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Blood, 15 August 2008, Vol. 112, No. 4, pp. 1005-1012.
Prepublished online as a Blood First Edition Paper on May 13, 2008; DOI 10.1182/blood-2008-02-140665.
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Submitted February 19, 2008
Accepted April 14, 2008
Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia
Kimmo Porkka*, Perttu Koskenvesa, Tuija Lundan, Johanna Rimpilainen, Satu Mustjoki, Richard Smykla, Robert Wild, Roger Luo, Montserrat Arnan, Benoit Brethon, Lydia Eccersley, Henrik Hjorth-Hansen, Martin Hoglund, Hana Klamova, Havar Knutsen, Suhag Parikh, Emmanuel Raffoux, Franz Gruber, Finella Brito-Babapulle, Herve Dombret, Rafael F. Duarte, Erkki Elonen, Ron Paquette, C Michel Zwaan, and Francis YF Lee
Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland
Departments of Clinical Chemistry and Medicine/Hematology, Helsinki University Central Hospital, Helsinki, Finland
HUSLAB, Department of Molecular Pathology, Helsinki University Central Hospital, Helsinki, Finland
North-Karelia Central Hospital, Joensuu, Finland
Bristol-Myers Squibb Research and Development, Princeton, NJ, United States
In Vivo Pharmacology, OSI Pharmaceuticals, Boulder, CO, United States
ICO-Hospital Duran i Reynals, Barcelona, Spain
Pediatric Hematology, Hopital Saint-Louis, Paris, France
Ealing Hospital, Middlesex, United Kingdom
St Olavs Hospital and Department of Molecular Medicine and Cancer Research, Norwegian University of Science and Technology, Trondheim, Norway
Uppsala University Hospital, Uppsala, Sweden
Institute of Hematology and Blood Transfusion, Prague, Czech Republic
Akershus University Hospital, Lorenskog, Norway
Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC, United States
Hopital Saint-Louis, Paris, France
University of Tromso, Tromso, Norway
Hematology Research Unit, Biomedicum Helsinki, Finland
UCLA, Los Angeles, United States
Pediatric Oncology, Erasmus MC, Rotterdam, Netherlands
* Corresponding author; email: kimmo.porkka{at}helsinki.fi.
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 due to poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (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, while imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease was achieved with continued dasatinib 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 seven patients. In three additional patients, isolated CNS relapse occurred during dasatinib therapy and in two 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).
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