Nilotinib-Associated Molecular Responses Achieved in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients with a Suboptimal Molecular Response to Imatinib.

Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for adult patients with Ph+ CML in chronic and accelerated phase who are resistant or intolerant to imatinib. The achievement of a major molecular response (MMR), defined as a 3 log reduction of the Bcr-Abl transcript level from the baseline mean, is a favorable prognostic factor for the disease at any time point. This multi-center, open-label study was designed to assess the impact of nilotinib on Bcr-Abl molecular response dynamics in patients who have achieved complete cytogenetic response but have demonstrated a suboptimal molecular response to imatinib.

This study evaluates the change in Bcr-Abl kinetics in 2 groups of CML-CP patients (n=160) who achieve CCyR but have a suboptimal molecular response to imatinib defined either as: (Group 1) treated > 1 year with imatinib, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1 log increase in Bcr-Abl transcript levels regardless of the imatinib treatment duration. At study entry, patients are treated with nilotinib 300 mg b.i.d. The primary endpoint is to measure the change on a logarithmic scale of Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR after 12 months on treatment with nilotinib. Since there is a paucity of efficacy data published for suboptimal responders to imatinib, this preliminary analysis was performed on a small cohort of patients enrolled as of the data cut-off date of July 21, 2009.

11 CML-CP suboptimal molecular responding patients have been treated with a median of 2.6 months on nilotinib. One patient entered the study as a Group 2 patient and ten entered into Group 1. 1 patient was deemed ineligible due to lack of evidence of CCyR at baseline. The remaining 10 entered the trial with a baseline CCyR. Prior to enrollment, patients were treated with at least 400mg QD imatinib; the mean dose of prior imatinib treatment was 463 mg/day (range 377 – 573 mg/day). The median duration of prior imatinib treatment was 39.5 months (range 14.0-106.4 mo). 1 patient was previously treated with interferon.

8 patients have been treated for >3 months. Out of these 8 patients, 2 have been treated for > 6 months and 1 patient has been treated for > 9 months. Aside from these 8 patients, another 3 did not yet reach end of Month 3 at the time of analysis. Six out of 8 evaluable patients (75%) achieved MMR; 4 patients after three months on nilotinib, 1 patient after 4.5 months on nilotinib (measured at end of study), and 1 patient after 9 months on nilotinib. Overall, patients achieved a median log reduction of PCR transcript levels of 3.1 (range 2.1-4.5) from the standardized baseline (based on the IS) at the end of Month 3.

4 out of 11 patients were dose reduced for nilotinib related adverse events (AEs). No grade 4 AEs were reported. 1 patient experienced a grade 3 headache and two cases of grade 3 elevated ALT were reported. Brief dose interruptions were sufficient to manage most AEs. The median dose intensity was 600 (range 400-600 mg/day). No patients discontinued from the study due to an AE as of the data cut-off date. No patients who experienced QTcF changes had differences >34 msec from baseline. No QTcF prolongation >500 msec was observed.

Nilotinib treatment results in high rates of molecular response in CML-CP patients with suboptimal molecular responses to imatinib. 75% of the evaluable patients who switched to nilotinib achieved MMR at the time of analysis, and all evaluable patients achieved a median > 3 log reduction of PCR transcripts from the standardized baseline within 3 months of starting therapy. No patients were discontinued due to AEs. Outcomes for additional patients enrolled and longer term follow-up will become available.

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Bcr-Abl trends for patients enrolled on study Bcr-Abl % on IS

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Bcr-Abl trends for patients enrolled on study Bcr-Abl % on IS

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Yang:Bristol Myers Squibb: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Esai: Speakers Bureau; Therepi: Equity Ownership. Off Label Use: Nilotinib for suboptimal responders to imatinib therapy. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Akard:Novartis: Consultancy, Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Speakers Bureau. Goldberg:Novartis Pharmaceuticals: Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Radich:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding.