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).
OBJECTIVE
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.


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 microM. This is significantly lower than the median Day 14 ASN level of 4 microM 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.
Jarrar
Mohammad
M
Department of Pediatrics, Division of Hematology/Oncology, USC Keck School of Medicine, Childrens Hospital Los Angeles, Los Angeles, California, USA.
Gaynon
Paul S
PS
Periclou
Antonia P
AP
Fu
Cecilia
C
Harris
Richard E
RE
Stram
Daniel
D
Altman
Arnold
A
Bostrom
Bruce
B
Breneman
John
J
Steele
David
D
Trigg
Michael
M
Zipf
Theodore
T
Avramis
Vassilios I
VI
D000917:Antibody Formation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001215:Asparaginase / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D001216:Asparagine / Q000187:drug effects* / Q000378:metabolism; D002648:Child; D005260:Female; D018698:Glutamic Acid / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D012008:Recurrence; D012074:Remission Induction; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D018698:Glutamic Acid; D011092:Polyethylene Glycols; D001216:Asparagine; C042705:pegaspargase; D001215:Asparaginase