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 Ͻ10 × 10 9 /l and were aged between 1 and 2 or 7 and 10 years, or a leukocyte count Ͻ50 × 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.

Asparaginase‐induced acute parotitis: An uncommon and self‐limiting complication

“…We hypothesize that individual genetic difference in response to Asp depletion may account for such variation. Since our four patients received two different Asp preparations (1 with Elspar, 3 with Leunase), manufacturing differences do not appear to be a contributory factor [7].…”

Long-term results of Taiwan Pediatric Oncology Group studies 1997 and 2002 for childhood acute lymphoblastic leukemia

“…1,3 Table 1 shows the risk classification system used to stratify patients into very high risk (VHR; 'high risk' in other studies), high risk (HR; 'intermediate risk' in other studies), and SR groups. Tables 2 and 3 summarize the treatment of protocols TPOG-2002 SR and HR, and of protocols TPOG-2002 VHR, respectively.…”

“…As our earlier experience had revealed that Escherichia coli L-asparaginase (Leunase) at 10 000 IU/m 2 per dose led to a higher mortality rate, 1 this agent has been used at 5000 IU/m 2 since 1997. In the subsequent study, TPOG- ALL-2002ALL- (2002ALL- -2007, we limited the use of cranial irradiation, replacing it with early intensification of triple intrathecal therapy; 2,3 SR patients were randomized to receive single or double reinduction therapy.…”

Multiplex RT‐PCR assay for the detection of major fusion transcripts in Taiwanese children with B‐lineage acute lymphoblastic leukemia

“…Cytogenetic analysis of the blast cells was performed using a direct method or short-term unstimulated cultures. The immunophenotyping was performed by flow cytometry using monoclonal antibodies against HLA-DR, CD34, CD19, CD10, cIgM, sIgM, CD7, CD2, CD5, CD3, CD13, CD14, CD33, CD41, and CD61 [22]. Written informed consent was obtained from parents or their legal guardians.…”