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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.
 Previous Article | Table of Contents | Next Article 
CLINICAL TRIALS AND OBSERVATIONS
Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome–positive leukemia
Kimmo Porkka1,2,
Perttu Koskenvesa1,2,
Tuija Lundán1,3,
Johanna Rimpiläinen4,
Satu Mustjoki1,2,
Richard Smykla5,
Robert Wild6,
Roger Luo5,
Montserrat Arnan7,
Benoit Brethon8,
Lydia Eccersley9,
Henrik Hjorth-Hansen10,
Martin Höglund11,
Hana Klamova12,
Håvar Knutsen13,
Suhag Parikh14,
Emmanuel Raffoux15,
Franz Gruber16,
Finella Brito-Babapulle9,
Hervé Dombret15,
Rafael F. Duarte7,
Erkki Elonen2,
Ron Paquette17,
C. Michel Zwaan18,19, and
Francis Y. F. Lee5
1 Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland;
2 Departments of Clinical Chemistry and Medicine/Hematology, and
3 HUSLAB, Department of Molecular Pathology, Helsinki University Central Hospital, Helsinki, Finland;
4 North-Karelia Central Hospital, Joensuu, Finland;
5 Bristol-Myers Squibb Research and Development, Princeton, NJ;
6 OSI Pharmaceuticals, In Vivo Pharmacology, Boulder, CO;
7 ICO-Hospital Duran i Reynals, Barcelona, Spain;
8 Hôpital Saint-Louis, Pediatric Hematology, Paris, France;
9 Ealing Hospital, Southall, United Kingdom;
10 Department of Hematology, St Olavs Hospital and Department of Molecular Medicine and Cancer Research, Norwegian University of Science and Technology, Trondheim, Norway;
11 Uppsala University Hospital, Uppsala, Sweden;
12 Institute of Hematology and Blood Transfusion, Prague, Czech Republic;
13 Akershus University Hospital, Lorenskog, Norway;
14 Duke University Medical Center, Pediatric Blood and Marrow Transplant Program, Durham, NC;
15 Hôpital Saint-Louis, Paris, France;
16 University of Tromsø, Tromsø, Norway;
17 University of California-Los Angeles;
18 Erasmus Medical Center (MC), Pediatric Oncology, Rotterdam, The Netherlands; and
19 The Innovative Therapies for Children with Cancer (ITCC) Consortium, Paris, France
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
[GenBank]
(#NCT00108719
[ClinicalTrials.gov]
) and CA180015
[GenBank]
(#NCT00110097
[ClinicalTrials.gov]
).
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