Newer TKIs: Efficacy in Newly Diagnosed CML (continued)
In the BELA study, bosutinib 500 mg once daily (N=250) was compared with imatinib 400 mg once daily (N=252) for treatment of newly diagnosed CML. The primary end point in this study was CCyR at 12 months.17 There was no significant difference between treatment groups on the primary end point (Figure 3), but bosutinib produced higher MMR rates at 12 months (P<0.001). The rate of disease progression with a median treatment duration of 13.8 months was lower with bosutinib. Both cytogenetic and molecular responses were achieved earlier with bosutinib than imatinib and were independent of Sokal risk scores.17 Adverse events led to discontinuation in 19% and treatment interruptions in 61% of patients taking bosutinib (versus 6% and 42%, respectively, with imatinib).17 Grade 3/4 toxicities that occurred with bosutinib and imatinib included diarrhea (11% vs. 1%, respectively), elevated ALT (22% vs. 3%, respectively), and neutropenia (11% vs. 24%, respectively).17 Bosutinib currently is not recommended in the first-line setting.1
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Ponatinib, an oral TKI approved in December 2012, was designed specifically to overcome T315I resistance.16 Recently, results of a phase 1 dose-escalation study with ponatinib in patients exhibiting primary resistance to other TKI therapy were published. Among those with CML, 91% had received previous treatment with two or more TKIs. With a median follow-up of 56 weeks, 98% of the CML patients (n=43) had achieved CHR, 72% MCyR (27 of 31 of whom had a CCyR), and 44% achieved MMR. Notably, response rates were quite high in patients with the T315I mutation (n=12/43): MCyR in 92%, CCyR in 75%, and MMR in 67%.16 The major dose-limiting toxicity was pancreatitis; other adverse events were similar to those seen with this class of drugs.16
Summary
With the availability of imatinib and newer generation TKIs, CML has become a treatable, and potentially curable, chronic disease for most patients.6 With more than 8 years of imatinib clinical experience, overall survival remains high, progression rates low, and molecular remission common. Dasatinib and nilotinib present additional options for newly diagnosed patients, particularly those considered to be at higher risk for progression based on their age and baseline disease parameters. Newer TKIs have been shown to produce additional cytogenetic and molecular responses in patients resistant to or intolerant of imatinib and/or other TKIs. However, issues of resistance continue to undermine some patients’ progress. There are few, if any, studies comparing newer TKIs with one another. Subtle differences in their molecular targets, efficacy against mutations, and side effects help to guide treatment choice.1,3
