Reversible Cardiotoxicity With Tyrosine Kinase Inhibitors

Reversible Cardiotoxicity With Tyrosine Kinase Inhibitors

Jawad Francis, MD,1 Manmeet S. Ahluwalia, MD,2 Meir Wetzler, MD,2 Eunice Wang, MD,2 Pamela Paplham, RN, FNP,2 Shannon Smiley, MD,2 Philip L. McCarthy, MD,2 I. Larry Cohen, MD,3 Edward Spangenthal, MD,2 and Minoo Battiwalla, MD2

1Department of Medicine, State University of New York at Buffalo, Buffalo, New York; 2Department of Medicine, 3Department of Anesthesiology and Pain Medicine, Roswell Park Cancer Institute, Buffalo, New York


Tyrosine kinase inhibitors (TKIs) that target the BCRABL gene have recently been utilized as selectively targeted

noncytotoxic therapy for a variety of malignant conditions, including chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), chronic eosinophilic leukemia, systemic mastocytosis, chronic myelomonocytic leukemia, and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL).1 Cardiotoxicity has been noted as an infrequent occurrence with BCR-ABL TKIs.2 TKIs have received regulatory approval on the basis of studies with relatively few patients, and the true frequency of cardiotoxicity could have been under-recognized. Reversible cardiotoxicity has been documented in the literature, with normalization in some cases without supportive treatment. Several aspects of the association between cardiotoxicity and the BCR-ABL TKIs are yet to be fully understood. Although there are growing data linking imatinib (Gleevec, Novartis) to cardiac toxicity, the frequency of such events—in other words a “class effect”—with newer generation TKIs (dasatinib [Sprycel, Bristol-Myers Squibb] and nilotinib [Tasigna, Novartis]) is not known. Reports have described TKI-induced cardiomyopathy in patients with CML, and there are such anecdotal accounts in patients with GIST and chronic eosinophilic leukemia, but not ALL. There is a lack of clear understanding of the pathogenesis of the cardiomyopathy and of the appropriate therapy. Finally, there is controversy regarding susceptibility: Is it idiosyncratic or dependent on pre-existing cardiac comorbidities? We report on the instructive case of a young, athletic patient who had 3 discrete episodes of documented cardiomyopathy in relation to treatment with imatinib, nilotinib, and dasatinib.

Case Report


A previously healthy 27-year-old athletic female was diagnosed with Ph+ ALL in June 2004, when she presented with recurrent infections, weight loss, and a total white blood cell count of 56 × 109/L. Lumbar puncture excluded central nervous system involvement. Induction therapy was per Cancer and Leukemia Group B (CALGB) protocol 9111.3 The cumulative dose was 135 mg/m2 for daunorubicin and 1,200 mg/m2 for cyclophosphamide. The patient was then enrolled in CALGB 10001, a phase II trial of sequential chemotherapy and imatinib.4 Because a fully matched donor was unavailable, the patient underwent an autologous stem cell transplant. Her left ventricular ejection fraction (LVEF) prior to the autologous transplant was 60%. The myeloablative conditioning regimen, administered in December 2004, included total body irradiation (1,320 cGy in 11 fractions), cyclophosphamide (100 mg/kg), and etoposide.

This hospitalization was complicated by typhlitis as well as by Streptococcus viridans and Escherichia coli septicemia that required vasopressor support. The patient was restarted on imatinib maintenance therapy at 400 mg twice daily after count recovery. One year following her autologous transplant (November 2005), the patient developed a persistent headache and was diagnosed with central nervous system relapse. No marrow involvement was detected. Imatinib was discontinued after 17 months of therapy, and the patient was treated with cranial irradiation (150 cGy × 8 fractions), followed by re-induction with high-dose cytarabine and mitoxantrone.5 This treatment was complicated by septic shock with gram-negative bacteremia that required vasopressor support for 1 day. Three days later, a diastolic murmur prompted administration of an echocardiogram that revealed a dilated hypokinetic left ventricle with an ejection fraction of 20–25%; no vegetations were noted. Cardiac enzymes were within normal limits, but brain natriuretic peptide (BNP) was elevated at 470 pg/mL (normal range, 0–100 pg/mL). An electrocardiogram showed sinus tachycardia without signs of ischemia. The patient was placed under watchful observation, and she experienced a dramatic recovery with a repeat ejection fraction of 50% 1 week later. The patient was discharged in a stable condition 2 weeks later.

Maintenance nilotinib (400 mg twice daily) therapy was started in January 2006 and lasted for 3 months. In April 2006, the patient underwent a 9/10 human leukocyte antigen–matched unrelated donor transplant. The conditioning regimen included fludarabine (25 mg/m2 x 5 days) and melphalan (70 mg/m2 × 2 days). Severe mucositis required intubation and ventilatory support for 1 week. Upon extubation, the patient required bilevel positive airway pressure for another week when she was re-intubated for increasing shortness of breath related to congestive heart failure. An echocardiogram showed an LVEF of 30% with an elevated BNP of 3,725 pg/mL. Cardiac enzymes revealed minor elevations in the creatine kinase muscle-brain fraction to 9.8 ng/mL (normal range, 0.0–5.0) and in troponin I to 1.99 ng/mL (normal range, 0.0–0.10). The patient was treated with invasive hemodynamic monitoring– guided use of vasopressors and nicardipine. She was successfully extubated 8 days later, with normalization of the LVEF to 55% and the BNP to 84 pg/mL. She was discharged 3 weeks after extubation.

