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With the recent approval of asparaginase Erwinia chrysanthemi, three commercially available asparaginase products are on the US market.
Asparaginase therapy is an important component of acute lymphoblastic leukemia treatment. This review will highlight similarities and differences between the agents while comparing indications, dosing and toxicities.
Background
Native Escherichia coli asparaginase (Elspar, Lundbeck Inc.) was the only commercially available product in the US for a number of years.
In 1994, the FDA approved E. coliderived pegaspargase (Oncaspar, Sigma Tau Pharmaceuticals). Pegaspargase is a conjugate of a polyethylene glycol (PEG) moiety with the E. coli-derived asparaginase. Then, in November 2011, the FDA approved asparaginase E. chrysanthemi (Erwinaze, EUSA Pharma).
All three preparations deliver a bacterially derived enzyme, L-asparaginase, which results in the depletion of plasma asparagine through the hydrolysis of asparagine into aspartic acid and ammonia. Normal human cells can produce their own asparagine; however, many leukemia cells are unable to produce asparagine and therefore are dependent on exogenous sources. Depletion of plasma asparagine by asparaginase kills the leukemia cells.
Pharmacology
Asparagine depletion is dose-dependent, with higher enzyme levels resulting in greater levels of asparagine depletion. Asparaginase does not cross the blood-brain barrier; however, cerebrospinal fluid asparagine levels are reduced proportionally to the reduction of blood asparagine. The Erwinia preparation has the shortest elimination halflife of 16 hours. The native E. coli preparation has a half-life of approximately 1 day, whereas the pegylated product has a half-life of approximately 6 days.
Asparaginase levels have traditionally been easier to measure than actual asparagine depletion. Trough asparaginase levels of at least 0.1 IU/mL correspond with asparagine depletion below the limits of detection. Clinical benefit has been associated with asparaginase activity and depletion of asparagine. Therefore, patient outcomes are dependent on maintaining dose and schedule intensity of the asparaginase preparation to ensure adequate asparagine depletion.
Toxicities
Asparaginase products are associated with a number of noteworthy toxicities, many of which are distinct from what one expects from traditional chemotherapy.
Development of toxicity can affect the oncologist's ability to maintain asparaginase as a component of treatment and occasionally can impact the delivery of other chemotherapeutic agents. All products can cause nausea, vomiting and fatigue, which are not unique. However, these products also can cause a variety of toxicities, including hypersensitivity reactions,...