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Usefulness of the 2012 European CVD risk assessment model to identify patients at high risk of cardiovascular events during nilotinib therapy in chronic myeloid leukemia

Leukemia volume 29, pages 1206–1209 (2015)Cite this article

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Nilotinib is a tyrosine kinase inhibitor (TKI) targeting the BCR-ABL1 oncoprotein with high potency and shows activity against most BCR-ABL1 kinase domain mutants.1 It is approved at 400 mg twice daily (BID) for chronic phase (CP)- or accelerated phase (AP)- chronic myeloid leukemia (CML) with resistance or intolerance to imatinib and at 300 mg BID for newly diagnosed CP-CML.2, 3 Whereas nilotinib was initially considered as well-tolerated, postmarketing reports raised concerns about an association between the drug and onset of arterial occlusions.4, 5, 6 In the phase 3 randomized trial ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Patients) the 5-year rate of ischemic cardiovascular events was 2.1% in the imatinib arm, 6.8% in the nilotinib 300 mg BID arm and 12.6% in the nilotinib 400 mg BID arm.7 A growing body of evidence suggests that these cardiovascular events may be influenced by several factors including pro-atherogenic and anti-angiogenic properties of nilotinib, propensity to increase glycemia and cholesterolemia, nilotinib dosing regimen and risk factors for atherosclerotic cardiovascular diseases (CVD).4, 5, 6, 7, 8, 9, 10 However, how to precisely assess the risk of cardiovascular events during nilotinib treatment remains unclear. In the general European population, a model updated in 2012 by the European Society of Cardiology is used to assess the CVD risk and to guide prevention.11 It relies on CVD history, risk factors and SCORE (Systematic Coronary Risk Evaluation). Its endpoint is the 10-year atherosclerotic CVD mortality. We designed a single center retrospective study to ask whether CVD risk determination according to this model was useful to identify CML patients at high risk of fatal and non-fatal clinical manifestation of arterial stenosis or occlusion during the early stages of nilotinib therapy.

Patients were at least 18 year old at the start of nilotinib. Nilotinib was given upfront or after failure of imatinib or dasatinib for CP- or AP-CML. The choice of nilotinib was solely driven by CML-related parameters such as BCR-ABL1 mutational status or type of intolerance to the prior TKIs. We integrate CVD risk factors and comorbidities into our TKI selection criteria since the year 2012. To avoid such selection bias, only patients in whom nilotinib treatment was initiated before 2012 were included. Informed consent was obtained in accordance with the Declaration of Helsinki. CVD risk factors were collected at baseline and the CVD risk was assessed. In the 2012 European CVD risk assessment model, individuals are classified into four risk groups:11 Very high: documented CVD, asymptomatic atherosclerosis, diabetes mellitus (DM) with end-organ damage or ⩾1 CVD risk factor, severe chronic kidney disease (CKD) or SCORE ⩾10%. High: elevated CVD risk factors, DM without other CVD risk factors or end-organ damage, moderate CKD or SCORE of ⩾5% and <10%. Moderate: SCORE ⩾1% and <5%. Low: SCORE <1%. SCORE is calculated using risk charts and is based on age, gender, blood pressure, cholesterol, tobacco use and country of origin.11 Individuals with a SCORE ⩾5% are at least at high risk and those with already other criteria for high or very high risk do not need SCORE calculation. Given the retrospective nature of our study, discriminating SCORE <1% from those ⩾1% and <5%, and SCORE ⩾10% from those ⩾5% was not feasible in all patients. For this reason, we classified patients into two groups: high/very high, having at least one of the following criteria: documented CVD, asymptomatic atherosclerosis, DM, moderate or severe CKD, elevated CVD risk factors or SCORE of ⩾5%, and low/moderate: none of the above. Responses to TKI treatment were assessed according to the European LeukemiaNet recommendations.12 Differences in rates of responses were analyzed with the Fisher’s exact test. The Mann–Whitney U-test was used to analyze differences between medians of two data sets. Two-tailed P<0.05 was considered statistically significant. Overall survival (OS) and arterial event-free survival were estimated by the Kaplan–Meier method and compared by the log-rank test.

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Authors and Affiliations

  1. Hématologie Adulte, Hôpital Saint-Louis, AP-HP, Paris, France

    D Rea, E Raffoux & H Dombret

  2. Médecine vasculaire, Hôpital européen Georges Pompidou, AP-HP, Paris, France

    T Mirault & E Messas

  3. INSERM UMR970, PARCC, Paris Descartes University, Sorbonne Paris Cité, Paris, France,

    T Mirault & E Messas

  4. Hématologie Adolescents et Jeunes Adultes, Hôpital Saint-Louis, AP-HP, Paris, France,

    N Boissel

  5. Centre d’Investigation Clinique, Hôpital Saint-Louis, AP-HP, Paris, France,

    A L Andreoli

  6. Hématologie et Oncologie, Hôpital André Mignot, Université de Versailles, Le Chesnay, France,

    P Rousselot

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  1. D Rea
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Correspondence to D Rea.

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Competing interests

DR and PR have received honoraria from Novartis, Bristol Myers Squibb, Pfizer and Ariad. EM has received honoraria from Novartis, Bristol Myers Squibb and Ariad. HD has received honoraria from Novartis and Ariad. TM has received honoraria from Novartis. The remaining authors declare no conflict of interest.

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Author Contributions

DR, TM and EM designed the study, acquired and analyzed the data and wrote the manuscript. All authors made substantial contribution to patient care, collection of clinical information, critical revision of the article and agreement on its content and final approval of the version to be published.

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This work has not received any funding from the pharmaceutical industry.

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Rea, D., Mirault, T., Raffoux, E. et al. Usefulness of the 2012 European CVD risk assessment model to identify patients at high risk of cardiovascular events during nilotinib therapy in chronic myeloid leukemia. Leukemia 29, 1206–1209 (2015). https://doi.org/10.1038/leu.2014.342

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