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Abaji et al. Cancer Drug Resist 2019;2:242-55 I http://dx.doi.org/10.20517/cdr.2018.24 Page 243
[5]
a significant challenge . The incorporation of ASNase into adults and young adult protocols is still limited
[6]
due to its toxicity profile in this population . On the other hand, the introduction of ASNase into pediatric
regimens for ALL treatment and the intensification of its use, along with dexamethasone and vincristine
[1]
(VCR), is to be credited for most of the improvement in ALL treatment outcome . A typical ALL treatment
protocol consists of phases that focus on remission-induction, consolidation and maintenance. ASNase is
usually administered during the induction phase as well as throughout the consolidation therapy where it is
[5,7]
administered for 20-30 weeks together with glucocorticoids and vincristine .
ALL accounts for 30% of pediatric cancers and is the most common childhood malignancy in developed
and underdeveloped countries [1,8,9] . The past few decades have witnessed a revolution in the treatment of
ALL as survival rates increased considerably from less than 40% in the mid-sixties to currently exceed
90% for most international protocols [1,2,10-12] . This result was achieved by the creation and continuous
optimization of multi-agent protocols through evidence based medicine, refined stratification of patients
into risk groups, personalized chemotherapy that exploit the differences in the characteristics between host
and leukemia cells, and improvement in supportive care [5,12-14] . While these figures seem quite encouraging,
there is a large margin for improvement as treatment failure, cancer relapse, and treatment-related toxicities
[8]
continue to jeopardize the lives of a significant percentage of children with ALL . It is estimated that almost
50% of patients will experience at least one acute severe toxicity, and that a considerable percentage of
mortality among leukemia patients is attributable to adverse-events of the treatment rather than the actual
sickness [2,12,15] . In fact, these toxicities can often be life-threatening and are the primary cause of interruption
[2]
[10]
or discontinuation of chemotherapy and are a frequent cause of sequelae on the long-term . Indeed, the
recent improvement in survival rate has resulted in a gradual shift towards putting more focus on reducing
the toxicity burden of chemotherapy [2,15] .

Consequently, several research groups are investigating biomarkers that can predict the risk of treatment
resistance or treatment-related adverse effects even before starting the therapy in the hope of being able to
modify the treatment in a patient-tailored manner that would increase the probability of response and reduce
the risk of side-effects. This is the core goal of pharmacogenetics (PGx) which aims at enhancing treatment
efficacy and safety by providing a better understanding of the genetic basis of variability and its effect on
the pharmacological responses [14,16] . Indeed, there are several success stories in which PGx discoveries
have restructured the medical practice and the classical example is the genotyping of TPMT gene to guide
the dosing of mercaptopurine which is considered mandatory in almost all recent practice guideline .
[17]
Accordingly, many groups studied the pharmacogenetics of ASNase aiming to uncover the genes mediating
ASNase antileukemia effect and the genetic basis of interpatient variability in response. However, the
implementation of such findings in ALL management remains debatable. In this review, we highlight the
most important findings reported up-to-date which tackled the PGx of ASNase-related complications and
treatment outcome. We used different search-engine tools - but mainly the ones embedded in the NCBI
platform- to identify eligible scientific papers that included the word asparaginase along with either the
term pharmacogenomics or pharmacogenetics. Upon evaluating the content of these papers, a filtering step
was applied in order to retain only the articles that specifically addressed the PGx of ASNase, which are
summarized in Table 1.

MECHANISM OF ACTION, RESISTANCE AND FORMULATIONS
The exact mechanism of the anti-leukemic effect of ASNase is still not fully understood. However, it is
generally accepted that this enzyme works by hydrolysing asparagine - and glutamine - in the serum,
thus depleting the extracellular compartment from these amino acids essential for survival of all cells
[Figure 1] [7,10,14,18,19] . Asparagine is produced by the enzyme asparagine synthetase, encoded by the ASNS
gene, which catalyzes the transfer of an amino group to aspartic acid to form asparagine, and may thus
counteract the effect of asparaginase and produce resistance as suggested by in vitro experiments conducted
in leukemia cell lines and patient lymphoblasts [5,10,18] .