title: Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia.
abstract: We have previously hypothesized that higher systemic exposure to asparaginase may cause increased exposure to dexamethasone, both critical chemotherapeutic agents for acute lymphoblastic leukemia. Whether interpatient pharmaco-kinetic differences in dexamethasone contribute to relapse risk has never been studied. The impact of plasma clearance of dexamethasone and anti-asparaginase antibody levels on risk of relapse was assessed in 410 children who were treated on a front-line clinical trial for acute lymphoblastic leukemia and were evaluable for all pharmacologic measures, using multivariate analyses, adjusting for standard clinical and biologic prognostic factors. Dexamethasone clearance (mean ± SD) was higher (P = 3 × 10(-8)) in patients whose sera was positive (17.7 ± 18.6 L/h per m(2)) versus nega-tive (10.6 ± 5.99 L/h per m(2)) for anti-asparaginase antibodies. In multivariate analyses, higher dexamethasone clearance was associated with a higher risk of any relapse (P = .01) and of central nervous system relapse (P = .014). Central nervous system relapse was also more common in patients with anti-asparaginase antibodies (P = .019). In conclusion, systemic clearance of dexamethasone is higher in patients with anti-asparaginase antibodies. Lower exposure to both drugs was associated with an increased risk of relapse.
authors: Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, TN 38105-2794, USA.
authors: Jitesh D
authors: JD
authors: Kawedia
authors: Chengcheng
authors: C
authors: Liu
authors: Deqing
authors: D
authors: Pei
authors: Cheng
authors: C
authors: Cheng
authors: Christian A
authors: CA
authors: Fernandez
authors: Scott C
authors: SC
authors: Howard
authors: Dario
authors: D
authors: Campana
authors: John C
authors: JC
authors: Panetta
authors: W Paul
authors: WP
authors: Bowman
authors: William E
authors: WE
authors: Evans
authors: Ching-Hon
authors: CH
authors: Pui
authors: Mary V
authors: MV
authors: Relling
mesh_terms: D000293:Adolescent; D000328:Adult; D000465:Algorithms; D000906:Antibodies / Q000097:blood* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D016273:Occupational Exposure; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism; D012008:Recurrence; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000906:Antibodies; D003907:Dexamethasone; D001215:Asparaginase