Dasatinib

L01XE06

Cytostatic

Tyrosine kinase inhibitor

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Dasatinib is a tyrosine kinase inhibitor, which finds use as a drug for treatment of certain malignant diseases (chronic myeloid leukemia ( CML) and Philadelphia chromosome - positive acute lymphoblastic leukemia ( Ph ALL) ).

Dasatinib was developed by Bristol -Myers Squibb under the project designation BMS - 354825. The generic name derives from the name of one of the involved in the synthesis at Bristol Myers Squibb chemist, Jagabandhu The decreases. As a drug it is since June 2006 in the U.S., or approved in the EU since November 2006 and is marketed under the trade name Sprycel. The application was initially limited to the treatment of adult patients with imatinib - resistant or intolerant (so-called second-line ), the end of 2010 was the approval for the first-line treatment.

Pharmacology

Operation

As the already approved in 2001 drug imatinib, dasatinib is a specific tyrosine kinase inhibitor of BCR -ABL kinase and SRC kinase. However, dasatinib nor affects 32 of 33 known mutations in the Philadelphia chromosome, in which imatinib has no effect. Only when mutation T315I binding to the specific binding site of the tyrosine kinase is obviously prevented.

Efficacy study

In a study published in June 2006 Phase 1 clinical trial for dose adjustment dasatinib was tested on patients who showed an imatinib resistance or intolerance. In 37 of 40 patients in chronic phase CML, a complete hematologic remission was achieved. A clear response of the blood values ​​was in 31 of 44 patients achieved that were in accelerated phase CML or blast crisis or Philadelphia chromosome - positive acute lymphoblastic leukemia ( Ph ALL) were diagnosed. The current 24 months data ( ASH Abstract # 734) further demonstrate the high efficacy of dasatinib. By dasatinib initiated cytogenetic response remains in patients with CML in chronic phase (CP- CML) who are resistant to imatinib or can not abide permanently.

Duration of efficacy

In 95% of patients in the chronic phase, the efficacy was sustained for a mean observation period of more than twelve months. Of the patients in the accelerated phase of CML were 82% during a mean observation period of 5 months in remission. Almost all patients in blast crisis CML or Ph ALL relapsed within 6 months. Progression-free survival at 15 months was 90 %, while overall survival was 96%. Dose interruptions were required in 87% of patients, and a dose reduction of 73%; the average daily administered dose was 101 mg ( between 11-171 ).

Side effects

Long-term effects and side effects of dasatinib are investigated in currently ongoing studies. The following more common side effects are known: headache, diarrhea, nausea, fatigue, skin rashes, edema, shortness of breath, pleural effusions, fungal diseases and joint pain. Much less common are: loss of appetite, pneumonia and intestinal bleeding. Very rarely are: congestive heart failure, cardiac arrhythmias, hypertension, pulmonary edema, superficial edema, elevated liver and creatinine and calcium deficiency. Reports of a lack of blood platelets ( thrombocytopenia) Grade 3/4 and a decrease in the number of neutrophils in the blood ( neutropenia) were recorded at 48 % and 49 % of patients. Non- haematological adverse events consisted mainly of diarrhea (37 %), headache (32% ), fatigue (31%) and dyspnea (30 %). 27% of patients had a pleural effusion (abnormal collection of fluid in the pleural cavity ); which was classified as grade 1-2 in 21% and grade 3-4 in 6% of patients. The pharmacovigilance a correlation between the treatment with Sprycel ® and the occurrence of high blood pressure in the pulmonary circulation (pulmonary arterial hypertension, PAH) was determined so that the manufacturer Bristol- Myers Squibb warned accordingly.