Metabolic syndrome and TKIS treatment in chronic myeloid leukemia

Background: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterised by a pathognomonic chromosomal translocation t(9;22)(q34;q11.2). The introduction of Tyrosin-Kinase Inhibitors (TKIs), with the aim of targeting this translocation, has dramatically improved life expectancy of CML patients. First (imatinib) and second generation TKIs (dasatinib and nilotinib) act on various molecular targets and this functional difference could explain the various adverse reactions. Besides non haematological side effects, the three groups of TKIs have different effects on glucose and insulin metabolism (GIM), but no data are available on the prevalence of Metabolic Syndrome (MS). MS is a cluster of interrelated metabolic disorders associated with insulin resistance and increased risk of cardiovascular disease. Aims: To evaluate the presence of MS defined by the National Institute of Health Cholesterol Education Program-ATP III in a cohort of CML patients treated with the three different classes of TKIs. Methods: A total of 90 unselected CML patients treated with TKIs and referred to our Hospital were included. Blood samples and other clinical variables were collected for each patient. We evaluated anthropometric parameters to define the presence of MS according to ATP III (>3 of following abnormalities): waist circumference >102 cm in men and >88 cm in women, serum tryglicerides level >150 mg/dl, HDL cholesterol level <40 mg/dl in men and <50 mg/dl in women, blood pressure >130 or >85 mmHg, or serum glucose level >100 mg/dl. We studied Beta-cell function assessed by HOMA-IR e HOMA-beta to estimate insulin-resistance and insulin-secretion, respectively. Results: Among our patients, 26 (31%) were confirmed with MS. The nilotinib treated group presented the highest percentage of MS (p<0.01). Adjusting data for sex and age, total (p<0.01) and LDL (p<0.01) cholesterol levels were significantly higher in the nilotinib group when compared to the imatinib and dasatinib groups, while the homocysteine level was significantly higher in the dasatinib treated group (p<0.01) and higher, but not significantly, in the nilotinib treated group, when compared to the imatinib one. The mean levels of HOMA-beta were lower in patients with MS compared to the non-MS patients (p<0.01) in the three groups, while HOMA-IR, weight and BMI were higher (p<0.01). Summary and Conclusions: In our series MS is highly prevalent and CML patients treated with nilotinib presented a higher cardiovascular risk profile compared to the others. On the basis of our results, when nilotinib is the selected drug, we suggest a multidisciplinary approach with the patient, with the aim to reduce cardiovascular risk and improve long term clinical outcomes.