Asparagine depletion after pegylated E. coli asparaginase treatment and induction outcome in children with acute lymphoblastic leukemia in first bone marrow relapse: A Children's Oncology Group study (CCG‐1941)

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Abstract
Purpose Re‐induction outcomes vary for children with acute lymphoblastic leukemia (ALL) and marrow relapse. We explored possible relationships among asparaginase (ASNase) activity levels, asparagine (ASN) depletion, anti‐ASNase antibody titers, and response to re‐induction therapy in children and adolescents with ALL and an ‘early’ first marrow relapse. Patients and methods After appropriate informed consent, we enrolled children and adolescents 1–21 years old with ALL and first marrow relapse within 12 months of completion of primary therapy. Induction therapy included intramuscular pegylated ASNase on Days 2 and 16. We assessed ASNase activity, anti‐ASNase antibody titers against native and pegylated (E. coli) ASNase, and amino acid levels of asparagine (ASN) and glutamine (GLN) on Days 0, 14, and 35 of re‐induction. Results Ninety‐three patients were at least partially assessable. Among 21 patients with M1 marrow status at Day 35, the median Day 14 ASN level was <1 µM. This is significantly lower than the median Day 14 ASN level of 4 µM in the group of patients with M3 marrow at Day 35. Neither Day 0 nor Day 35 antibody titers predicted ASNase enzymatic activity level on Day 14. Surprisingly, Day 14 ASNase activity did not predict serum ASN level on Day 14. However, Day 0 and Day 35 anti‐native ASNase antibody titers, and Day 0 anti‐PEG ASNase antibody titers correlated positively with Day 14 serum ASN levels as one might expect from neutralizing antibody. Day 35 anti‐PEG ASNase antibody titers did not. Conclusions Patients with greater ASN depletion were more likely to achieve second remission in the context of six‐drug therapy. Pediatr Blood Cancer

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