Background: Nilotinib is a novel, selective BCR-ABL inhibitor, designed to bind the ATP-binding site of BCR-ABL protein with higher affinity than imatinib. It is more potent than imatinib (IC50 <30 nM) against wild-type BCR-ABL and active against 32/33 imatinib-resistant BCR-ABL mutants.

Methods: This open-label study was designed to evaluate the safety and efficacy of nilotinib in patients (pts) with Philadelphia (Ph+) imatinib-resistant or -intolerant CML-CP. Planned nilotinib dose was 400 mg twice daily (BID) with escalation to 600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR) determined on the conventional intent-to-treat patient population. Cytogenetic response (CyR) was assessed by bone marrow karyotyping; peripheral blood FISH was used if a marrow sample cannot be obtained.

Results: This analysis includes data from 320 pts who received at least 6 months of nilotinib therapy (70.6% imatinib-resistant; 29.4% imatinib-intolerant). The median age was 58 years, the median duration of CML was 57.3 months, and 50.3% were males. Treatment with nilotinib is ongoing in 188 pts (58.8%) and 132 pts (41.3%) discontinued the treatment [51 (15.9%) for disease progression, 51 (15.9%) for adverse events (AE)]. The median duration of nilotinib exposure was 341 (1–624) days and the median average dose intensity was 792.1 mg/d (47.9–1111.6 mg/d). The dose was escalated to 600 mg BID in only 51 pts (15.9%). Complete hematological remission (CHR) at baseline was reported in 114 pts. Of the remaining 206 pts, 157 (76.2%) achieved CHR in 1 month. MCyR was observed in 180 pts (56.3%): 128/320 pts (40.0%) had complete cytogenetic response (CCyR). The median time to CHR and to first MCyR was 1.0 and 2.8 months, respectively. The median duration of MCyR has not been reached. Minor and Minimal CyR was seen in 22 (6.9%) and 42 (13.1%) patients respectively. The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (27%), neutropenia (30%), anemia (9%), and asymptomatic serum lipase elevation (15%).

Conclusion: The present study confirms nilotinib is an effective therapeutic option in CML-CP pts with imatinib-resistance or -intolerance, with an acceptable safety and tolerability profile. With longer follow up, cytogenetic response continues to increase and no change in safety profile has been observed on nilotinib therapy.

Topics:
imatinib mesylate, leukemia, myeloid, chronic-phase, nilotinib, brachial plexus neuritis, bcr-abl tyrosine kinase, adverse event, anemia, disease progression, disease remission, follow-up

Author notes

Disclosure:Consultancy: Hochhaus - Novartis; Baccarani - Novartis, BMS, Merck, Pfizer; Martinelli - Novaris, BMS. Research Funding: Kantarjian, le Coutre, Gattermann - Novartis; Hochhaus - Novartis, Bristol-Myers Squibb, INNOVIVE, Wyeth, and Merck; Bhalla - Merck; Giles - principal investigator, Novartis; Martinelli - Wyeth, BMS, Novartis. Honoraria Information: Hochhaus - Novartis, BMS; le Coutre, Bhalla, Gatterman - Novartis. Paid Export Testimony Information: Baccarani - Novartis Pharma, BMS, Schering AG, Pfizer. Membership Information: le Coutre - Novartis advisory board. Off Label Use: At submission, nilotinib was not FDA approved for use in the US.

2007, The American Society of Hematology
2007
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