title: Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.
abstract: Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
authors.affiliation: Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland. kimmo.porkka@helsinki.fi
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.forename: Perttu
authors.initials: P
authors.lastname: Koskenvesa
authors.forename: Tuija
authors.initials: T
authors.lastname: Lundán
authors.forename: Johanna
authors.initials: J
authors.lastname: Rimpiläinen
authors.forename: Satu
authors.initials: S
authors.lastname: Mustjoki
authors.forename: Richard
authors.initials: R
authors.lastname: Smykla
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.forename: Roger
authors.initials: R
authors.lastname: Luo
authors.forename: Montserrat
authors.initials: M
authors.lastname: Arnan
authors.forename: Benoit
authors.initials: B
authors.lastname: Brethon
authors.forename: Lydia
authors.initials: L
authors.lastname: Eccersley
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjorth-Hansen
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
authors.forename: Hana
authors.initials: H
authors.lastname: Klamova
authors.forename: Håvar
authors.initials: H
authors.lastname: Knutsen
authors.forename: Suhag
authors.initials: S
authors.lastname: Parikh
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Raffoux
authors.forename: Franz
authors.initials: F
authors.lastname: Gruber
authors.forename: Finella
authors.initials: F
authors.lastname: Brito-Babapulle
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Rafael F
authors.initials: RF
authors.lastname: Duarte
authors.forename: Erkki
authors.initials: E
authors.lastname: Elonen
authors.forename: Ron
authors.initials: R
authors.lastname: Paquette
authors.forename: C Michel
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Francis Y F
authors.initials: FY
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002648:Child; D020732:Cytogenetic Analysis; D000069439:Dasatinib; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012074:Remission Induction; D013129:Spinal Puncture; D015996:Survival Rate; D013844:Thiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib