Prospective Metabolic and Cardiovascular Assessment in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib 300 Mg Bid Frontline in the Gimema 0811 Trial

Background. Nilotinib 300 mg BID was approved as frontline treatment in chronic phase chronic myeloid leukemia (CP-CML) patients and allowed to reach deep molecular responses in a shorter median time with reduction of progression rate. Nilotinib is associated to a specific safety profile, with metabolic side effect as the most common events and increased probability of cardiovascular disorders.

Aim. Aim of our study is to prospectively assess metabolic changes and cardiovascular safety during treatment with nilotinib, in a single arm multicentric Italian GIMEMA trial (0811), testing the drug as frontline treatment with the primary endpoint to obtain MR4 at 24 months. All metabolic changes were classified according to CTC grade. Lipidic changes were assessed according to American Association of Clinical endocrinologist criteria of 2012 and glucose abnormalities according to American diabetologist association (ADA).

Results. One hundred and thirty patients were enrolled in 33 different centers: median age 50.5 years (range 18-85), 64.6% male. Mean body mass index (BMI) was 25.3, with 40% of patients being overweight/obese according to WHO classification. At last contact, 100 patients were still in treatment, the majority with full dose (86%). According to ADA criteria 47%, 10%, 4.6% and 6% of patients experienced grade 1 (101-125 mg/dl), grade 2 (126-150 mg/dl), grade 3 (151-200 mg/dl) and grade 4 (>200 mg/dl), increased fasting glucose, respectively. As compared to baseline, a significant variation was observed after 1 year (p<0.001). Glycosylated haemoglobin increased in 47% as grade 1 (5.7-6.49%), 10% as grade 2 (6.5-6.99%), 3% as grade 3 (7-7.99) and 4.6% as grade 4 (>8), respectively according to ADA criteria. AACE criteria identified a significant reduction of triglycerides (p<0.001) and a significant increase of cholesterol both in LDL and HDL fractions (p<0.001). Five patients (3.8%) experienced a peripheral arterial disorders (2 patients with claudication, 2 stenosis and 1 patient with arterial optic ischaemic): one patient required temporary reduction and 1 patient permanent discontinuation. Four patients experienced a venous thrombosis. Six patients (4.6%) had an ischemic cardiac disease and 7 patients (5.3%) an arrhythmia: five patients, based on physician judgment discontinued the treatment.

Conclusions. Prospective monitoring of metabolic safety during frontline treatment with nilotinib 300 mg BID showed consistent and specific profile with increased glycaemia and cholesterol level, mostly of grade 1-2. Possible occurrences of cardiovascular side effects impose identification of patients at risk at baseline and a correct monitoring during follow-up.