Low-Dosage Asparaginase Treatment of Childhood Acute Lymphocytic Leukemia

Abstract

Asparaginase was administered to children with acute lymphocytic leukemia in dosages less than those generally used. The objectives were to determine whether toxicity of the enzyme could be reduced without loss of efficacy, and to compare weekly with twice weekly administration. In five of 11 children who received 5,000 international units (IU)/sq m twice weekly for four doses and four of ten who received 10,000 IU/sq m once weekly for two doses, examination of bone marrow showed complete remission. Although the usual asparaginase-induced toxic reactions occurred, there were no deaths due to toxic reaction and no clinical signs of pancreatic dysfunction. Toxic reactions were comparable in the once weekly and twice weekly groups. Toxicity can be decreased without loss of efficacy by using these reduced dosage schedules.The enzyme asparaginase has been demonstrated to produce com¬ plete remission on bone marrow ex¬ amination in approximately 50% of children with acute lymphocytic leu¬ kemia refractory to conventional treatment.1" However, toxic reac¬ tions have been considerable. The en¬ zyme consistently produced fatty metamorphosis of the liver with de¬ rangement of hepatic function.:J-e-8-u Acute necrotizing pancreatitis was found in 10% of patients who failed to survive after asparaginase treatFollowing two to three weeks of enzyme therapy, anaphylac¬ toid reactions were common.'-17-9'"Abnormalities of blood coagulation factors1" were encountered frequent¬ ly but rarely were associated with fatal hemorrhage. In a previous study9 we found that weekly administration of asparagin¬ ase was as effective as a daily sched¬ ule in producing remissions and was accompanied by less toxic reaction.We also observed that treatment with asparaginase beyond two weeks did not result in further marrow im¬ provement when only partial remis¬ sions occurred.The objectives of this study were (1) to determine whether lower dos¬ age of asparaginase over shorter periods of time would result in de¬ creased toxicity without reduced fre¬ quency of remission induction, and(2) to compare once weekly and twice weekly administration with regard to efficacy and toxicity. Materials and MethodsAmorphous Escherichia coli asparagin¬ ase in vials containing 10,000 in¬ ternational units (IU) of the lyophilized powder was used. Specific activity of this preparation was 363 IU/mg protein. Prior to administration, 5 ml of water for in¬ jection was added to each vial and the cal¬ culated total dose was withdrawn. Each dose was further diluted with 5% dextrose in water to a total volume of 12 ml. This was administered intravenously over a pe¬ riod of five minutes.Patients were assigned by a randomiza¬ tion card technique to receive 10,000 IU/sq m of body surface area in¬ travenously weekly for two doses, or 5,000 IU/sq m twice weekly for four doses. Toxicity and response were evaluated follow¬ ing two weeks of treatment.Marrow response was quantitated ac¬ cording to the following criteria used at St. Jude Children's Research Hospital: (1) Complete remiss...

Long‐term neurological implications of somnolence syndrome in children with acute lymphocytic leukemia

“…Transient diffuse EEG slowing has accompanied these symptoms in reported patients who received high doses of the drug [20,25,311. None of our patients received high doses of asparaginase, however, and none had any appreciable EEG changes after the drug was given.…”

Alternative algorithm for L-asparaginase allergy in children with acute lymphoblastic leukemia

“…4 The frequency of clinical hypersensitivity reactions to E coli-asparaginase is quite variable, ranging from 0% to 45%. 3,[5][6][7][8] The risk factors for allergic reactions include doses higher than 6000 IU/m 2 /d, intravenous route of administration, repeated courses of treatment, and single-agent chemotherapy. 4 In case of hypersensitivity reactions, discontinuation of E coliasparaginase and substitution with Erwinia-or polyethylene glycol (PEG)-asparaginase is preferred.…”

Successful Treatment with Erwinia l -Asparaginase for Recurrent Natural Killer/T Cell Lymphoma

“…This patient did not show any anaphylactoid reaction, when Erwinia L-asparaginase was given intramuscularly. In general intramuscular administration causes fewer allergic reaction than intravenous administration of this agent [11,15] and because of this use we used Erwinia L-asparaginase intramuscularly.…”