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Abstract Oral dasatinib (Sprycel®) is effective in the treatment of patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML) or imatinib-resistant or imatinib-intolerant chronic-phase, accelerated-phase, or blast-phase CML. In particular, dasatinib is associated with better and faster responses than imatinib in patients with newly diagnosed chronic-phase CML. The response to dasatinib appears to be maintained in the longer-term. Dasatinib has an acceptable tolerability profile; it is associated with myelosuppression, with fluid retention being the most common nonhematologic adverse event. Thus, dasatinib is a highly effective, once-daily therapy for the first-line treatment of patients with chronic-phase CML and for the second-line treatment of imatinib-resistant or imatinib-intolerant CML.
1 What is the Rationale for Developing Dasatinib?
Chronic myeloid leukemia (CML) is caused by the malignant transformation of a hematopoietic stem cell [1, 2], In 90-95 % of patients, CML is characterized by a reciprocal translocation t(9;22)(q34;qll) that fuses the ABL receptor tyrosine kinase gene from chromosome 9 to the BCR gene on chromosome 22, to form the so-called Philadelphia (Ph) chromosome [1, 2], The aberrant BCR- ABL gene on the Ph chromosome encodes a constitutively activated tyrosine kinase that plays a central role in the development of CML [2],
Over 90 % of patients with CML are diagnosed dining the initial chronic phase [1], If left untreated, chronic-phase CML typically progresses to accelerated-phase CML and then to blast-phase CML, which can be differentiated as myeloid blast-phase CML or lymphoid blast-phase CML [3],
Imatinib was the first tyrosine kinase inhibitor approved for use in CML [1, 2], However; resistance or intolerance to imatinib is seen in about one-third of patients, meaning that alternative therapies are required [3], Dasatinib (Sprycel®) is an orally administered, small molecule inhibitor of multiple tyrosine kinases that is structurally unrelated to imatinib and is indicated for use in CML [3], Dasatinib is also indicated in the treatment of Ph-positive (Ph+) acute lymphoblastic leukemia; however, a discus- sion of its use in this indication is beyond the scope of this review.
2 How Does Dasatinib Work?
Dasatinib inhibits the activity of the oncogenic kinases BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, ephrin A receptor, and platelet-derived growth factor ß receptor (PDGFR-ß) at nanomolar concentrations [3], In vitro, dasatinib is a potent inhibitor of...