Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia

Jitesh D. Kawedia, Chengcheng Liu, Deqing Pei, Cheng Cheng, Christian A. Fernandez, Scott C. Howard, Dario Campana, John C. Panetta, W. Paul Bowman, William E. Evans, Ching Hon Pui, Mary V. Relling

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57 Scopus citations

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 pharmacokinetic 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 negative (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.

Original languageEnglish
Pages (from-to)1658-1664
Number of pages7
JournalBlood
Volume119
Issue number7
DOIs
StatePublished - 16 Feb 2012

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    Kawedia, J. D., Liu, C., Pei, D., Cheng, C., Fernandez, C. A., Howard, S. C., Campana, D., Panetta, J. C., Bowman, W. P., Evans, W. E., Pui, C. H., & Relling, M. V. (2012). Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. Blood, 119(7), 1658-1664. https://doi.org/10.1182/blood-2011-09-381731