Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia

被引：325

作者：

Porkka, Kimmo ^{[1
,2
,3
]}

Koskenvesa, Perttu ^{[1
,2
,3
]}

Lundan, Tuija ^{[1
,4
]}

Rimpilaeinen, Johanna ^{[5
]}

Mustjoki, Satu ^{[1
,2
,3
]}

Smykla, Richard ^{[6
]}

Wild, Robert ^{[7
]}

Luo, Roger ^{[6
]}

Arnan, Montserrat ^{[8
]}

Brethon, Benoit ^{[9
]}

Eccersley, Lydia ^{[10
]}

Hjorth-Hansen, Henrik ^{[11
,12
]}

Hoeglund, Martin ^{[13
]}

Klamova, Hana ^{[14
]}

Knutsen, Havar ^{[15
]}

Parikh, Suhag ^{[16
]}

Raffoux, Emmanuel ^{[17
]}

Gruber, Franz ^{[18
]}

Brito-Babapulle, Finella ^{[10
]}

Dombret, Herve ^{[17
]}

Duarte, Rafael F. ^{[8
]}

Elonen, Erkki ^{[2
,3
]}

Paquette, Ron ^{[19
]}

Zwaan, C. Michel ^{[20
,21
]}

Lee, Francis Y. F. ^{[6
]}

机构：

[1] Biomed Helsinki, Hematol Res Unit, FIN-00029 Helsinki, Finland

[2] Univ Helsinki, Cent Hosp, Dept Clin Chem, Helsinki, Finland

[3] Univ Helsinki, Cent Hosp, Dept Med Hematol, Helsinki, Finland

[4] Univ Helsinki, Cent Hosp, HUSLAB, Dept Mol Pathol, Helsinki, Finland

[5] N Karelia Cent Hosp, Joensuu, Finland

[6] Bristol Myers Squibb Res & Dev, Princeton, NJ USA

[7] OSI Pharmaceut, In Vivo Pharmacol, Boulder, CO USA

[8] ICO Hosp Duran & Reynals, Barcelona, Spain

[9] Hop St Louis, Paris, France

[10] Ealing Gen Hosp, Southall, Middx, England

[11] St Olavs Hosp, Dept Hematol, Trondheim, Norway

[12] Norwegian Univ Sci & Technol, Dept Mol Med & Canc Res, N-7034 Trondheim, Norway

[13] Univ Uppsala Hosp, Uppsala, Sweden

[14] Inst Hematol & Blood Transfus, CR-12820 Prague, Czech Republic

[15] Aker Univ Hosp, Lorenskog, Norway

[16] Duke Univ, Med Ctr, Pediat Blood & Marrow Transplant Program, Durham, NC USA

[17] Hosp St Louis, Paris, France

[18] Univ Tromso, Tromso, Norway

[19] Univ Calif Los Angeles, Los Angeles, CA USA

[20] Erasmus Med Ctr MC, Rotterdam, Netherlands

[21] Innovat Therapies Children Canc ITCC Consortium, Paris, France

来源：

BLOOD | 2008年 / 112卷 / 04期

关键词：

D O I：

10.1182/blood-2008-02-140665

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 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, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were 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 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 ion imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).

引用

页码：1005 / 1012

页数：8

共 36 条

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