Class II Human Leukocyte Antigen Variants Associate With Risk of Pegaspargase Hypersensitivity

Abstract

We conducted the first human leukocyte antigen (HLA) allele and genome‐wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St Jude Children’s Research Hospital’s Total XVI (TXVI, n = 598) and Children’s Oncology Group AALL0232 (n = 2,472) and AALL0434 (n = 1,189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort‐specific covariates and then combined using meta‐analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7 × 10−5 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P < 5.0 × 10−5) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA‐DQB1*02:02 was tagged by HLA‐DQB1 rs1694129 in EAs (r2 = 0.96) and less so in non‐EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome‐wide significance in EAs were in class II HLA loci, and were partially replicated in non‐EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P = 8.9 × 10−9) in non‐EAs. The HLA‐DQB1*02:02‐DRB1*07:01‐DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non‐PEGylated asparaginase, even though the antigens differ between the two preparations.

Lack of benefit from premedication for pegylated asparaginase during pediatric acute lymphoblastic leukemia/lymphoma therapy: A side‐by‐side comparison

“…10 A recent report exploring genomic variation associated with PEG HSR identified non-European descent, including patients self-identified as Hispanic/Latinx, as a variant conferring greater risk for developing a HSR. 29 There was no evidence of a disparity in the rate of moderate or severe HSR by ethnicity or any other patient subset in either institutional cohort, nor was there a signal for a differential response to UPM. However, we did note that younger patients receiving nonintensive therapy in our cohort had a higher Grade ≥3 reaction rate than anticipated from prior large consortia reports in ALL 30 (13-14 vs. 2%).…”

“…While relapse disparities in these subsets are likely in part due to disease biology, we hypothesized that asparaginase discontinuation secondary to HSR could be a contributing factor 10 . A recent report exploring genomic variation associated with PEG HSR identified non‐European descent, including patients self‐identified as Hispanic/Latinx, as a variant conferring greater risk for developing a HSR 29 . There was no evidence of a disparity in the rate of moderate or severe HSR by ethnicity or any other patient subset in either institutional cohort, nor was there a signal for a differential response to UPM.…”

Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia

“…There is conflicting evidence whether IGHMBP2 is associated with IgA nephropathy. 23 , 24 Polyethylene glycol conjugated (PEGylated) preparations of asparaginase (pegasparagase) were used in both AALL0232 and AALL0434, 25 and presence of anti-PEG IgM has been shown to accelerate blood clearance of the PEGylated products. 26 , 27 It is possible that rs12283870 influences hepatic toxicity by modifying exposure to asparaginase.…”

Progress and Challenges in Pharmacogenomics

“…summarize highly interesting insights on HLA‐related immunopharmacogenetics, 1 and novel data are presented by Liu et al . on HLA‐loci associated with hypersensitivity reactions of pegaspargase in pediatric patients with leukemia 2 …”

“…In this special issue on Pharmacogenetics and Pharmacogenomics, Deshpande et al summarize highly interesting insights on HLArelated immunopharmacogenetics, 1 and novel data are presented by Liu et al on HLA-loci associated with hypersensitivity reactions of pegaspargase in pediatric patients with leukemia. 2 However, as mentioned above, it is all about evidence. Most pharmacogenetic traits are related to genetic variants in drug metabolizing enzymes modulating the bioavailability of drugs.…”