Cardiovascular risk assessments in chronic myeloid leukemia allow identification of patients at high risk of cardiovascular events during treatment with nilotinib
Authors: Massimo Breccia, Gioia Colafigli, Matteo Molica, Giuliana Alimena
Journal: American Journal of Hematology (2015)

Nilotinib, a second-generation tyrosine kinase inhibitor, has been approved at the dose of 300 mg bis in die (BID) for newly diagnosed chronic phase chronic myeloid leukemia patients and at the dose of 400 mg BID for chronic or accelerated phase patients with resistance or intolerance to imatinib 1. In the last few years, several communications of arterial thrombotic events have been described during nilotinib therapy, but the exact pathogenetic mechanisms are still unknown 2. In the ENESTnd trial at the last follow-up of 5 years, an increased rate of ischemic events with nilotinib has been reported (6.8% with nilotinib 300 mg BID and 12.6% with nilotinib 400 mg BID) as compared to imatinib (2.1%) 3. Thus, it has become of great importance to evaluate the benefit/risk ratio at baseline, considering the overall cardiovascular risk profile of patients, taking into account pre-existing comorbidities and risk factors predisposing to atherosclerotic events. Our group and other investigators tried to retrospectively apply the European 2012 cardiovascular risk assessment model (SCORE chart) in order to identify patients at risk of atherosclerotic events during nilotinib treatment: both studies were able to demonstrate the validity of the ESC criteria to select patients at risk of cardiovascular events during treatment 4, 5. According to these ESC 2012 criteria, patients were stratified on the basis of age, sex, systolic pressure, smoking, and total cholesterol level 6. Indeed, other prognostic scores already existed: the Framingham risk score 7 which is a sex-specific algorithm developed in 1998 in order to calculate the 10-year cardiovascular individual risk. It was then modified and updated to include dyslipidaemia, age, hypertension treatment, smoking, total cholesterol level, with exclusion of diabetes, that was included in the first version, because this risk factor was considered to be a coronary heart disease equivalent. Another prediction algorithm for cardiovascular disease is the QRisk2 8 that uses traditional risk factors such as age, systolic pressure, smoking status, a ratio of total serum cholesterol to high-density lipoprotein cholesterol, but also the body mass index, ethnicity, family history, chronic kidney disease, rheumatoid arthritis, atrial fibrillation, diabetes, and anti-hypertensive treatment. A QRisk2 over 10%, indicating 10% risk of cardiovascular disease event over the next ten years, suggests that a therapy with lipid lowering therapy with a statin should be started. We retrospectively applied these two latter prognostic score to the same population of CML patients treated with nilotinib that we previously described 4. We included in this study 82 chronic myeloid leukemia in chronic phase (CML-CP) patients treated frontline with nilotinib (42 patients, with the dose of 600 mg BID) or after failure of other tyrosine kinase inhibitors (40, of whom 33 after imatinib and 7 after dasatinib, with the dose of 400 mg BID). In this cohort, there were 48 males and 34 females with a median age of 51 years (range 22–84). Seventeen patients (20.7%) had a concomitant type II controlled diabetes (without organ damage), 23 patients (28%) were smokers, 29 patients (35%) were receiving concomitant drugs for hypertension, and 15 patients (18%) had concomitant dyslipidaemia. Stratification of patients according to WHO classification for body mass index (BMI) identified that 42 patients were classified as normal weight (BMI < 25), 26 patients were overweight (BMI 26– <30), and 14 were obese (BMI > 30). We retrospectively classified the whole population according to the ESC criteria and found that 28 patients (34%) were in the low risk category, 30 patients (36%) were in the moderate risk, and 24 patients (29%) were in the high risk. In our cohort, the cumulative incidence of atherosclerotic events at 48 months was 8.5% (95% CI: 4.55–14.07): we did not observe any cardiovascular event in the low-risk patients, while 10% of events occurred in the moderate risk category and 29% in the high risk (P = 0.002). Therefore, atherosclerotic-free survival (AFS) was 100%, 89%, and 69% in the low, moderate, and high-risk population, respectively (P = 0.001). The same population was then stratified according to the Framingham score and the QRisk score (Table ). According to the modified Framingham score, 51 patients were classified as having a low risk and none of them experienced a cardiovascular events; 17 patients were classified as intermediate risk and 17.6% experienced an event, whereas 14 patients were high risk and 36% of them experienced an event (P = 0.001). According to the QRisk2 stratification, 33 patients had a cardiovascular risk less than 10% and none of them had an event; 33 were classified as having a risk between 10 and 20% and 8% of them had a cardiovascular events, whereas 16 were stratified as having a risk above 20% and 40% of them had a cardiovascular event (P = 0.0001, Table ). Overall, two patients developed an unstable angina with subsequent application of medicated stent. Another overweight patient developed an asymptomatic peripheral arterial occlusive disease (PAOD) (observed at posterior tibial in left leg, a grade 1 by Rutheford classification) that required antiplatelet aggregation treatment. One patient (affected by hypertension) had a stroke, one case of PAOD occurred in a patient with severe hypertension, diabetes, and hypercholesterolemia (with an anckle brachial index (ABI) < 0.9), and three patients experienced a myocardial infarction (all with more than three risk factors at baseline and with previous cardiac diseases). In summary, in our retrospective analysis, all cardiovascular risk assessments seem to well identify patients that should be considered at high risk of arterial thrombotic events, but in particular we found that QRisk evaluation, which includes also diabetes and obesity as predisposing risk factors, could be particularly useful in patients treated with nilotinib. With the possibility to choose the best therapeutic option for CML patients and the good outcome reported with treatment-free remission as a new endpoint to pursue, it is of paramount importance to select patients not only based on disease characteristics (type of resistance, mutation profile) but also on specific patient-related features (comorbidities and cardiovascular risk profile) 9. The determination of the individual cardiovascular risk profile may allow to exclude patients with multiple negative factors from exposure to TKIs associated with increased risk of arterial thrombotic events, if a different option exists. Otherwise, cardiovascular risk factors should be strictly monitored and corrected promptly during treatment. Our results suggest that it is of great importance to consider the comorbidity and cardiovascular profile at baseline and that all these information should be associated in new algorithms in order to select in an appropriate way the best therapeutic options both in frontline and in resistant-patients setting. Massimo Breccia*, Gioia Colafigli, Matteo Molica, and Giuliana Alimena Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy