Effective Dose of L-Asparaginase for Induction of Remission in Previously Treated Children with Acute Lymphocytic Leukemia: A Report from Childrens Cancer Study Group1

L-Asparaginase, in the dose of >6000 ID/sq m three times weekly, was demonstrated to be an effective agent in reinduction of remissions in childhood leukemia. Four hundred thirteen children with acute lymphocytic leu kemia were treated with L-asparaginase. Doses i.m. ranged from 300 to 12,000 lU/sq m. None of the patients had received prior asparaginase therapy. 6-Mercaptopurine was given p.o. concurrently. All of the patients had experienced several pre vious relapses, and their disease was not responsive to 6mercaptopurine. L-Asparaginase was found to be effective in reinducing remissions at the following rates: 9.5% for 300 ID/ sq m; 35.1% for 3,000 lU/sq m; 53.5% for 6,000 lU/sq m; and 62.5% for 12,000 lU/sq m. The drug was given three times weekly for four weeks. Hypersensitivity reactions oc curred in 6.5% of patients. INTRODUCTION L-Asparaginase has been highly successful for inducing re missions in acute leukemia since 1967 (11). The doses used ranged from 300 IU (13, 15) to 425,000 IU (7) per sq m i.v. or i.m. (1, 4, 7, 13-15). The interval of drug administration has ranged from daily to once weekly. A major toxicity of L-asparaginase has been hypersensitivity; one-fourth to one-third of the patients have shown significant reactions during the first course of i.v. therapy (12). Previously, we have shown that, by giving the enzyme i.m. and also by adding 6-mercaptopurine to therapy, the incidence of hyper sensitivity reactions to L-asparaginase can be decreased (9, 10). This paper summarizes the clinical results of a study to determine the most effective, but lowest, dosage of L-aspa raginase when combined with 6-mercaptopurine for the reinduction of remission in children with acute lymphocytic leuke mia in relapse. MATERIALS AND METHODS A cooperative study was initiated in 1971 by the Childrens Cancer Study Group to determine the most effective and least toxic dose schedule of L-asparaginase to be used for the reinduction of remission in children with previously relapsed acute lymphocytic, stem cell, or undifferentiated leukemia. L-Asparaginase2 was used after dilution with 0.9% NaCI solution (2 ml) without preservative. The enzyme was immedi ately injected i.m. Patients who developed CMS3 leukemia during induction therapy were treated with either i.t. methotrexate or radiation therapy. Patients were removed from the study if they failed to enter remission or if they had uncontrollable toxicity. Patients were eligible for the protocol if they had not received L-asparaginase before and if their disease was resistant to 6mercaptopurine as evidenced by either failing induction with 6mercaptopurine or relapsing while on 6-mercaptopurine main tenance. A review of evidence for resistance to 6-mercapto purine was performed retrospectively, and the patients with some question of 6-mercaptopurine resistance were not eligible for the induction evaluation. These patients were included in the evaluation for toxicity and other complications. The initial randomization was between L-asparaginase doses of 300 and 12,000 ID/sq m i.m. 3 times weekly (Chart 1) combined with 6-mercaptopurine (75 mg/sq m p.o. daily). The randomization was changed to 3000 IU versus 6000 IU when significant differences in the induction rate of the original regimens were detected. The L-asparaginase was to be started on Day 3. The selection of these doses for L-asparaginase represented narrowing the spectrum of the doses reported to have some activity. Bone marrow examination was performed after 14 and 28 days of therapy, and if the patient had not achieved a complete remission (6) within that time it was permissible to extend the therapy for 2 more weeks. RESULTS Between January 1971 and August 1975, 413 children were admitted to both randomizations of this study. Of these, 297 were documented to be resistant to 6-mercaptopurine (évalu able for induction). In the first randomization, the lowest dose of L-asparaginase (300 lU/sq m) used in combination with 6mercaptopurine was shown to have only minimal activity; 9.3% achieved an M-1 (bone marrow cell differential count with less than 5% blast forms) remission, while 55.3% reached an M-1 marrow on the higher dose of 12,000 lU/sq m (p = 0.0002). Following completion of this section of the study, patients were randomized between L-asparaginase doses of 3000 and 6000 lU/sq m. When the dose of 3000 lU/sq m was shown to be less effective (30.4% remissions, p = 0.04) than the higher dose of 6000 lU/sq m with 45.3% remissions, randomization ' Childrens Cancer Study Group investigators, institutions, and grant numbers are given in "Appendix." Address requests for reprints to Childrens Cancer Study Group Operations Office, 1721 Griffin Avenue, Los Angeles, Calif. 90031. Received February 8, 1979; accepted June 26, 1979. 2 Crasnitin was provided in 2.000and 10,000-unit vials by Bayer Co.. whose representative in the United States is Delbay Pharmaceuticals. Inc.. Bloomfield, N.J. 3 The abbreviations used are: CNS. central nervous system: i.t.. intrathecal.