Unexpected Mortality from the Use of E-Coli L-Asparaginase during Remission Induction Therapy for Childhood Acute Lymphoblastic Leukemia: A Report from the Taiwan Pediatric Oncology Group

Abstract

The relative efficacy and toxicity of E. coli L-asparaginase and epidoxorubicin used in remission induction therapy for childhood acute lymphoblastic leukemia (ALL) were assessed in a randomized trial conducted in Taiwan. All patients had standard-risk ALL, defined as a leukocyte count < 10 x 10(9) /l and were aged between 1 and 2 or 7 and 10 years, or a leukocyte count <50 x 10(9)/l and were aged between 2 and 7 years, without evidence of a T cell or mature B cell immunophenotype, central nervous system leukemia or expression of two or more myeloid-associated antigens. Ninety-three patients were randomized to receive E. coli L- asparaginase at 10 000 IU/m(2) thrice weekly for nine doses and 108 to receive epidoxorubicin at 20 mg/m(2) weekly for two doses during remission induction with daily prednisolone , weekly vincristine and, on day 22, a dose of etoposide plus cytarabine. Patients treated with L-asparaginase had a significantly higher rate of fatal infection with or without hemorrhage than did those who received epidoxorubicin during remission induction (six of 93 vs none of 108, P = 0. 009), resulting in a lower rate of complete remission in the former group (93.6 vs 99.1%, P = 0.05). In addition, patients treated with L-asparaginase had a higher frequency of hyperglycemia and hypoalbuminemia. The overall rate of event-free survival was lower in patients treated with L- asparaginase than in other patients (P = 0.06); estimated 3- year rates were 72% (95% confidence interval, 55-89%) and 87.2% (78-96%), respectively. We conclude that L- asparaginase(Leunase) given at 10 000 IU/m(2) for nine doses was poorly tolerated and resulted in excessive toxicity, both through its effects as a single agent and possibly through potentiation of etoposide.