Ibrutinib-induced cardiomyopathy

Abstract

LEARNINGOBJECTIVE #1: Recognize the existence of cardiovascular complications associated with Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitors (TKI) including axitinib LEARNING OBJECTIVE #2: Emphasize the importance of monitoring subjects on Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibtors (TKI) for cardiomyopathy CASE: Sixty year old male with history of hypertrophic cardiomyopathy, coronary artery bypass surgery and septal myectomy 6 years prior to presentation was started on axitinib for metastatic renal cell carcinoma. His co-morbidities included obstructive sleep apnea, chronic renal insufficiency and hypertension. He started axitinib in June 2013 after progression on sunitinib (VEGF tyrosine kinase inhibitor) and everolimus (mammalian target of Rapamycin (mTOR) inhibitor). A baseline echocardiogram prior to starting axitinib showed an ejection fraction of 40-45% with no wall-motion abnormalities. Six weeks after initiation of axitinib, the patient developed increased fatigue and dyspnea on exertion. His examination revealed bilateral lower extremity edema, normal S1 and S2, no murmurs nor elevated JVP. Repeat echocardiography demonstrated acute worsening in his ejection fraction to 25-30 % with mild dilation of the left ventricle. His EKG showed no acute changes and no acute coronary syndrome. His laboratory findings including a CBC and BMP were within normal limits. Though not previously reported, his clinical course suggested possible axitinib induced cardiomyopathy; axitinib was held and enalapril, carvedilol, and furosemide were initiated. The patient's symptoms improved off axitinib and a repeat echocardiogram 6 weeks later showed an improvement in his ejection fraction to 35-40 %. Subsequently, a case report of axitinib-induced Takotsubo like syndrome was published. 1 DISCUSSION: Myocardial toxicity is a known side effect of many cancer treatments. The anthracyclines doxorubicin, daunorubicin, epirubicin and mitoxantrone have known cardiotoxicity; additionally, myocardial injury has also been associated with tyrosine kinase inhibitors, alkylating agents, anti-metabolites, proteasome inhibitors and antimicrotubule agents. 2 Recently, a number of VEGF-R directed targeted therapies have been approved for the treatment of metastatic renal cancer. In this case, a patient with metastatic renal cell carcinoma and pre-existing cardiac disease developed a reversible cardiomyopathy while taking axitinib. Axitinib targets the vascular endothelial growth receptors 1, 2 and 3 and is approved as a second line therapy for metastatic renal cell carcinoma based on results of a Phase III AXIS study. 3 Four additional VEGF inhibitorssunitinib, pazopanib, sorafenib and bevacizumab- are also approved for the treatment of metastatic renal cell carcinoma. Traditionally, fatigue and hypertension have been the most commonly reported side effects with this class of targeted therapies. Cardiomyopathy has been associated with the use of sunitinib, bevacizumab, and sorafenib. An association between pazopanib or axitinib and cardiotoxicity has not been well described. 4 Phase III clinical trials for axitinib showed a small incidence of cardiomyopathy.3 Compared to anthracyclines, cardiotoxicity associated with tyrosine kinase inhibitors appears to be less profound but more acute in presentation and is not dose-dependent. Treatment of VEGF inhibitor associated cardiomyopathy includes cessation of therapy with close follow up to monitor for recovery of systolic function. The reversibility of this cardiomyopathy is unknown, although limited literature with suntinib induced cardiotoxicity suggests improvement in ejection LV function and symptoms after cessation of the drug.5 In our subject, cardiac function improved dramatically after discontinuing axitinib. Targeted therapies have an ever-expanding role in modern medicine, and likewise, VEGF inhibitors are commonly utilized for treatment of metastatic kidney cancer . Adverse effects of these new agents are continuing to be evaluated; further studies are needed to delineate their cardiovascular side effects. Generalists and subspecialists alike should be aware of possible cardiotoxicity in association with targeted therapies, especially in patients with cardiac comorbidities, and should monitor patients accordingly.