By Edward Li, PharmD, BCOP, Drugs and Biologics Editor
At the turn of the last century, imatinib revolutionized the treatment of chronic myeloid leukemia (CML). At the time, therapy for CML was not as well defined as it is today. Some treatment strategies for chronic phase disease called for the utilization of immunotherapy and/or chemotherapy; interferon, cytarabine, and busulfan were among these commonly used agents. The success of imatinib in the treatment of CML can be traced back to the identification of a chromosomal abnormality in patients with CML in 1960.
This chromosomal abnormality (i.e., the Philadelphia chromosome) was later determined to be the result of a translocation of the long arms of chromosomes 9 and 22, specifically the ABL region of chromosome 9 and the BCR region of chromosome 22. In the decades that followed, a deeper understanding of the molecular pathology of CML brought to light the oncogenic effect of the BCR-ABL pathway and the impact of the resultant tyrosine kinase fusion protein activity in the signaling pathway.
In a pharmacologic class of tyrosine kinase inhibitors that was considered novel at the time, imatinib was the first agent the U.S. Food and Drug Administration approved. Its targeted approach of inhibiting the BCR-ABL tyrosine kinase fusion protein and its desirable safety and efficacy profile led imatinib to quickly become the standard of care. Initial results from a phase III trial that compared imatinib to interferon with cytarabine showed, quite substantially, that imatinib induced more major cytogenetic responses and prevented more patients from progressing into accelerated phase or blast crisis. Follow-up studies and an accumulation of subsequent experience have confirmed that imatinib confers an excellent survival advantage.
Despite the advances made in treating CML with imatinib, there is still room for improvement. For example, treatment with imatinib is not a cure. Rather, it is chronic, long-term management of a disease. Some patients eventually will develop resistance to imatinib; this can appear in the early stages of therapy or following a comparatively longer period of treatment.
There are many different mechanisms of resistance to imatinib. The reasons a particular individual becomes resistant to imatinib therapy may be multifactorial and are either BCR-ABL–dependent or BCR-ABL–independent. BCR-ABL–independent reasons may be pharmacokinetic in nature and could include issues with drug adherence, changes in bioavailability, or altered metabolism (e.g., through drug interactions). Of the BCR-ABL–dependent reasons, BCR-ABL kinase domain mutations are emerging as an area of importance. It is estimated that 30 to 50 percent of patients with secondary resistance to imatinib have a kinase domain mutation. So far, there have been more than 100 different point mutations identified in the kinase domain of BCR-ABL in patients with imatinib resistance. Dasatinib and nilotinib, the two second-generation tyrosine kinase inhibitors, have been effective in patients who develop resistance to imatinib. The level of resistance to imatinib, nilotinib, and dasatinib depends on the mutation identified, as specific mutations may be preferentially treated with specific agents. Notably, the T315I mutation has gained some notoriety because it imparts resistance to imatinib, dasatinib, and nilotinib.
Based on these issues, how will the future of CML treatment unfold? Recently, two studies published in The New England Journal of Medicine challenge the notion of imatinib as first-line therapy for CML. These two studies found a superior effect in terms of complete cytogenetic remission, time to remission, and a lower rate of progression to accelerated or blast phase when treating newly-diagnosed chronic-phase CML patients with nilotinib or dasatinib rather than with imatinib. As the science progresses and better assays for detecting and reporting BCR-ABL kinase domain mutations and broader-spectrum tyrosine kinase inhibitors against various kinase domain mutations are developed, the paradigm for treating CML may be on the cusp of change again.
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