Monitoring Response

Using a system developed in the IRIS trial, the International Scale (IS) defines major molecular response (MMR) as a 3-log reduction from a standardized baseline in the ratio of BCR-ABL to a control gene, often ABL (ie, 0.1% IS).6 A complete molecular response (CMR) is achieved when BCR-ABL is undetectable, generally defined as a 4.5-log decrease from baseline; however, this value is a moving target in an era of increasingly sensitive quantitative RT-PCR.6

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IRIS demonstrated the positive prognostic value of early cytogenetic and molecular response: at 8 years, progression occurred in only 3% of those who achieved complete cytogenetic response (CCyR), and none of those who achieved MMR by 12 months, a pattern seen across studies of newer TKIs.4,7-11

Resistance Mechanisms 

In the 8-year follow-up from IRIS, 16% of patients had discontinued imatinib due to drug resistance, evidenced by a lack of efficacy.4  From 15% to 25% of patients demonstrated primary cytogenetic resistance to imatinib, defined as failure to achieve any cytogenetic response (CyR) at 6 months, major CyR (MCyR) at 12 months, or CCyR by 18 months.1 Additionally, point mutations in the BCR-ABL gene—specifically the ABL kinase domain—are a frequent mechanism of secondary resistance to imatinib and differentially affect response to other TKIs as well.1 Secondary resistance develops in 2% to 4% of patients treated with imatinib annually, peaking in the second year of treatment and declining thereafter in long-term IRIS follow-up.12

Some TKIs have activity against select imatinib-resistance mutations, which varies by the specific agent. Switching to an alternate TKI after imatinib resistance is a recommended approach and has produced CCyR rates ranging from 33% to 46% in clinical trials.6,13 Nilotinib and bosutinib, for instance, have achieved responses in patients who previously experienced treatment failure with imatinib and another TKI.14,15 However, the T315I “gatekeeper” mutation blocks all four currently available TKIs from accessing their adenosine 5′-triphosphate (ATP)-binding site, conferring a high degree of resistance and a generally poor prognosis.1,6,16

Newer TKIs: Efficacy in Newly Diagnosed CML

In newly diagnosed CML, dasatinib, nilotinib, and bosutinib have provided higher response rates compared with imatinib on some or all measures.1 With all these agents, the time to cytogenetic and/or molecular response was faster compared with imatinib, which may have clinical relevance.7,17-19

Dasatinib, a dual inhibitor of Src family kinases and BCR-ABL, demonstrated significant efficacy in patients with CML who are resistant to or intolerant of imatinib and produced MCyR in 63% and CCyR in 50% with the currently recommended dose (100 mg once daily).20 Dasatinib also has efficacy in imatinib-resistant advanced disease.20 The DASISION study, with 2-year follow-up data recently published, evaluated dasatinib 100 mg once daily compared with imatinib 400 mg once daily for treatment of newly diagnosed CML, with a primary end point of confirmed CCyR at 12 months. Dasatinib produced significantly higher rates of cytogenetic and molecular response at 12 months and 24 months (Figure 1).18 At the 24-month follow-up, 17% of patients treated with dasatinib versus 8% of patients treated with imatinib  had achieved 4.5-log reduction in BCR-ABL (MMR4.5), suggesting complete molecular response.9