Patients (Pts) with Ph+ Chronic Myeloid Leukemia In Chronic Phase (CML-CP) with a Suboptimal Molecular Response to Imatinib (IM) Can Achieve Deeper Responses When Switched to Nilotinib

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 IM and for frontline CML treatment. The achievement of a complete cytogenetic response (CCyR) and a major molecular response (MMR), defined as ≥ 3 log reduction of Bcr-Abl transcript levels from a standardized baseline (equivalent to ≤ 0.1% international scale [IS]) are favorable prognostic factors. Achieving CCyR and MMR are associated with significantly lower rates of disease progression (Saglio, G. et al. N Engl J Med 2010; 362:2251). This multi-center, open-label US study was designed to assess the impact of nilotinib on Bcr-Abl molecular response dynamics in pts with CCyR but have demonstrated a suboptimal molecular response to IM.

This study evaluates the change in Bcr-Abl kinetics in 2 groups of CML-CP pts (target enrollment n=50) who achieved CCyR but have a suboptimal molecular response to IM. Suboptimal molecular response was defined either as: (Group 1) pts treated ≥ 1 year with IM, but have not reached MMR; or (Group 2) pts with > 1 log increase in Bcr-Abl transcript levels from best response regardless of the IM treatment duration. Pts are treated with nilotinib 300 mg BID on study; if dose reductions are required, pts are treated with nilotinib 400 mg QD. Quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) analysis is performed by a central lab at baseline and then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR at baseline, monthly for the first 3 mos and then every 3 mos on study. 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 mos on treatment with nilotinib. This analysis was performed on the 14 pts enrolled as of the data cut-off date of June 30, 2010.

Fourteen pts (Group 1:13; Group 2:1) have been treated with a median of 9.8 mos (range: 3.4–22.3 mos) on nilotinib. Thirteen pts entered the trial with a baseline CCyR. One pt (Group 1) was discontinued due to lack of evidence of CCyR at baseline (protocol deviation); however was included in the analysis since the pt had at least one post-baseline evaluation performed. Prior to enrollment, pts were treated with ≥ 400mg QD IM; the mean dose of prior IM treatment was 505 mg/day (range 377 – 786 mg/day). The median duration of prior IM treatment was 40.5 mos (range 15.3 – 115.8 mos). The median Bcr-Abl log reduction at baseline was 2.5 (0.32%IS). Overall 12/14 pts achieved MMR on study; 9 pts after 3 mos, 1 pt after 4.5 mos (measured at end of study due to a protocol deviation), and 2 pts after 9 mos. Overall, pts achieved a median 3.11 log reduction (0.078%IS) at Month (Mo) 3; median 3.33 log reduction (0.047%IS) at Mo 6, and a median 3.72 log reduction (0.019% IS) at Mo 9. Of the pts who were treated at least 12 mos, 6/7 (85.7%) reached MMR after switching to nilotinib and the median Bcr-Abl transcript log reduction at 12 mos was 3.66 (0.022% IS,1° endpoint). Nilotinib was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Five of 14 pts were dose reduced for nilotinib-related AEs. The median dose intensity was 536 mg (range 300 – 600 mg/day). One of each of the following Grade 3 AEs were reported: rash, pneumonia, squamous cell carcinoma, bladder prolapse, and uterine prolapse. Only the rash was suspected to be due to nilotinib. No Grade 4 AEs were reported. One pt experienced serious AEs; pancreatitis was suspected to be related to nilotinib and pneumonia was not suspected to be related to nilotinib. Nilotinib was interrupted and the pt recovered from both events. Four pts were discontinued from the study, 3 due to abnormal labs (Grade 2–3 ALT, Grade 2 bilirubin) and 1 due to a protocol deviation. The median Bcr-Abl log reduction of these 4 pts at end of study was 3.03 logs (0.096% IS). A protocol amendment has since instated a more liberal dose reduction guideline. No pts who experienced QTcF changes had differences > 33 msec from baseline. No QTcF prolongation >500 msec was observed.

Nilotinib treatment resulted in an improvement of molecular response in pts switched from IM and was well tolerated. Overall 12/14 (85.7%) of the pts who switched to nilotinib achieved MMR at the time of analysis, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.66 from the standardized baseline (0.022% IS).

Figure 1.

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Bcr-Abl trends (%|S) for patients enrolled on study

Figure 1.

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Bcr-Abl trends (%|S) for patients enrolled on study

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Miller: Novartis: Consultancy, Honoraria, Research Funding. Off Label Use: Nilotinib is being studied patients with suboptimal response in the context of a clinical trial. Ailawadhi: Novartis: Consultancy, Honoraria. Radich: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. DeAngelo: Novartis: Consultancy; BMS: Consultancy. Goldberg: Novartis: Consultancy, Honoraria, Research Funding. Williams: Novartis: Employment, Equity Ownership. Lin: Novartis: Employment. Akard: Novartis: Consultancy, Honoraria.