Background: Nilotinib is a novel, orally bioavailable ATP-competitive inhibitor of BCR-ABL, which is significantly more potent (IC50 >30 fold) than imatinib.

Methods: This pivotal, open-label, phase II study was designed to evaluate the safety and efficacy of nilotinib in pts with Philadelphia chromosome-positive (Ph+) CML with imatinib resistance or intolerance in AP. Imatinib resistance was defined as treatment with imatinib ≥600 mg/d with disease progression (≥50% increase in WBCs, blasts, basophils, or platelet counts) or no HR in bone marrow after 4 wks. Imatinib intolerance was defined as no major cytogenetic response (MCyR) and discontinuation of imatinib due to Grade 3/4 AEs or persistent (>1 mo) or recurrent Grade 2 AE (recurred >3 times) despite optimal supportive care. The primary and the key secondary endpoints were rate of confirmed hematologic response (HR) and best cytogenetic response (CyR) respectively, on the conventional ITT population. Nilotinib was started at 400 mg BID and escalated to 600 mg BID for inadequate responses in the absence of safety concerns.

Results: 119 pts who received at least 6 mo of nilotinib were included in the analysis; 96 (80.7%) were resistant and 23 (19.3%) were intolerant to imatinib. Median age was 58 (22–79) y; median time since first CML diagnosis was 71.1 (2.2–298.2) mo; 55.5% were males. Confirmed HR occurred in 56 (47.1%) pts (31 [26.1%] complete HR; 11 [9.2%] marrow responses or no evidence of leukemia; 14 [11.8%] returned to chronic phase). MCyR occurred in 35 pts (29.4%) (19 complete CyR; 16 partial CyR), 16 (13.4%) minor CyR, and 28 (23.5%) minimal CyR. Time to first MCyR and complete CyR was 2 and 3.3 mo, respectively. Rate of MCyR for imatinib-resistant and -intolerant CML-AP pts was 27.1% and 39.1%, respectively. Median duration of nilotinib exposure was 202 (2–611) d and median average dose intensity for all pts was 790 mg/d (180.1–1149). Nilotinib dose was escalated to 600 mg BID in 29 (24.4%) pts. At data cutoff, treatment was ongoing for 48/119 (40.3%) pts, and 71 (59.7%) pts had discontinued. Discontinuations were due to disease progression for 35/119 (29.4%) pts and AEs for 15/119 (12.6%) pts. Most common Grade 3/4 hematologic lab abnormalities included thrombocytopenia (38.7%), neutropenia (39.1%), anemia (26.5%), elevated serum lipase (17.7%).

Conclusion: Nilotinib resulted in significant response rates and was generally well tolerated in CML-AP pts with imatinib-resistance/intolerance. This study demonstrates nilotinib to be an effective therapeutic option in this advanced CML population, for whom treatment options are limited. With longer follow-up, cytogenetic responses continue to increase and no change in safety profile has been observed on nilotinib therapy.

Topics:
imatinib mesylate, leukemia, myeloid, accelerated phase, nilotinib, brachial plexus neuritis, disease progression, anemia, bcr-abl tyrosine kinase, follow-up, leukemia, neutropenia

Author notes

Disclosure: Employment: Haque, Gallagher--Novartis. Consultancy: Larson - Novartis; Baccarani - Novartis, BMS, Merck, Pfizer. Research Funding: le Coutre, Giles, Gatterman, Larson, Kantarjian - Novartis; Kim - Novartis, BMS. Honoraria Information: le Coutre, Larson - Novartis; Apperley - Bristol-Myers Squibb, Novartis as syposia speaker; Gatterman - Novartis as lecturer; Kim - Novartis, BMS symposia. Paid Export Testimony Information: Larson - Novartis; Baccarani - Novartis, BMS, Schering AG, Pfizer. Membership Information: Kim - Novartis, BMS advisory boards. Off Label Use: At the time of submission, nilotinib is not FDA-approved for use in the United States.

2007, The American Society of Hematology
2007
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