Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia
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- Kimmo Porkka
- Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland;
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- Perttu Koskenvesa
- Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland;
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- Tuija Lundán
- Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland;
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- Johanna Rimpiläinen
- North-Karelia Central Hospital, Joensuu, Finland;
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- Satu Mustjoki
- Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland;
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- Richard Smykla
- Bristol-Myers Squibb Research and Development, Princeton, NJ;
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- Robert Wild
- OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, CO;
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- Roger Luo
- Bristol-Myers Squibb Research and Development, Princeton, NJ;
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- Montserrat Arnan
- ICO-Hospital Duran i Reynals, Barcelona, Spain;
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- Benoit Brethon
- Hôpital Saint-Louis, Pediatric Hematology, Paris, France;
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- Lydia Eccersley
- Ealing Hospital, Southall, United Kingdom;
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- Henrik Hjorth-Hansen
- Department of Hematology, St Olavs Hospital and Department of Molecular Medicine and Cancer Research, Norwegian University of Science and Technology, Trondheim, Norway;
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- Martin Höglund
- Uppsala University Hospital, Uppsala, Sweden;
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- Hana Klamova
- Institute of Hematology and Blood Transfusion, Prague, Czech Republic;
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- Håvar Knutsen
- Akershus University Hospital, Lorenskog, Norway;
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- Suhag Parikh
- Duke University Medical Center, Pediatric Blood and Marrow Transplant Program, Durham, NC;
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- Emmanuel Raffoux
- Hôpital Saint-Louis, Paris, France;
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- Franz Gruber
- University of Tromsø, Tromsø, Norway;
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- Finella Brito-Babapulle
- Ealing Hospital, Southall, United Kingdom;
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- Hervé Dombret
- Hôpital Saint-Louis, Paris, France;
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- Rafael F. Duarte
- ICO-Hospital Duran i Reynals, Barcelona, Spain;
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- Erkki Elonen
- Departments of Clinical Chemistry and Medicine/Hematology, and
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- Ron Paquette
- University of California-Los Angeles;
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- C. Michel Zwaan
- Erasmus Medical Center (MC), Pediatric Oncology, Rotterdam, The Netherlands; and
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- Francis Y. F. Lee
- Bristol-Myers Squibb Research and Development, Princeton, NJ;
書誌事項
- 公開日
- 2008-08-15
- DOI
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- 10.1182/blood-2008-02-140665
- 公開者
- American Society of Hematology
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>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).</jats:p>
収録刊行物
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- Blood
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Blood 112 (4), 1005-1012, 2008-08-15
American Society of Hematology