A 39-year-old woman with chronic myeloid leukemia is referred to the cardio-oncology clinic for cardiovascular assessment and surveillance while receiving a tyrosine kinase inhibitor. She was diagnosed with chronic myeloid leukemia about 10 years ago. Her chronic myeloid leukemia was treated with imatinib, and she has been on imatinib since then with deep molecular response (>4-4.5 log reduction). She is asymptomatic from the cardiovascular perspective and has no cardiovascular risk factors. On physical examination, she is hemodynamically stable and without focal clinical findings. An electrocardiogram shows normal sinus rhythm with normal PR, QRS, and QTc. A transthoracic echocardiogram is ordered because of long-term exposure to imatinib to assess left ventricular (LV) function. The echocardiogram reveals normal biventricular and biatrial dimensions, LV hypertrophy, LV ejection fraction = 45%, grade I diastolic dysfunction, and small pericardial effusion. The rest of the study was unremarkable. Cardiac magnetic resonance imaging (MRI) is requested, which shows LV hypertrophy, LV ejection fraction = 45%, small pericardial effusion, and diffuse sub-endocardial late gadolinium enhancement of LV as well as left atrium.
Which of the following statements is correct?
The correct answer is: B. Further work-up, including a cardiac biopsy, is needed to rule out other causes of LV dysfunction.
Imatinib is a selective inhibitor of ABL, platelet-derived growth factor receptor, and c-kit and shows significant antileukemic effect in patients with chronic myeloid leukemia.1 In 2006, Kerkelä et al.2 reported heart failure in 10 patients who were receiving imatinib, lending clinical credence to in vitro and murine studies suggesting that imatinib can cause cardiotoxicity and cardiomyopathy. However, since that time, long-term outcomes reports on imatinib trials have not confirmed the increased incidence of heart failure with imatinib.3,4 Prospective cardiac imaging in patients on imatinib also showed a low incidence of LV dysfunction.5 It is important to note that patients receiving imatinib may develop side effects such as peripheral edema and, less commonly, pleural and pericardial effusion. The edema is usually mild, localized to the periorbital region or lower extremities, and responds to diuretics. The mechanism of fluid retention has been attributed to the inhibition of the platelet-derived growth factor receptor by imatinib.6-9 Fulminant lethal myocarditis has been reported in patients receiving treatment with immune checkpoint inhibitors10 but has not been reported in patients receiving imatinib.
During work-up for diagnosis of cardiotoxicity, other causes of LV dysfunction should be ruled out. In this case, MRI features and echocardiographic features are suggestive of infiltrative cardiomyopathy and cardiac amyloidosis.11,12 Cardiac biopsy to rule out infiltrative cardiomyopathy and amyloidosis would be a reasonable approach. Patients who develop cardiotoxicity during cancer treatment often require modifications or withdrawal of life-saving cancer therapies, which can profoundly impact the cancer outcome. As such, other causes for LV dysfunction should be carefully investigated during the work-up for a presumed cardiotoxicity to avoid unnecessary withdrawal or modification of cancer treatment.
O'Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.
Kerkelä R, Grazette L, Yacobi R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006;12:908-16.
Hochhaus A, Larson RA, Guilhot F, et al. Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia. N Engl J Med 2017;376:917-27.
Baccarani M, Druker BJ, Branford S, et al. Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study. Int J Hematol 2014;99:616-24.
Estabragh ZR, Knight K, Watmough SJ, et al. A prospective evaluation of cardiac function in patients with chronic myeloid leukaemia treated with imatinib. Leuk Res 2011;35:49-51.
Cohen MH, Williams G, Johnson JR, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002;8:935-42.
Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031-7.
Esmaeli B, Prieto VG, Butler CE, et al. Severe periorbital edema secondary to STI571 (Gleevec). Cancer 2002;95:881-7.
Shimazaki C, Ochiai N, Uchida R, et al. Intramuscular edema as a complication of treatment with imatinib. Leukemia 2003;17:804-5.
Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016;375:1749-55.
Falk RH, Quarta CC, Dorbala S. How to image cardiac amyloidosis. Circ Cardiovasc Imaging 2014;7:552-62.
Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol 2016;68:1323-41.