Newer TKIs: Efficacy in Newly Diagnosed CML (continued)
Nilotinib is a highly selective BCR-ABL inhibitor more potent than imatinib.1 It produces MCyR and CCyR rates of 56% and 41%, respectively, in the setting of imatinib-resistant CML, and has demonstrated efficacy in imatinib-resistant or intolerant accelerated-phase disease as well.21,22 Nilotinib was evaluated for newly diagnosed CML in the ENESTnd study, with 3-year follow-up data recently published. Patients in this multicenter phase 3 study were randomly assigned to receive nilotinib at a dose of either 300 mg or 400 mg twice daily, or to imatinib 400 mg once daily (300 mg twice daily became the recommended dose in this setting). The primary end point was MMR at 12 months.19 Both doses outperformed imatinib on the primary and other efficacy end points at 12 months and 36 months (Figure 2); responses were independent of Sokal risk scores.8,10,11,19 At 36 months, 32% of the patients treated with nilotinib versus 15% of the patients treated with imatinib have achieved MMR4.5 (P<0.001).10,11
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Like dasatinib, bosutinib is a dual inhibitor of Src and BCR-ABL.17 It differs from other TKIs because of its limited activity against c-KIT and PDGF, receptors that may be involved in TKI-related toxicities.13 A phase 1/2 study evaluated the efficacy of bosutinib in patients resistant to or intolerant of imatinib (second-line) or those previously treated with multiple TKIs (third-line).13,15 Overall, 25% of those who had not achieved MCyR on imatinib did so on bosutinib.13 In both analyses, MCyR response rates of about 30% were achieved with bosutinib across patient types; about one in four patients achieved CCyR. Molecular response rates for patients who achieved CCyR in the second-line setting were approximately 65%. In the third-line setting, 15% of the total cohort achieved MMR.13,15 Patients with dual imatinib/dasatinib resistance had lower response rates than those with TKI intolerance or nilotinib resistance.15
