Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia.
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).
Porkka
Kimmo
K
Hematology Research Unit, Biomedicum Helsinki, Helsinki, Finland. kimmo.porkka@helsinki.fi
Koskenvesa
Perttu
P
Lundán
Tuija
T
Rimpiläinen
Johanna
J
Mustjoki
Satu
S
Smykla
Richard
R
Wild
Robert
R
Luo
Roger
R
Arnan
Montserrat
M
Brethon
Benoit
B
Eccersley
Lydia
L
Hjorth-Hansen
Henrik
H
Höglund
Martin
M
Klamova
Hana
H
Knutsen
Håvar
H
Parikh
Suhag
S
Raffoux
Emmanuel
E
Gruber
Franz
F
Brito-Babapulle
Finella
F
Dombret
Hervé
H
Duarte
Rafael F
RF
Elonen
Erkki
E
Paquette
Ron
R
Zwaan
C Michel
CM
Lee
Francis Y F
FY
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
D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib