HLA Locus-Specific Outcomes in Double Umbilical Cord Blood Reduced Intensity Transplantation (DCBT) in Adults.
Authors: Delaney Meghan , Yeap Beow , Haspel Richard L. , Spitzer Thomas R. , McAfee Steven L. , Dey Bimalangshu , Attar Eyal , Kao Grace , Alyea Edwin , Lee Stephanie , Cutler Corey , Ho Vincent , Soiffer Robert J. , Antin Joseph H. , Karen Ballen 
Published: April 2020

The use of two umbilical cord blood units provides effective stem cell replacement for patients receiving reduced intensity transplants. However, these unique transplants have two donors, both of which are usually HLA mismatched (MM) at 1 – 2 loci. There are few data exploring the effect of locus-specific allele-level mismatching on outcomes in recipients of DCBT. Therefore, we inquired whether compatibility determined by high-resolution typing at HLA-A, B, C, DR, DQ influences overall survival (OS), disease-free survival (DFS), engraftment, and acute graft versus host disease (aGVHD). Forty-three consecutive patients (19 – 64y) were recipients of a reduced intensity DCBT. Diseases treated were AML (14), ALL (1), NHL (13), HD (5), CLL (3), MDS (4), other (3). Conditioning regimen was fludarabine, melphalan, and rabbit antithymocyte globulin. Cord units were at least a 4/6 allele level HLA-A, B, DR match with the patient and each other with a minimum pre freeze combined cell dose of &gt;3.7 × 107 TNC/kg. Twenty-one patients received cyclosporine and mycophenolate mofetil (CYA/MMF) and 22 patients received sirolimus and tacrolimus (SIR/TAC) for GVHD prophylaxis. We retrospectively studied patient/donor(s) HLA mismatching of both cords combined, and in the predominant cord, defined as the cord that contributes &gt;60% peripheral blood leukocytes at 90 days. Patients receiving HLA-DR matched cord blood units had a lower risk of aGVHD grade II–IV (p=0.018) as shown in table 1. The results were consistent within each GVHD protocol. Moreover, patient and predominant cord matching follows the same trend, although not as robustly (p=0.064). This finding is particularly intriguing, given that high resolution matching for DR is known to be important for aGVHD in other transplant settings. We also found modest evidence that HLA-DQ matching was associated with less aGVHD, however this was not significant.

Neutrophil engraftment was faster in patients who have better HLA-B matching to their combined cords (p=0.006). Median days to platelets &gt;20K were also faster in patients who had no HLA-B MM (p=0.023). A similar effect was observed when compatibility between the patient and the predominant cord was assessed for neutrophils (p=0.035), but not platelets (p=0.124), see table 2.

HLA-A or C MM had no observed effect on engraftment or aGVHD. HLA matching did not effect OS, DFS, or which cord blood unit eventually predominated. In conclusion,

HLA-DR matching is associated with lower risk of aGVHD, HLA-B matching is associated with faster neutrophil engraftment, HLA matching does not affect OS, DFS, nor does it predict which cord will become predominant, although the power of the analysis is limited by the small sample size.

Table 1. HLA-DR Mismatch and aGVHD Combined Cords Predominant Cord Number of MM 0 – 1 ≥2 0 ≥1 Total aGVHD (% patients) 14 33 19 32 CYA/MMF 21 57 30 57 SIR/TAC 0 21 0 20 Table 2. HLA-B Mismatch and Engraftment Combined Cords Predominant Cord Number of MM 0–1 ≥1 0 ≥1 ANC &gt;500 19 22 17.5 21 Platelets &gt;20K 40 47 41 44