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[12]
and corticosteroids, this still does not prevent ASNase inactivation . It is important to mention that higher
systemic exposure to ASNase was associated with a lower clearance of dexamethasone, and thus a higher
systemic exposure and an increased risk of osteonecrosis. Nonetheless, studies also found that the formation
of ASNase antibodies can increase the systemic clearance of dexamethasone, consequently reducing its
serum levels and increasing the risk of Central Nervous System relapse [1,26-28] .

HSRs are the most common side-effect and can manifest as pain around the injection site, urticaria,
flushing, fever, chills, dyspnea, bronchospasm edema/angioedema, and hypotension. They could arguably
occur in as much as 75% of patients and could manifest as life-threatening anaphylactic reactions in 10%
of them and usually require changing the drug formulation [2,5,7-10,12,18,25,29] . The incidence is dependent on
different factors which include the number of doses received, route of administration, type of formulation
used, re-challenging after a period of interruption, and the administration of concomitant medications
during the course of treatment [1,8,9,12,25,30] .

One of the pioneer studies in the context of PGx of HSRs was a GWAS which aimed at identifying germline
genetic polymorphisms that could contribute to the risk of allergy in an ethnically diverse population of 485
ALL children treated with ASNase on St. Jude Children’s Research Hospital treatment protocol Total Therapy
XV. They interrogated over 500,000 single nucleotide polymorphisms (SNPs) and had many significant hits.
Essentially, the results demonstrated an overrepresentation of SNPs in genes located on chromosome 5q33 in
general (which is already known to be associated with several inflammatory or autoimmune diseases), and
in the GALNT10 and GRIA1 genes in particular. Indeed, the associations of five of the polymorphisms (i.e.,
rs4958381, rs10070447, rs6890057, rs4958676, and rs6889909) in GRIA1 gene with HSRs were successfully
[25]
validated within the same study in an independent replication cohort and were later replicated in an
independent Slovenian population of 146 pediatric ALL patients mainly treated according to one of Berlin-
[31]
Frankfurt-Münster (BFM) treatment protocols . Moreover, the authors reported an association between
the frequency of ASNase allergy and racial ancestry; with patients of Caucasian origins developing allergic
[25]
reactions at a higher frequency than those of Black or Hispanic ones . Another group tried to replicate
the results by targeting 20 SNPs in GRIA1 and GALNT10 genes in a candidate-gene fashion in a group of
Hungarian ALL children treated as part of the BFM Study Group. Briefly, they were unable to replicate
any of the results in the total cohort. However, interestingly, they found an opposite association between
rs4958381 in GRIA1 and reduced risk of HSRs in the T-cell ALL subgroup but not in the pre-B-cell ALL
patients. Moreover, they reported significant associations of two SNPs in GRIA1 not identified in the original
work (but only in the medium risk group), which can still serve as a further evidence of the implication of
the GRIA1 gene in the modulation of the risk of ASNase induced HSRs and might suggest that the influence
[9]
can vary depending on subgroups .
In another study that involved a total of 1870 patients of European ancestry, the authors imputed human
leukocyte antigen (HLA) alleles and searched for significant associations with ASNase hypersensitivity in
childhood ALL patients from Jude Children’s Research Hospital and the Children’s Oncology Group. They
reported a strong association of HLA-DRB1*07:01 allele in both groups and demonstrated that HLA-DRB1
alleles that confer high-affinity binding to ASNase epitopes contribute to the observed higher frequency of
[4]
HSRs .
Another GWAS was performed on a cohort of 3,308 pediatric ALL patients treated according to St. Jude
Children’s Research Hospital protocols or Children’s Oncology Group protocols and demonstrated that
variants within genes regulating the immune response, particularly genes involved in T-cell function,
strongly influenced the risk of ASNase hypersensitivity. The authors found a strong association between
a polymorphism in the nuclear factor of activated T cells 2 (NFATC2), rs6021191, and hypersensitivity to
ASNase. They also reported that the association was strongest among patients receiving native E. coli ASNase