Overcoming resistance in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia (CML) is characterized by the BCR–ABL fusion protein produced as a result of the reciprocal translocation between a portion of the ABL tyrosine kinase gene on chromosome 9 and a region within the BCR gene on chromosome 22. The BCR–ABL oncoprotein displays constitutively elevated tyrosine kinase activity that drives the pathogenesis of CML by activating multiple signaling pathways including the RAS/MAPK, PI3K/AKT and JAK2/STAT5 pathways. The development of tyrosine kinase inhibitors (TKIs) aimed at BCR–ABL revolutionized the treatment of CML. Imatinib was the first of the TKIs to become available after it was approved by the US FDA in 2002 based upon data from the IRIS. Indeed, imatinib was associated with unprecedented rates of hematologic, cytogenetic and molecular responses in comparison with IFN-a with complete hematologic response (CHR) rates of 97%, complete cytogenetic response (CCyR) rates of 82% and major molecular response (MMR) rates on the international scale (IS) of 86% [1]. Treatment with imatinib also resulted in significantly improved rates of freedom from progression in comparison with IFN-a with an 8-year freedom from progression to accelerated or blast phase of 92% and afforded patients who were able to remain on treatment an 8-year overall survival (OS) of 85% [1]. However, imatinib use has been complicated by the development of resistance. Resistance led to 24% of patients in IRIS failing to achieve a CCyR at 18 months, which represented treatment failure [2]. Resistance also led 17% of patients on imatinib in IRIS to develop relapsed disease and 7% to develop progressive disease [2]. These numbers are, in fact, likely to be underestimates given the number of patients in the IRIS study who came off the trial and were not ultimately included in analysis. Treatment failure and disease progression due to resistance is also seen in patients treated with the subsequently approved second-generation TKIs, dasatinib, nilotinib and bosutinib. The etiology of resistance to TKIs is multifactorial and involves BCR–ABL independent and dependent mechanisms. Insufficient plasma levels of imatinib due to noncompliance, drug–drug interactions or binding to acute-phase inflammatory proteins can all result in resistance. It is known that trough plasma levels of imatinib are important for good clinical outcomes, and it has been demonstrated that patients with high imatinib exposure have better rates of CCyR, MMR and event-free survival [3]. Imatinib and all three of the second-generation TKIs are substrates for, and are extensively metabolized by, the cytochrome P450 enzymes including CYP3A4. As there are multiple drugs, food products and supplements that either induce or inhibit CYP3A4 activity, the potential for drug interactions is high. Alpha 1 acid glycoprotein has been identified as an acutephase inflammatory product that binds directly to imatinib and is frequently “As the number of drugs available for the treatment of chronic myeloid leukemia has expanded, so have the strategies for overcoming or avoiding resistance.”