Treatment Outcome of Discontinued L-Asparaginase in Children with Standard-Risk Acute Lymphoblastic Leukemia: Tokyo Children's Cancer Study Group (TCCSG) Study L99-15.

Abstract

BACKGROUND: L-asparaginase (L-asp) is one of the key drugs in the treatment of acute lymphoblastic leukemia (ALL) in children. However, L-asp often produces severe adverse effects including anaphylaxis resulting in its discontinuation.OBJECTIVE: To evaluate retrospectively the outcome of discontinuation of L-asp in patients with ALL.PATIENTS AND METHODS: Children newly diagnosed as ALL between 1999 and 2003 were consecutively enrolled on the TCCSG L99-15 study. Risk stratification was based on the age, initial white blood cell count, immunophenotype, cytogenetics and the response to prednisolone monotherapy. Totally, 267 (35%) out of 770 children were categorized into a standard-risk group (SR), 317 (41%) into a high-risk group (HR) and 186 (24%) into a very high-risk group (HEX). Allogeneic stem cell transplantation was indicated approximately in 50% of the HEX patients. L-asp was used 9 times in the induction phase in all the risk groups. The total number of L-asp administration all through the treatment was 19 in SR, 20 in HR and at least 10 in HEX. Patients were divided into two groups in the analysis: group A patients who received at least 50% of scheduled doses of L-asp and group B patients who received less than 50%.RESULTS: Remission was obtained in 259 (97%) patients in SR, 311 (98%) in HR and 171(92%) in HEX. In the patients who achieved remission and were analyzed, 195 (83.7%) in SR, 223 (78.8%) in HR and 123 (83.7%) in HEX received all the scheduled doses of L-asp. Event-free survival (EFS) (SE) and overall survival (OS) (SE) at 5 years for all the risk groups are shown in the table. Notably, EFS in group A (92.9%) and in group B (74.1%) in SR was significantly different (p=0.025).CONCLUSION: The outcome in patients who received less than 50% of scheduled dose of L-asp was inferior to that in the patients who received more than 50% of the scheduled dose. This suggests that modification or intensification of the treatment should be considered for the patients who discontinued L-asp in SR.EFS and OS in each groupRisk groupEFS ± SE(%)OS ± SE(%)(No. in A /B)group Agroup Bp valuegroup Agroup Bp valueSR (223 /10)92.9±2.474.1±16.10.02597.8±1.188.9±10.50.066HR (269 /14)78.5±3.266.7±19.20.96988.9±2.650.0±25.00.158HEX (142 /5)58.2±5.575.5±21.70.51475.6±4.380.0±17.90.873