title: Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571).
abstract: Isolated central nervous system (CNS) relapse occurred in 5 out of 24 patients (20.8%) with chronic myeloid leukemia (CML) lymphoid blast crisis (2), Philadelphia (Ph) chromosome positive acute lymphoblastic leukemia (ALL) (2) or CML with biphenotypic markers (1) treated on imatinib mesylate (IM) protocols at our institution. CNS relapse occurred despite peripheral blood (5) and bone marrow (3) complete responses. Median time to CNS relapse was day 32 (range 23 to 100). This observation raised the possibility that IM may not penetrate into the CNS. Simultaneous plasma and cerebral spinal fluid (CSF) IM levels were determined in four subsequent patients by liquid chromatography and mass spectrophotometric assay. Levels of IM were found to be approximately two logs lower in CSF than in plasma (0.044 microg/ml (0.088 +/- 0.029 micrro) vs 3.27 microg/ml (6.54 +/- 0.93 microM)). CSF levels were substantially below the concentration required for inhibition of BCR-ABL and killing of cell lines in vitro. These results suggest that IM may not penetrate the intact blood/brain barrier and its implications are discussed.
authors.affiliation: Oregon Health and Sciences University, Adult Bone Marrow Transplant Program, Portland, OR 97201, USA. leisj@ohsu.edu
authors.forename: Jose F
authors.initials: JF
authors.lastname: Leis
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Stepan
authors.forename: Peter T
authors.initials: PT
authors.lastname: Curtin
authors.forename: John M
authors.initials: JM
authors.lastname: Ford
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.forename: Susan
authors.initials: S
authors.lastname: Schubach
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Richard T
authors.initials: RT
authors.lastname: Maziarz
mesh_terms: D000328:Adult; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy / Q000473:pathology*; D001812:Blood-Brain Barrier; D016543:Central Nervous System Neoplasms / Q000209:etiology*; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D011743:Pyrimidines / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D012008:Recurrence; D012074:Remission Induction / Q000379:methods; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate