Small Molecules in Hematology

Dasatinib

Small Molecules in Hematology

Recent results in cancer research Fortschritte der Krebsforschung Progrès dans les recherches sur le cancer, January 2018

30069624

978-3-31-991438-1, 978-3-31-991439-8

Markus Lindauer, Andreas Hochhaus, Lindauer, Markus, Hochhaus, Andreas

Dasatinib is an oral available short-acting inhibitor of multiple tyrosine kinases. It was designed to inhibit ABL and SRC, but also has activity in multiple other kinases, including c-KIT, PDGFR-α, PDGFR-β, and ephrin receptor kinases. Dasatinib is a very potent inhibitor of BCR-ABL and an effective treatment for the BCR-ABL-driven diseases chronic myeloid leukemia (CML) and Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), characterized by the constitutively active tyrosine kinase, BCR-ABL. Dasatinib is approved for the treatment of CML (all phases) including children and for the treatment of Ph+ ALL, resistant or intolerant to prior imatinib treatment. Randomized trials in CML comparing dasatinib with imatinib show that first-line dasatinib causes significantly deeper and faster molecular remissions. In accelerated and blastic phase CML, as well as in Ph+ ALL, dasatinib frequently induces complete hematologic and cytogenetic remissions even in imatinib pretreated patients. Remissions however are often short. Dasatinib is administered independent of food intake as a once-daily dose of 100 mg in chronic phase CML and 140 mg in Ph+ ALL or blastic phase. Side effects of dasatinib are frequent but mostly moderate and manageable and include cytopenias and pleural effusions. The review presents the preclinical and clinical activity of dasatinib with a focus on clinical studies in CML.