A 40-year-old man without previous history of cardiovascular disease has been referred to the cardio-oncology clinic for cardiovascular assessment before starting nilotinib. He has been recently diagnosed with chronic myeloid leukemia. He has a history of diet-controlled diabetes and has dyslipidemia, for which he is on atorvastatin. His vitals are within normal limits, and his physical exam is unremarkable. His total cholesterol is 3.26 mmol/L (triglycerides = 0.92 mmol/L, high-density lipoprotein = 1.06 mmol/L, and low-density lipoprotein = 1.78 mmol/L).
Which of the following statements is correct?
Show Answer
The correct answer is: D. An increased risk of peripheral arterial disease (PAD) has been observed in patients treated with nilotinib; yearly ankle-brachial index (ABI) is recommended.
Nilotinib is an effective second-generation BCR-ABL tyrosine kinase inhibitor (TKI) approved for treatment of chronic myeloid leukemia.1 Nilotinib is an inhibitor of CYP 3A4 and increases levels of atorvastatin. Pravastatin and rosuvastatin are not significantly metabolized by CYP3A4 and are less susceptible to CYP interactions and can be used safely with nilotinib and other inhibitors of CYP 3A4.2 Nilotinib increases the risk of or worsens diabetes and dyslipidemia, and close monitoring of blood sugar and cholesterol levels is recommended while patients are receiving this TKI. However, diabetes and dyslipidemia are not contraindications for using nilotinib.3,4 Nilotinib does not increase risk of PAH; dasatinib is the BCR-ABL TKI that increases risk of PAH.5 The reports of increased cardiovascular events and PAD have raised concerns about safety of nilotinib, especially in patients with multiple pre-existing risk factors.6-8 Surveillance ABI for patients who are receiving ponatinib or nilotinib has been recommended by experts,9 but evidence is lacking for this recommendation. European LeukemiaNet recommends surveillance ABI (or duplex ultrasonography) every 6-12 months in patients on ponatinib or nilotinib.10 Currently, there are no data regarding the rate of progression of PAD in patients receiving nilotinib or ponatinib. The time course of an individual converting from asymptomatic PAD to symptomatic PAD is also unclear in these patients. In patients receiving nilotinib or ponatinib, abnormal ABI or progression of PAD should be communicated with hematologist/oncologist for consideration of change in medication. Patients must receive education about red flags for limb ischemia, and modifiable cardiovascular risk factors should be managed aggressively.
References
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Haouala A, Widmer N, Duchosal MA, Montemurro M, Buclin T, Decosterd LA. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood 2011;117:e75–87.
Franklin M, Burns L, Perez S, Yerragolam D, Makenbaeva D. Incidence of Type II Diabetes Mellitus and Hyperlipidemia in Patients Prescribed Dasatinib or Nilotinib As First or Second Line Therapy for Chronic Myelogenous Leukemia (CML). Blood 2016;128:4766.
Racil Z, Razga F, Drapalova J, et al. Mechanism of impaired glucose metabolism during nilotinib therapy in patients with chronic myelogenous leukemia. Haematologica 2013;98:e124-6.
Montani D, Bergot E, Günther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 2012;125:2128-37.
Kim TD, le Coutre P, Schwarz M, et al. Clinical cardiac safety profile of nilotinib. Haematologica 2012;97:883-9.
Levato L, Cantaffa R, Kropp MG, Magro D, Piro E, Molica S. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in chronic myeloid leukemia: a single institution study. Eur J Haematol 2013;90:531-2.
Le Coutre P, Rea D, Abruzzese E, et al. Severe peripheral arterial disease during nilotinib therapy. J Natl Cancer Inst 2011;103:1347-8.
Herrmann J, Yang EH, Iliescu CA, et al. Vascular Toxicities of Cancer Therapies: The Old and the New--An Evolving Avenue. Circulation 2016;133:1272-89.
Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia 2016;30:1648-71.
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