Introduction
Imatinib has been invented by a group of scientists led by Nicholas Lydon at Ciba-Geigy laboratories (later on merged with Sandoz to form Novartis) in the early 1990s. Clinical development of imatinib, called initially STI571 (from signal transduction inhibitor), was led by Brian Druker, although John Goldman had a substantial role in this process and the first clinical trial in patients with chronic myeloid leukemia (CML) started in 1998.
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In CML, a constitutively active tyrosine kinase, encoded by BCR-ABL1 oncogene, is responsible for malignant transformation of hematopoietic stem cells. Imatinib activity results from competitive binding to the ATP-binding site in BCR-ABL1 kinase domain and preventing autophosphorylation of BCR-ABL1.
This results in abrogation of several pathways activated by BCR-ABL1 and involved in the control of the cell adhesion, cytoskeleton organization, apoptosis, DNA damage response, cell cycle and responsible for uncontrolled proliferation of leukemic cells in CML.1
The clinical safety and the effective dose of imatinib of 400 mg once daily was established in the Phase I trial initiated in June 1998.2 In the subsequent Phase II trials, the effectiveness of imatinib at this dose was established.
Thatwas the base for the approval decision of imatinib for therapyof CML by the United States Food and Drug Administration(US FDA) in May 2001.3
The current management of patientswith CML has substantially changed over the past 15 years,with new considerations of using a second- and third-generationtyrosine kinase inhibitors (2G-TKIs and 3G-TKIs,respectively) in patients resistant or intolerant to initial doseof imatinib and even in the first-line setting.
Nevertheless,the efficacy of imatinib at a higher dose of 600 mg dailyor 800 mg daily used in first- and second-line treatment ofCML in chronic phase (CML-CP), as well as in accelerated(AP) and blast crisis/blastic phase (BP) of CML has beenevaluated in several clinical trials.
The understanding of theplace in therapy for the various doses of imatinib could playan important role in the optimization of a patient’s clinicaloutcome.
