A 45-year-old white man with history of chronic myeloid leukemia was referred to the cardio-oncology clinic for cardiovascular assessment before being started on ponatinib (a third-generation BCR-ABL tyrosine kinase inhibitor [TKI]). He had no previous history of cardiovascular disease and no known risk factors. On initial exam, his jugular venous pressure was normal, blood pressure was 120/80 mmHg, heart rate was 79 bpm, and heart and lung auscultations were normal. His blood work showed that his hemoglobin A1C was 5.7% and his total cholesterol was 251 mg/dl (high-density lipoprotein = 72 mg/dl; low-density lipoprotein = 147 mg/dl).
His current 10-year risk for future atherosclerotic cardiovascular disease was calculated at 1.7%.
Which of the following statements is correct about this patient?
The correct answer is: D. Both B and C.
Ponatinib is a potent BCR-ABL TKI with potential to inhibit all BCR-ABL1 mutants reported in patients with resistance to first-generation and second-generation TKIs.1 Ponatinib received accelerated approval in December 2012 after it was found to be effective in treatment of patients with resistance to multiple lines of TKIs. Data obtained in October 2013 from the PACE (Ponatinib Ph-Positive Acute Lymphoblastic Leukemia and CML Evaluation) trial1 showed that ponatinib was associated with an increased incidence of cardiovascular events. At a median follow-up of 28 months, cumulative cardiovascular, cerebrovascular, and peripheral adverse events were 10%, 7%, and 7%, respectively.2 In the phase 2 trial of ponatinib in refractory chronic myeloid leukemia, arterial occlusive events were observed in 27% of patients after a median follow-up of 38 months. The frequency of arterial events was even higher in the EPIC (Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia) trial than in the phase 2 study, with at least 35% of ponatinib-treated patients experiencing fatal myocardial infarction, stroke, severe peripheral vascular disease, and the need for urgent revascularization procedures, leading to the termination of the trial.3,4
The US Food and Drug Administration allowed reintroduction of ponatinib into the market, subject to a boxed warning informing patients and health professionals about increased risk of serious cardiovascular events. It mandated that the increased risk be communicated with the patient before starting treatment.5
Treatment with ponatinib requires that hematologists and cardiologists follow the patient closely and identify modalities of surveillance and risk factor modification.6 Estimating global risk of cardiovascular disease in patients with chronic myeloid leukemia receiving ponatinib has not been investigated yet. Currently, it is recommended that patients who receive treatment undergo yearly ankle-brachial index and close monitoring by both cardiologists and hematologists, with plans for risk factor modification and cardiovascular surveillance during treatment.2,7,8
Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 2013;369:1783-96.
Li W, Croce K, Steensma DP, McDermott DF, Ben-Yehuda O, Moslehi J. Vascular and Metabolic Implications of Novel Targeted Cancer Therapies: Focus on Kinase Inhibitors. J Am Coll Cardiol 2015;66:1160-78.
Lipton JH, Chuah C, Guerci-Bresler A, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:612-21.
FDA Drug Safety Communication: FDA requires multiple new safety measures for leukemia drug Iclusig; company expected to resume marketing (US Food and Drug Administration website). 2018. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm379554.htm. Accessed December 17, 2017.
Breccia M, Pregno P, Spallarossa P, et al. Identification, prevention and management of cardiovascular risk in chronic myeloid leukaemia patients candidate to ponatinib: an expert opinion. Ann Hematol 2016;96:549-58.
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.