AbstractImatinibhas been approved by the FDA as an oral drug for the treatment of ChronicMyeloid Leukemia ( CML ), gastrointestinal stromal tumors (GISTs) and hypereosinophilicsyndrome. Although imatinib is well tolerated, the incidence of edema anddyspnea are reported to be as high as 66 and 16%, respectively. Imatinib-induced cardiotoxicity is a veryuncommon adverse event <1% 1-11. A 53-year-old male with history of Chronic Myeloid Leukemia ( CML ) on Imatinib for the past 5 years. He presentedwith symptoms of exertional dyspnea, poor exercise performance, fatigue, andleg swellings. Chest X ray revealed cardiomegaly, and pulmonary edema. Electrocardiogramshowed normal sinus rhythm, no ischemic changes.
Cardiac enzymes were normal. 2D Echocardiogram showed ejection fraction EFof 35%, normalpulmonary systolic pressure, no wall motion abnormality, with normal valvularfunction .In our case report, we highlight the association between Imatinib use andcongestive heart failure, which may need discontinuing the medication andprompt treatment of congestive heart failure. Keywords: Imatinib,Congestive Heart Failure, Mitochondrial dysfunction, Chronic Myeloid Leukemia. IntroductionImatinibis a revolutionary drug for the treatment of CML by targeting ABL; itefficiently inhibits BCR-ABL+ CML cells, blocks phosphorylation andinduces apoptotic cell death 14-17. Myocardial tissue homeostasis dependslargely on mitochondrial function; therefore, impairment in mitochondrialfunction eventually leads to cardiomyocyte and endothelial cell death andconsequent cardiovascular dysfunction. Several chemical compounds and drugshave been known to alter cardiac mitochondrial function, which can account bothfor the toxicological and pharmacological properties of these substances 17-23. Case PresentationA 53-year-old male with history of Chronic Myeloid Leukemia ( CML ) on Imatinib for the past 5 years as maintenance therapy.
He presented withsymptoms of exertional dyspnea,paroxysmal nocturnal dyspnea, poor exercise performance, fatigue, and legswellings. Vitalsigns: Blood pressure was 123/74 mmHg, pulse rate 96 beats/ min regular,temperature 98.0 F ( 36.7 C ) Tympanic, respiratory rate 20, SpO2 94% on roomair.Electrocardiogramshowed normal sinus rhythm, no ST, T wave changes. Chestradiograph showed evidence of cardiomegaly, and pulmonary edema.
Tow dimensional Echocardiogram showed ejection fraction EF of 35%, normal pulmonary systolicpressure, otherwise unremarkable. Labs: WBC 4,600 /microL, Hemoglobin Hgb 11.9 g/dl, HCT 34.7 %, MCV 83fL, Platelets 210,000 /microL, INR 1.0, PTT 25s, Glucose 101 mg/dl, Urea 13mg/dl, S. Creatinine 0.9 mg/dl, GFR 97 mL/min/1.
73 m2 ,Sodium 133 meq/L, Potassium 4.2 meq/L, S. Troponin I 0.01- 0.
041– 0.01 ng/ml,BNP 6450 pg/ml.Adiagnosis of acute heart failure was made and imatinib discontinued. He wasprescribed comprehensive therapy including oxygen, diuretics and vasodilators according to the ACC/AHA guidelines for the diagnosis and management ofheart failure in adults. Patient wassent home on Carvedilol 3.125 mg po BID, Lisinopril 5 mg po daily, and Furosemide 40 mg po daily.
Afollow up after 3 months revealed patient’s symptoms and signs of heart failurehad resolved and findings of biochemical tests, chest X-ray film andechocardiogram were all consistent with recovery, where repeat 2DEchocardiogram showed EF of 55%. DiscussionChronic myeloid leukemia (CML) is amyeloproliferative disorder caused by an acquired mutation of hematopoieticstem cells. This mutation results in a reciprocal translocation betweenchromosomes 9 and 22 termed the Philadelphia chromosome (t9;22q34;q11) andgenerates a novel fusion gene, BCR-ABL, which encodes tyrosine kinase. Imatinibmesylate (Gleevec), a small-molecule inhibitor of multiple tyrosine kinases,selectively prevents phosphorylation of BCR-ABL and inhibits downstreamsignaling and growth of BCR-ABL–positive cells 3-9. Cardiomyocytes utilize an enormousamount of adenosine triphosphate (ATP), being in a constant energy-consumingcontractile state. To maintain constant ATP production, malfunctioningmitochondria are constantly replaced by newly synthetized organelles byprocesses involving mitochondrial biogenesis and replication andautophagy/mitophagy .
These processes work in a tightly regulated manner, withmitochondrial fusion and fission allowing the dynamic formation and remodelingof a reticulated mitochondrial network . Since mitochondria are responsible forthe production of ATP, agents that interfere with the physiological myocardialmitochondrial function are expected to induce depletion of ATP pool.Eventually, these processes may lead to subsequent myocardial dysfunction 12-19.BNP is a cardiac neurohormone that issecreted by membrane granules in the cardiac ventricles in response toventricular volume overload and pressure overload. BNP concentrations arereflective of LV diastolic filling pressures and increased in patients with symptomatic LVdysfunction.
In the present case, the concentration of BNP was 6450 pg/mL,reflecting deterioration in cardiac function and Systolic heart failure. Afterwithdrawal of imatinib, not only were the symptoms relieved, but also the BNPconcentration decreased significantly, which implied that systolic heartfailure in this patient was imatinib-related 7-13. Insummary, imatinib therapy uncommonly causes heart failure and mainly occurs inelderly patients with preexisting cardiovascular conditions. Our casedemonstrates imatinib induced cardiotoxicity in young patient with nopreexisting cardiovascular disease. We recommend that when patients developsymptoms of congestive heart failure, should be monitored closely and treatedaggressively with standard medical therapy, including diuretics, andvasodilators. In addition, imatinib mesylate should be discontinued or thedosage reduced 17-21.
ConclusionTheeffect of imatinib on the heart is dose, time, and age dependent. This is clinically important as imatinibtreatment is life long and that cardiac damage can be cumulative, thateventually causes congestive heart failure 6,7,8.Weconclude that imatinib is an uncommon cause of cardiotoxicity with incidence< 1%, and that the cardiovascular adverse events that occur are manageablewhen recognized and treated. Imatinib remains a potential cardiotoxin, and thecardiac consequences of its long-term use remain unknown. Werecommend treatment of risk factors for cardiovascular disease in imatinibtreated patients according the American Heart Association guidelines for theprevention and treatment of heart failure, along with frequent monitoring ofsigns/symptoms of heart failure.