Molecular Advances: The Imatinib(Drug information on imatinib) Era
Lugo et al discovered a relationship between cell-signaling via BCR-ABL tyrosine-kinase phosphorylation and the generation of oncogenic protein products in the BCR-ABL cells.[15] Resulting drug development targeted this specific tyrosine kinase. In vitro screening for a selective BCR-ABL tyrosine inhibitor led to the discovery of molecules with inhibitory effects on BCR-ABL cells in vitro[14,16] and further development of STI571, or imatinib, which was first used successfully in a phase I trial published in 2001.
In this study, 53 of 54 patients receiving more than 300 mg of imatinib daily achieved a complete hematologic response.[17] This activity was later confirmed in phase II studies.[18-20] CML patients in chronic phase who had been previously treated with interferon-alpha had remarkable remission rates with imatinib, and the US Food and Drug Administration (FDA) approved the drug for treatment of previously treated CML patients.[21,22] Imatinib was then explored in newly diagnosed CML patients in the ongoing controlled study IRIS (International Randomized study of Interferon-alpha plus cytarabine(Drug information on cytarabine) vs STI571), which compared imatinib to standard of care-interferon alfa-2b plus cytarabine. Imatinib was approved as first-line therapy for CML after interval results in this trial exhibited significantly higher rates of complete cytogenetic response in the imatinib group (81% vs 32%) and an improved toxicity profile.[10,23,24]
At the time of the initial interval IRIS results, we had limited information on the durability of the remissions, the impact on survival, and the nature of resistance. With almost 5 years of follow-up since the start of the IRIS study, the natural history of the disease with imatinib therapy is better articulated. Complete hematologic response rates have surpassed 90%, and over 86% of newly diagnosed CML patients have achieved a complete cytogenetic response, with an additional 6% developing a partial cytogenetic response while on imatinib (Figure 1).[25] Since the outset of the IRIS trial, approximately 4% of patients have developed resistance or progression annually. These risks are reduced among patients with a complete cytogenetic response, but significantly increased in those who do not have at least a partial cytogenetic response. With only 5 years of follow-up, the long-term outcome of therapy is still unknown, but the impact of imatinib on survival, thus far, appears to be dramatic.
