recipient pair was matched at 4/6 or less, both groups were comparable regarding OS [62% (95%CI, 40-78%) in group high versus 57% (95%CI, 32-75%) in group low, P=0.41] and PFS [54% (95%CI, 33-71%) in group high versus 45% (95%CI, 24-64%) in group low, P=0.26].

Conclusion
These preliminary data suggest that in contrast to standard HLA matching, HR HLA matching at HLA-A, -B, -C and –DRB1 loci affect patients outcome after double UCB allo-SCT. Furthermore HR HLA matching overcome impact of cell doses regarding OS in multivariate analysis. This highlight the need to reassess the curent strategy for UCB unit selection in the setting of double UCB allo-SCT, where HLA-A and -B typing should be performed at the allele level and matching at HLA-C should be included. Prospective randomized studies are needed to confirm these results and analyze the impact of each HLA locus at the allele level.

Disclosures:
Moreau: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.