Abstract 2767: Effect of obesity on glutamine levels after L-asparaginase

Abstract

Abstract L-asparaginase is used as a first-line agent in the treatment of acute lymphoblastic leukemia (ALL). It is believed to act primarily via depletion of the non-essential amino acid asparagine (ASN), since ALL cells are unable to synthesize sufficient ASN to meet their high metabolic demands. However, there is evidence that the depletion of glutamine (GLN) by L-asparaginase might also be important in its anti-leukemia activity. We have previously shown that children who are obese at the time they are diagnosed with high-risk ALL have a 50% higher chance of relapse. Since adipose tissue is known to produce GLN, the present study was designed to test whether obese subjects diagnosed with high-risk ALL would have less suppression of GLN after an injection of PEG-Asparaginase than their lean counterparts. Four lean (BMI 35 ± 19 %ile, 2 male/2 female) and 3 obese (BMI 98 ± 1 %ile, 2 male/1 female) adolescents with new diagnosis of high-risk ALL were studied so far. Amino acid levels were measured by HPLC in the CHLA clinical laboratory prior to and at weekly interval after injection of PEG-Asparaginase (2500 IU/m2). One lean subject received the drug intravenously, the remainder intra-muscularly. The other drugs used in induction were vincristine, daunomycin and prednisone, per CCG 1961 protocol, not on study. No dose adjustments were made based on obesity. Prior to treatment, there were no differences in plasma ASN (44.3±17.2 vs. 42.5±17.3 μM obese vs. lean, p=0.90) or GLN (539±78 vs. 567±247 μM, obese vs. lean, p=0.85) levels between groups. Two weeks after treatment, ASN levels were suppressed to ≤2 μM in both groups. In contrast, GLN levels after PEG-Asparaginase were different in obese vs. lean patients: in the obese patients, GNL level significantly increased by the second week after treatment (709±111 μM, p=0.02 vs. week 0) while no significant changes were detected in lean subjects (509±141 μM, p=0.36 vs. week 0). The change in GLN level from week 0 to 2 was +170±43 and −58±107 μM in obese and lean subjects, respectively (p=0.02). Thus, obesity appears to affect GLN levels after a single injection of PEG-Asparaginase. The differences in plasma GLN levels might reflect larger differences in GLN levels in the local leukemia microenvironment (e.g. bone marrow, adipose tissue). Although the clinical significance of this observation is limited by the small patient sample, these data highlight the need for further studies to investigate the role of obesity on the efficacies of chemotherapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2767.