Genetic Variants in the HLA-genes Are Associated with PEG-asparaginase Allergy - a Genome Wide Association Study on the NOPHO ALL2008 Protocol

Introduction: Asparaginase is a cornerstone in treatment of childhood acute lymphoblastic leukemia (ALL). However, balancing positive anti-leukemic effect against toxicities has proven difficult. A frequent toxicity is allergy; 13% of children treated according to the Nordic NOPHO ALL2008 protocol develop an allergic reaction to pegylated asparaginase (PEG-asparaginase) causing acute morbidity and necessitating truncation of therapy. (Henriksen et al, PBC, 2014 and 2017) . Background: Children with allergic reactions have no enzyme activity at any time-point during their treatment (Henriksen et al, PBC, 2017, Tong et al, Blood, 2014), thus they do not benefit from asparaginase administered prior to the allergic reaction. These allergic reactions are true allergic type 1 IgE-mediated reactions as opposed to allergy-like reactions and silent inactivation. We speculate that a subset of children with ALL have a genetic predisposition to developing allergy to PEG-asparaginase. Objectives and Methods: To investigate a genetic predisposition to PEG-asparaginase allergy, we performed a genome-wide association study (GWAS) on 1288 children (age 1-17.9 years) with ALL and treated according to the NOPHO ALL2008 protocol from July 2008 - December 2014. Of these, 178 (13.8%) were registered with an allergic reaction to PEG-asparaginase. Registration relied solely on the physician's ability to recognize symptoms of an allergic reaction, which can be difficult because of the diverse clinical manifestations. To define allergy and increase specificity, we used asparaginase enzyme measurements, only including children with available enzyme measurements; after quality control, 63 children with clinical allergy and without enzyme activity (< 25 IU/l in all samples) and 360 children with enzyme activity (≥ 25 IU/l in any sample) were included as cases and controls. Germline DNA was genotyped on Illumina Omni2.5exome-8 BeadChip arrays. Logistic regression analyses were performed in PLINK, adjusting for age and genetic ancestry, and excluding single nucleotide polymorphisms (SNPs) with a minor allele frequency < 0.01. Results: Median age was 3 years (IQR: 2-6) for cases and 4 years (IQR: 3-8) for controls, and the frequency of males was 44.4% and 55.3% in cases and controls, respectively. Cases developed allergy after a median of 3 (IQR: 2-4) injections of PEG-asparaginase, and 49% of the cases had a severe allergic reaction grade 3 or 4, of those 5 cases had an anaphylactic rea