A Canadian Expanded Access Trial of Oral Nilotinb in Adult Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Blast Crisis, Accelerated Phase or Chronic Phase

Patients received nilotinib orally at a dose of 400 mg twice daily. Adverse events were monitored throughout the study and assessments of cardiac, hematology and blood chemistry were performed every 3 months at a minimum. The efficacy assessments were performed every 6 months at a minimum and comprised of cytogenetic analysis of bone marrow, evaluation of extramedullary disease, and cancer related symptoms.

Sixty-five patients were enrolled in the study. The median age was 56 (range 21–85) years; 50.8% were male, and 89.2% Caucasian. The majority of patients (92.3%) were in chronic phase; 3.1% and 4.6% of the patients were in blast crisis and accelerated phase respectively. Twenty-five (38.5%) patients were imatinib-resistant, thirty-seven (56.9%) imatinib-intolerant and three (4.6%) both imatinib-resistant and -intolerant. The overall median duration of treatment with nilotinib was 27.2 (range 0.3 – 48.8) months. Thirty-six patients (55.4%) were still on treatment at study end. The main reasons for discontinuation were adverse events (16.9%) and unsatisfactory therapeutic effect (12.3%).

Treatment related adverse events reported in at least 10% of patients, irrespective of severity, included rash (23.1%), pruritus (20%), fatigue (18.5%), muscle spasms (15.4%), headache (16.9%), alopecia (13.8%), abdominal pain (10.8%) and lipase elevation (10.8%). Grade 3 and 4 adverse events reported in at least 5% of patients, irrespective of study drug relationship, included thrombocytopenia (12.3 %), anemia (6.2%), neutropenia (6.2%) and lipase elevation (6.2%). Three patients (4.6%) discontinued due to cardiac disorders including tachycardia (1), myocardial infarction (1), and palpitations (1). Clinically significant abnormal ECG results were uncommon and mostly transient. There was no evidence of toxicity to a major organ system. One patient died within 28 days after study discontinuation due to progression of recently diagnosed multiple myeloma and chronic obstructive pulmonary disease deterioration not suspected to be related to study drug.

Thirty patients received treatment for at least 30 months with nilotinib on study. At month 30, 14 (82.4%) of 17 patients who underwent a bone marrow aspirate achieved a complete cytogenetic response. Seven of these fourteen patients (50%) had never previously achieved complete cytogenetic response with imatinib.

This phase IIIB trial provided nilotinib to 65 patients with imatinib-resistant or -intolerant chronic CML in all phases on expanded access for 44 months, allowing evaluation of its safety profile. Nilotinib treatment was reasonably well-tolerated with an overall safety profile similar to that reported in previous studies, without the occurrence of unexpected adverse events. Real-time quantitative RT-PCR of BCR-ABL mRNA levels was not a study endpoint but is used routinely in Canada to monitor patients in complete cytogenetic response instead of cytogenetic assessments which likely explains the low compliance with cytogenetic assessments in this study.

Turner:Novartis Pharmaceuticals Canada: Research Funding, Speakers Bureau. Leber:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hasegawa:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Leitch:Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Bence-Bruckler:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Sandeep:Novartis Pharmaceuticals: Honoraria. Laneuville:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Woo:Novartis Pharmaceuticals Canada Inc.: Employment. Beauparlant:Novartis Pharmaceuticals Canada Inc: Employment. Lipton:Novartis Pharmaceuticals Canada Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees.