Page 108 - Read Online

Page 246 Abaji et al. Cancer Drug Resist 2019;2:242-55 I http://dx.doi.org/10.20517/cdr.2018.24

Figure 1. Mechanism of action of Asparginase. Illustration of the mechanism of action of asparaginase as an anti-leukemic agent. The
activity of asparaginase leading to the depletion of extra-cellular asparagine and/or glutamine and eventual cell death is counteracted
by the intra-cellular production of these amino acids through asparagine synthetase and glutamine synthetase, respectively. To be
noted: the relative difference in size between the Asparagine and Glutamine Pathways is meant to reflect the magnitude of the effect of
Asparaginase on amino acide depletion which is more prominenet in the context of the asparagine compared to glutamine

as a contributor to ASNase sensitivity with primary involvement of ADSL and DARS genes. The authors were
[19]
also able to reproduce significant associations in primary ALL leukemic blasts .

Historically, three asparaginase preparations were commercially available and each of them has different
pharmacokinetic properties. The original preparation was derived from Escherichia coli (and is referred
to as E. coli asparaginase), but it has been abandoned by most developed countries due to its toxicity
profile (particularly allergic reactions), and the adoption of its less immunogenic pegylated form (PEG-
asparaginase). While PEG-asparaginase is relatively more expensive than its parent-compound, it is
considered to be a safer and more effective treatment with a prolonged duration of activity. The third
product is a formulation derived from Erwinia chrysanthemi (Erwinia asparaginase) and is generally
associated with lower immunogenic properties and less toxicity. However, its pharmacokinetic profile
was reported to be associated with poorer treatment outcome when compared to other formulations at
a similar posology (mainly attributed to its shorter duration of activity), suggesting the need for higher
doses and increased frequency of administration in order to achieve optimal asparagine depletion. Thus,
its use is usually restricted to patients who develop allergic reactions “or silent inactivation” to the E. coli/
PEG-asparaginase owing to the lack of cross-reactivity [1,5,7,8,10,22] ; although it is important to mention that
[23]
controversies on ASNase antibodies formation and its activity have been reported . Several clinical trials
have reported associations between success of ALL treatment and ASNase dose intensity or formulation [10,22] .
Of note, enzyme variants with reduced L-glutaminase coactivity are being tested for their clinical utility
as antileukemic agents with potentially lower side effects (since several studies suggested that the depletion
of L-glutamine may correlate with many of the side effects of the enzyme). For example, a recent study
demonstrated that novel low L-glutaminase variants derived from modifications to Erwinia asparaginase
[24]
can offer high efficacy against both T-Cell and B-Cell ALL while provoking less toxicities .
PHARMACOGENETICS OF ASPARAGINASE
Hypersensitivity reactions, pancreatitis and thrombosis
Since ASNase is a foreign protein produced in bacteria, it is not surprising that all formulations of ASNase,
to varying extents, have the immunogenic potential to provoke the formation of antibodies which can either
be associated with clinical symptoms manifested in ASNase allergy and hypersensitivity reactions (HSRs),
or can be asymptomatic but still capable of neutralizing the activity of ASNase leading to suboptimal
response and thus referred to as “silent hypersensitivity” or “silent inactivation” which occurs in up to 30% of
patients [1,8,9,12,25] . While the allergic symptoms can be mitigated through premedication with anti-histamines