The Case for High Resolution Extended 6-Loci HLA Typing for Identifying Related Donors in the Indian Subcontinent

Abstract

Three-loci low-resolution (LR) or intermediate-resolution HLA typing is generally considered adequate in the related blood and marrow transplantation (BMT) context. However, a single high-resolution (HR) mismatch may have a similar adverse impact on BMT outcome as an LR one. We sought to determine the frequency of mismatches that may go undetected when standard typing (LR or 3-loci HR) is used compared with 6-loci HR typing for related donor compatibility testing, and to assess its impact on relevant BMT outcomes. We analyzed data from a total of 2554 6-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) HR sequence-based typing (full typing [FT]) from 754 patients, 1011 siblings, and 789 parents done at DKMS Germany (www.DKMS.de) between January 1, 2014, and June 21, 2016. We also studied 38 cases in which the family had undergone 3-loci HLA typing (standard typing [ST]). Patients were from India (70%), Pakistan (22%), and Sri Lanka (8%). The IMGT/HLA database (www.ebi.ac.uk/ipd/imgt/hla) was used to tease out nonpermissive DPB1 mismatches. HLA disparity-related outcomes, such as rejection and graft-versus-host disease (GVHD) were assessed in a retrospective matched-pair cohort of 50 patients (25 with ST and 25 with FT) who underwent BMT for severe thalassemia from compatible related donors. We found fully matched (either 12/12 HR matches or with a single permissive DPB1 mismatch) related donors for 285 patients (38%). Of these donors, 89% were siblings and 11% were parents. The likelihood of matching on an individual locus on LR but not on HR was found to be 5%. A total of 9 donors (3%; 7 siblings and 2 parents) who would have been considered a full match by HR typing on A, B, and DRB1 alone were not a match by extended 6-loci HR typing. Five of these 9 donors had a mismatch on C or DQB1, and 4 had a nonpermissive DPB1 mismatch. In this group, 5 donors (56%) belonged to a consanguineous family, in 2 donors (22%) there was no reported consanguinity, and in 2 donors (22%) consanguinity was unknown. We identified 18 donors (6%; 13 siblings and 5 parents) who would have been considered a 12/12 match by LR HLA typing alone but were found not to match on extended HR typing. In this group, 11 donors (61%) were from consanguineous families, 3 donors (17%) had no reported consanguinity, and in 4 donors (22%) consanguinity was unknown. Outcome analysis showed that the actuarial proportion of patients with GVHD was 4% in the FT group compared with 16% in the ST group, with log-rank P = .1952. The ST group included 2 patients with grade III-IV acute GVHD and 1 patient each with moderate and severe chronic GVHD, whereas the FT group only 1 patient with grade III acute GVHD. We conclude that even in the context of related donors, the use of LR and/or 3-loci (A, B, and DRB1) HR HLA typing might result in a sizable risk of missing a clinically relevant mismatch, which may have an adverse impact on transplantation outcomes. In the Indian subcontinent, this observation is not limited to putatively compatible parents or consanguineous ...

High-Resolution HLA Typing of HLA-A, -B, -C, -DRB1, and -DQB1 in Kinh Vietnamese by Using Next-Generation Sequencing

“…Recently, it has been shown that both high-resolution HLA typing and haplotyping are important in hematopoietic stem cell transplantation for both unrelated and related donors in reducing post-transplantation adverse outcomes (Agarwal et al, 2017;Buhler et al, 2019); a single high-resolution HLA mismatch may lead to a similar negative effect on outcomes as a low-resolution one (Fuji et al, 2015;Armstrong et al, 2017). Therefore, it has been suggested that highresolution HLA typing can reduce the likelihood of missing a clinically significant mismatch compared to traditional lowresolution typing, especially in developing countries where highresolution HLA typing methods are not widely available (Agarwal et al, 2017). With a 3-field resolution, our typing process can distinguish between HLA-A * 24:02:01, HLA-A * 24:02:13, and HLA-A * 24:02:40 and between HLA-C * 07:01:01 and HLA-C * 07:01:02, which are considered high-resolution mismatches.…”

Splenomegaly May Increase the Risk of Rejection in Low-Risk Matched Related Donor Transplant for Thalassemia, This Risk Can Be Partially Overcome by Additional Immunosuppression during Conditioning

“…All of our mother donors (2 in regimen A and 8 in regimen B) were 12/12 HLA identical by high-resolution typing. It is likely that they were fully genoidentical due to a high degree of consanguinity, resulting in shared haplotypes within families among the South Asian population [49].…”

Information Technology–Assisted Treatment Planning and Performance Assessment for Severe Thalassemia Care in Low- and Middle-Income Countries: Observational Study

“…Identification of candidates suitable for transplantation led to 391 patients getting human leukocyte antigen-typed and prepared for bone marrow transplantation from these centers. In all, 43 were transplanted with overall survival of 93% and disease-free survival of 77% at a mean cost of US $13,000 per transplant, including pretransplant preparation and late complications [45,46]. For these patients, online software specific for bone marrow transplantation was used [47].…”