Abstract 112

Asparaginase, an important antileukemic agent for ALL, is isolated from bacterial sources, and hence hypersensitivity reactions frequently occur; these reactions may attenuate its enzymatic activity and thus its antileukemic effect. Inherited genomic variations are known to affect the risk of hypersensitivity to some medications, but those that affect the risk of asparaginase allergy are not known. We interrogated 500,000 single nucleotide polymorphisms (SNPs) in 485 children with ALL treated on a single clinical trial to identify SNPs associated with allergy to native E. Coli (Elspar) asparaginase. A total of 204 (41%) patients developed an allergic reaction, most of which were NCI grade 2. We divided the patients into a discovery (n = 322) and a validation (n = 163) cohort, balancing for age, sex, treatment arm, race, and the occurrence of asparaginase allergy. Among the top 100 SNPs significantly associated with allergy in the discovery cohort, SNPs on chromosomes 5 and 19 were overrepresented, hosting 12 SNPs annotated to genes. Among these 12 SNPs, only one SNP (rs4958381 in GRIA1 on chromosome 5q33) replicated in the validation cohort (p = 2.8 ′ 10−5 and 2.0 ′ 10−3 in the discovery and validation cohorts, respectively). This locus has been associated with asthma or atopy. We further found that an additional 11 SNPs annotated to GRIA1 (a glutamate receptor gene) associated with asparaginase allergy at p < 0.05 in the discovery cohort, 4 of which replicated in the validation cohort (rs10070447, rs6890057, rs4958676, and rs6889909) at p < 0.05. Based on GRIA1 SNP rs4958381, the cumulative incidence of asparaginase allergy (Figure) was 74%, 44%, and 32% for those with the AA, AG, and GG genotypes, respectively (n = 485, p = 4.2 ′ 10−8). The 5q33 region hosts several cytokine and immunomodulatory genes, with multiple genome-wide studies implicating this locus in asthma and atopy. An agnostic genome-wide approach implicates genomic variations in GRIA1 on chromosome 5q33 as predisposing to the risk of asparaginase allergy.

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Disclosures:

No relevant conflicts of interest to declare.

Topics:
asparaginase, chromosomes, hypersensitivity, leukemia, lymphocytic, acute, childhood, genetic variation, asthma, atopy, antileukemic agents, cytokine, glutamate receptors

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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