Page 110 - Read Online

Page 248 Abaji et al. Cancer Drug Resist 2019;2:242-55 I http://dx.doi.org/10.20517/cdr.2018.24

as compared to PEG-ASNase and that carrier-status of this intronic variant was associated with a higher
expression of the gene’s messenger RNA compared to noncarriers (both in ALL leukemic blast samples
and lymphoblastoid cell-lines). Moreover, looking at the association of nonsynonymous coding variants
with HSRs, they found that the most significant association was that of rs17885382 in HLA-DRB1 which
is in almost perfect linkage disequilibrium with HLA-DRB1*07:01 mentioned earlier and can be used as a
confirmation of the importance of the latter in influencing the risk of ASNase hypersensitivity. Importantly,
this finding extends the role of the polymorphism to non-European patients; since the new cohort was
ethnically diversified as opposed to the previous one which only involved patients with European ancestry.
Furthermore, the authors also demonstrated that the risk of HSRs associated with carrying the risk alleles of
[30]
rs6021191 in NFATC2 and rs17885382 in HLA-DRB1 was additive .
In a study performed on samples from 359 Hungarian childhood ALL patients treated with one of the
BFM protocols and aimed at using next-generation sequencing to identify associations between ASNase
hypersensitivity and polymorphisms of the Human Leukocyte Antigen (HLA) Class II region alleles, the
authors further confirmed that variations in HLA-D region can influence the development of ASNase HSRs.
For example, patients with HLA-DRB1*07:01 allele or HLA-DQB1*02:02 allele had a significantly higher risk
of developing this toxicity compared to non-carriers. Moreover, a significant association with the haplotype
HLA-DRB1*07:01-HLA-DQB1*02:02 was observed as carriers of this haplotype were at higher risk than
carriers of only one of the risk alleles. Furthermore, carrying the HLA-DRB1*07:01-HLA-DQA1*02:01-HLA-
DQB1*02:02 haplotype was associated with the highest risk of ASNase hypersensitivity. Of note, this study
also reported that HLA-DQB1*02:02 allele was significantly less frequent in the proportion of patients with
[32]
T-cell ALL than in pre-B-cell ALL patients .
Since patients with PEG-asparaginase HSRs were demonstrated to have no ASNase enzymatic activity, a
more recent study investigated genetic predisposition to PEG-asparaginase hypersensitivity in a GWAS
analysis by defining the hypersensitivity phenotype as both having clinical hypersensitivity and no
enzymatic activity. The genetic analysis was performed on fifty-nine cases and 772 control pediatric patients
treated on the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol.
The study found rs73062673 polymorphism of the CNOT3 gene to be associated with PEG-asparaginase
allergy. Of note, this gene was previously shown to regulate the transcription of HLA and to act as a tumour
suppressor which is frequently mutated in T‐cell ALL. The study also reported the detection of two other
associations involving rs9272131 and rs115360810 variants in the HLA-DQA1 and TAP2 genes, respectively.
While these associations were not significant on a genome-wide level, they remain of a particular interest
since the variants are located in a region known to be highly involved in allergic responses. These results
further suggest the implication of genetic variations in the HLA region, as well as regulators of these genes,
[33]
in the mechanisms leading to asparaginase hypersensitivity .
Other common adverse-events to ASNase are acute pancreatitis and cerebrovascular accidents, such
as thrombosis, which can occur in 18% and 5% of ALL patients, respectively; and are usually dose
limiting [2,10,12,15,18] . Pancreatitis symptoms can range from being mild and self-resolving, to a more severe
[15]
systemic inflammatory response syndrome and failure of pancreatic function . While the risk of mortality
due to ASNase induced acute pancreatitis is relatively low, the risk of recurrence upon re-challenge is almost
50% and patients affected by it have a higher risk of developing chronic or relapsing pancreatitis as well as
acute or persistent diabetes mellitus [12,15,34] . Clinical factors of ASNase associated pancreatitis include Native
[35]
American ancestry, older age, and higher cumulative ASNase exposure . While the role of genetics in
predisposition to acute recurrent and/or chronic pancreatitis of different etiologies has been the focus of
many studies (PRSS1, PRSS2, SPINK1, CFTR, CLDN2, CAP1) [34,36-39] , ASNase-related acute pancreatitis have
only started emerging recently.