Molecular Response, Efficacy and Safety Analysis of 168 Adult French Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) From the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of Ph+ CML patients (pts) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study, which is a Phase IIIb, open label, multicenter study, was initiated to obtain additional efficacy and safety information in pts with imatinib-resistant or -intolerant CML in CML-CP, CML-AP, or blast crisis (BC) in a clinical practice setting outside of a registration program.

Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Cytogenetic and hematological responses were provided by investigator assessment and monitored according to the current European Leukemia Network (ELN) recommendations. Safety assessments included monitoring for all adverse events (AEs), serious AEs and cardiac procedures. A centralized approach to molecular testing in France facilitated matching of the PCR results to ENACT pts who were monitored for molecular response as a standard of care. BCR-ABL/ABL ratio (in %) were reported on the international scale (IS), French physicians followed the current ELN recommendations and monitored pts by PCR at baseline and every 3 months thereafter. Major molecular response (MMR) was defined as IS ≤ 0.1%. In addition, pts with ≤ 0.003% IS are reported. Confirmed loss of MMR was defined as IS > 0.1% on two consecutive PCR tests in pts previously in MMR

A total of 168 French CML-CP pts enrolled in the ENACT study between Jan. 2006 and Oct. 2008 with molecular response data available for 77% of pts. The median age of pts was 57 years, 56% were imatinib-resistant and 43% were imatinib-intolerant as determined by physician assessment. At study completion, 108 (64%) pts were continuing on nilotinib. The main reasons for treatment discontinuation were unsatisfactory therapeutic effect and AEs (16% for both). Median (range) duration of nilotinib exposure was 363 (4–765) days; median (range) average dose intensity was 793 (222–913) mg/day. Dose interruptions and reductions lasting longer than 5 days occurred in 36.9% and 11.9% of pts, respectively, with AEs being the main reason. The majority of nilotinib-related grade 3/4 AEs were hematologic, with thrombocytopenia (22.6%) and neutropenia (14.9%) being the most common. Non-hematologic AEs were mostly grade 1/2, not study drug-related and included fatigue, headache and rash. No incidence of grade 3/4 QT prolongation (QTcF > 500 msec) was observed and no pts experienced study drug-related grade 3/4 pancreatitis or pleural effusion on study. Overall major cytogenetic response (MCyR) and complete hematologic response (CHR) rates were both 54%, which are higher than those observed in the overall ENACT CML-CP cohort at 45% and 43%, respectively. Among the pts with molecular response data, 10 (7.8%) came to the study with MMR, one had a confirmed loss of MMR but subsequently regained MMR. The proportion of pts with post-baseline MMR (regardless of baseline response) was 42% (55 pts); 38% of pts achieved an MMR on study. The proportion of pts with a post-baseline ratio ≤ 0.003% IS was 16% (21 pts). The achieved molecular responses were durable with only 4 pts with confirmed loss of MMR, while another 3 pts met the criteria for loss of response but subsequently regained MMR. Of the 61 pts with CCyR and molecular data available, 72% also achieved MMR (see Table).

This analysis of the French CML-CP subset of a large expanded access study further demonstrates that nilotinib is well tolerated and effective in heavily pretreated pts with CML-CP. A majority of pts (72%) with CCyR also had MMR. This data supports the use of nilotinib at 400 mg bid as the recommended dose in French pts.

Nicolini:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Bordessoule:Novartis Pharmaceuticals: Honoraria. Belanger:Novartis Pharmaceuticals: Employment. Lamy:Novartis Pharmaceuticals: Honoraria. Gardembas-Pain:Novartis Pharmaceuticals: Honoraria. Maloisel:Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Calgene: Research Funding. Rea:Novartis Pharmaceuticals: Honoraria. Johnson-Ansah:Novartis: Consultancy. Lenain:Novartis Pharmaceuticals: Honoraria. Szczudlo:Novartis: Employment. Wang:Novartis Pharmaceuticals: Employment. Duh:Novartis Pharmaceuticals: Research Funding.