Background: Nilotinib is an oral tyrosine kinase inhibitor with high selectivity towards Bcr-Abl and approximately 30-fold more potent than imatinib, and is effective in patients with CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims: To investigate the efficacy and safety of nilotinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP (or with <1 months of therapy with imatinib) were eligible and received nilotinib 400mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Forty-nine pts have been treated for a median of 13 months (mo). The median age was 47 years (yrs) (range, 21 to 81); 69% are Sokal low risk. Eight (16%) had received imatinib for <1 months. Overall, 46/48 (96%) of evaluable CP pts achieved a complete cytogenetic response [CCyR]. The rate of CCyR at 3, 6 and 12 mo for pts in CP compares favorably to those observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Months on therapy Nilotinib Imatinib 400mg Imatinib 800mg P value 3 93 (45) 37 (49) 62 (202) < 0.0001 6 100 (36) 54 (48) 82 (199) < 0.0001 12 96 (27) 65 (48) 86 (197) 0.0003 18 92 (12) 68 (38) 89 (179) 0.0042 24 91 (11) 70 (40) 88 (173) 0.0151 MMR was observed in 45% at 6 mo and 52% at 12 mo. Two of 44 (5%) evaluable pts have achieved confirmed complete molecular response, and 3 others unconfirmed (ie, only achieved on their last assessment). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia in 10%, neutropenia in 12%, and anemia in 2%. Grade 3–4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%. 19 (36%) pts had transient treatment interruptions and 17 (32%) had dose reductions. The actual median dose is 800mg daily. Three pts have come off study: 1 pt’s choice and 2 because of toxicity (1 liver, 1 pericardial effusion). One of them (liver toxicity) transformed to blast phase shortly after coming off study. Estimated 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 95%. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Accrual is ongoing.
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Cortes et al. (2008) studied this question.