title: Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia.
abstract: BACKGROUND
  Many antileukaemic agents or their metabolites are inactivated by liver enzymes. Most anticonvulsant drugs induce drug-metabolising enzymes and thereby increase the clearance of anticancer agents. We investigated whether anticonvulsants compromise the efficacy of cancer chemotherapy.
  
  
  METHODS
  We identified whom of 716 children treated consecutively for acute lymphoblastic leukaemia at a single academic hospital in the USA between 1984 and 1994 received treatment for 30 days or longer with anticonvulsants (phenytoin, phenobarbital, carbamazepine, or a combination) at the same time as antileukaemic therapy. Cox's proportional-hazards models were used to assess the prognostic significance of anticonvulsants on event-free survival and risk of haematological and central-nervous-system (CNS) relapse, with stratification for treatment protocol.
  
  
  RESULTS
  40 (5.6%) of 716 patients received anticonvulsants. Use of these drugs was associated with age over 10 years (p=0.003), non-hyperdiploid leukaemia (p=0.031), and T-cell immunophenotype (p=0.022). After adjustment for age and ploidy, anticonvulsant therapy was significantly related to worse event-free survival (hazard ratio 2.67 [95% CI 1.50-4.76]; p=0.0009), haematological relapse (3.40 [1.69-6.88]; p=0.0006), and CNS relapse (2.90 [1.01-8.28]; p=0.047) among the 566 patients with B-lineage leukaemia. No such associations were seen among the 114 patients with T-cell leukaemia (p=0.61, 0.35, and 0.53, respectively). Faster clearance of teniposide (p=0.0001) and methotrexate (p=0.051), but not cytarabine (p=0.26) was found among patients receiving anticonvulsants.
  
  
  CONCLUSIONS
  Long-term anticonvulsant therapy increases the systemic clearance of several antileukaemic agents and is associated with lower efficacy of chemotherapy. Alternatives to enzyme-inducing anticonvulsants should be prescribed for patients receiving chemotherapy for acute lymphoblastic leukaemia.
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN 38105, USA. mary.relling@stjude.org
authors.forename: M V
authors.initials: MV
authors.lastname: Relling
authors.forename: C H
authors.initials: CH
authors.lastname: Pui
authors.forename: J T
authors.initials: JT
authors.lastname: Sandlund
authors.forename: G K
authors.initials: GK
authors.lastname: Rivera
authors.forename: M L
authors.initials: ML
authors.lastname: Hancock
authors.forename: J M
authors.initials: JM
authors.lastname: Boyett
authors.forename: E G
authors.initials: EG
authors.lastname: Schuetz
authors.forename: W E
authors.initials: WE
authors.lastname: Evans
mesh_terms: D000927:Anticonvulsants / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants