Plasma asparaginase activity, asparagine concentration, and toxicity after administration of Erwinia asparaginase in children and young adults with acute lymphoblastic leukemia: Phase I/II clinical trial in Japan.

BACKGROUND

A phase I/II study of Erwinia asparaginase in Japanese children and young adults with acute lymphoblastic leukemia (ALL) was performed to investigate its activity and toxicity.

PROCEDURE

Eligible patients were in remission and had developed allergy to Escherichia coli asparaginase. Erwina asparaginase was intramuscularly administrated on days 2, 5, 7, 9, 11, and 13. To measure the plasma l-asparagine concentration (PAC), amino acids were derivatized with N -(5-fluoro-2,4-dinitrophenyl)-l-leucinamide.

RESULTS

Six consecutive patients completed the phase I study with 25,000 IU/m per dose without dose-limiting toxicity and 18 patients completed the phase II study with 25,000 IU/m per dose. Median age of 24 patients was 7.5 (range 2-16) years. The half-life of plasma asparaginase activity (PAA) was 16.9 ± 7.5 hr and the maximum PAA was 3.10 ± 1.47 IU/ml (n = 23, noncompartment model). PAA of 0.1 IU/ml or more was achieved in all 23 patients (100%) 48 hr and in 18 of 23 patients (78.3%) 72 hr after the first administration. During the 2-week study, 94.2% (65 of 69) of the 48-hr samples and 80.4% (37 of 46) of the 72-hr samples had PAA of 0.1 IU/ml or more. PAC less than 1.0 μM was achieved in 95.7% patients 48 and 72 hr after administration. PAC values in all the samples were greater than the limit of quantitation (0.0625 μM). Karnofsky performance status of all patients was good during the 2-week study.

CONCLUSIONS

Erwinia asparaginase 25,000 IU/m per dose × six intramuscular administrations in 2 weeks was well tolerated, pharmacologically efficacious, and safe in Japanese patients with ALL/lymphoblastic lymphoma.