BCR-ABL1 plays a key role in the pathogenesis of chronic myeloid leukemia (CML), and it has been investigated as a druggable target of tyrosine kinase inhibitors (TKIs) over two decades. Since imatinib, the first TKI for anti-cancer therapy, was successfully applied in CML therapy, further generation TKIs and a novel allosteric inhibitor targeting the myristate binding site have been developed as alternative options for CML management. However, significant concerns regarding toxicity profiles, especially in long-term treatment, have emerged from TKI clinical data. Efforts to reduce adverse events and serious complications are warranted not only for survival, but also quality of life in CML patients. A better understanding of the mechanism of action will help to identify on-and off-target effects of TKIs, and guide personalized TKI drug selection in each individual CML patient. Herein, this review summarizes the biologic mechanism of BCR-ABL1 inhibition and differential target spectra, and related off-target effects of each TKI.
We describe a 50-year-old man with von Willebrand disease type 2A who suffers from angiodysplasia and has required many transfusions for gastro-intestinal haemorrhage. Various investigative modalities have not demonstrated a single source for this. Following a case report of successful use of recombinant activated factor VII (NovoSeven; Novo Nordisk, Copenhagen, Denmark), the patient was treated with it but suffered a large myocardial infarct. As the patient has risk factors for atherosclerotic disease, we presume the recombinant activated factor VII promoted coagulation at a pre-existing atherosclerotic lesion.
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