L-Asparaginase and PEG Asparaginase— Past, Present, and Future

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Abstract
L-asparaginase is an enzyme which hydrolyses asparagine. Since the 1960s it has been known that some leukemic cells are deficient in asparagine synthetase and therefore cannot manufacture sufficient quantities of this essential amino acid to maintain cell viability. L-asparaginase is predominantly useful in acute lymphocytic leukemia (ALL) although responses have been noted in patients with acute myeloid leukemia, lymphoma, and rarely other tumors. L-asparaginase has been used in conjunction with methotrexate and ara-C in combination programs in leukemia. The major side-effect limiting the usefulness of L-asparaginase is allergic reactions. In addition, it is probable that neutralizing antibodies develop which shorten the half life of the drug so that the goal of depletion of plasma levels of asparagine cannot be attained or maintained. Polyethylene glycol (M.W. 5000) can be conjugated to L-asparaginase at sites not involving the active site of the enzyme. This enables free access of a small molecule, asparagine, to the active site of the enzyme but prevents uptake by the reticuloendothelial system, greatly decreasing the probability of developing antibodies against the asparaginase and prolongs the circulating half life of the drug. In a phase I/II study conducted at the M.D. Anderson Cancer Center, 37 heavily pretreated patients with refractory hematologic malignancy were treated. The age range from 15 to 73 years, median 49 years. Nineteen patients had ALL, 15 lymphoma, two myeloma, and one Hodgkin's disease. The dose levels of PEG L-asparaginase varied from 250 IU/m2 up to 8000 IU/m2. The pharmacokinetic profile demonstrated a mono-phasic half life consistent with a one compartment model with a single elimination phase. The mean t1/2 of PEG L-asparaginase was 357 hours compared with 20 hours for L-asparaginase. The major side effects were nausea and vomiting, peripheral edema, hypoalbuminemia and hepatic dysfunction. Three patients developed allergic reactions. There was no clear relationship between the dose of PEG L-asparaginase and toxicity. Three patients achieved complete remission, two with lymphoma, and one with ALL. Doses were repeated at two week intervals. Asparaginase depletion was documented to persist until the next dose. Thus PEG L-asparaginase allows for less frequent dosing, good tolerance, and persistent asparagine depletion with an acceptable toxicity profile. Further evaluation of the role of PEG L-asparaginase in patients who are documented to be hypersensitive to native L-asparaginase is indicated and additional clinical trials are being conducted to evaluate response.