In August 2006, the patient was initiated on maintenance dasatinib 70 mg orally twice daily. Skin and gastrointestinal graft versus host disease required immunosuppressive therapy, including steroids. Ten months after initiation of dasatinib therapy, the patient was admitted with worsening bilateral pleural effusions and progressive shortness of breath. Dasatinib was discontinued on admission. However, on the fourth day of hospitalization, the patient became unresponsive with pulseless electrical activity. Aggressive cardiopulmonary resuscitation included emergent intubation. On arrival in the intensive care unit, an echocardiogram revealed an LVEF of 10–15%. A continuous cardiac output, fiberoptic pulmonary artery catheter was placed. The initial hemodynamic parameters included a cardiac output/index of 1.6 L/min and 1.0 L/min, a pulmonary artery wedge pressure of 36 mm Hg, and a systolic arterial pressure of 120 mm Hg. A dobutamine infusion was initiated, and on intensive care unit day 3, a nicardipine drip was added. Her cardiac output tripled over this time, and filling pressures returned toward normal. The patient was also treated with high-dose corticosteroids and was extubated 11 days later. A repeat echocardiogram, 4 days later, showed an ejection fraction of 55%. The patient was discharged after 4 weeks. Shortly thereafter, she developed recurrent central nervous system relapse and expired suddenly.


Our young patient, who had a history of modest anthracycline exposure, developed several episodes of severe reversible cardiomyopathy after 17 months of imatinib therapy, 3 months of nilotinib therapy, and 10 months of dasatinib therapy. The episodes occurred within 2 weeks after discontinuation of imatinib, 3 weeks after discontinuation of nilotinib, and 4 days after discontinuation of dasatinib. The unique aspects of this case were the multiple episodes that occurred in a single patient, the fulminant onset of symptoms within days after the TKI was stopped, severity that required either ventilatory and/or vasopressor support in all 3 instances, and rapid reversibility. There could have been alternative contributing factors to the transient reduction in left ventricular systolic function, including gram-negative sepsis in the first episode, afterload reduction by nicardipine producing a negative inotropic effect in the second episode, and a stunned myocardium following cardiac arrest in the third episode. Additionally, this unfortunate woman received anthracyclines and was later treated with mitoxantrone. All of these agents are known to result in the cumulativedose type of cardiotoxicity that results in cell death. The patient then went on to receive TKIs.

The recurrence of cardiomyopathy with different TKIs suggests that our patient had some underlying susceptibility, as traditional coronary risk factors—such as old age, male sex, diabetes mellitus, hypertension, dyslipidemia, smoking, and family history of disease—were absent. The clinical development of TKI therapies has been accompanied by growing awareness of rare but serious cardiac toxicity (Table 1). Kerkelä and colleagues discussed 10 patients who developed significant left ventricular dysfunction during their course of therapy with imatinib.6 All 10 patients had normal left ventricular function before imatinib therapy but presented after a mean of 7.2 plus/minus 5.4 months of therapy with heart failure, including significant volume overload and symptoms corresponding to New York Heart Association class 3–4 heart failure. Several letters in response to this article emphasized that of the 10 patients, 3 had been previously diagnosed with coronary artery disease, 7 had hypertension, and 4 had diabetes; the frequency of other cardiovascular risk factors, such as smoking and hyperlipidemia, was not reported.7,8 Two case reports discussed by Park and coworkers showed sudden, dramatic, reversible cardiomyopathy after 4 weeks of imatinib in a GIST patient and after 5 weeks of imatinib in a chronic-phase CML patient.9 Both patients had hypertension and diabetes. Perik and coauthors, however, demonstrated in 55 patients with GIST that imatinib did not increase plasma proBNP levels, and that prospective monitoring of proBNP and cardiac troponins could not identify imatinib-induced cardiotoxicity.10

Imatinib is a small-molecule inhibitor of the fusion protein BCR-ABL, an inhibitor of the tyrosine kinase enzyme. It is used widely in the treatment of patients with CML, GIST, Ph+ chromosome ALL, and systemic mastocytosis associated with chronic eosinophilic leukemia, a myeloproliferative variant of idiopathic hypereosinophilic syndrome. It has demonstrated clinical and hematologic response in the last 2 diseases without inducing cardiotoxicity.11,12 Ribeiro and associates showed that imatinib was not related to systemic deterioration of cardiac function in their study of 103 CML patients.13 Furthermore, Tiribelli and colleagues also confirmed that there was no evidence of cardiotoxicity in CML patients who were treated with imatinib.14 Our patient, unlike the reported cases in the literature, was a Ph+ ALL patient who probably experienced cardiotoxicity induced by multiple TKIs compounded by other clinical factors (cardiotoxins such as anthracycline exposure and/or sepsis). Although the association was most dramatically noted with dasatinib, in retrospect it became clear that the patient’s previous episodes of decompensation were likely related to prior imatinib and nilotinib therapy. As seen in other cases, this response was manifested by development of congestive heart failure characterized by a drop in ejection fraction and an increase in BNP indicative of volume and pressure overload (Figure 1).9,13 However, in sharp contrast to the gradual deterioration seen in most cases, our patient had sudden and severe episodes of cardiac decompensation. The delay between TKI therapy and the onset of cardiac failure in our patient has not been described previously. Questions arise regarding the relationship between TKI-induced cardiotoxicity and exposure to an anthracycline.

In the report by Atallah and colleagues, of the 22 subjects with congestive heart failure, only 3 had prior anthracycline exposure, 12 had received prior interferon therapy, and 18 had pre-existing medical comorbidities predisposing to cardiac disease.8 Anthracycline cardiotoxicity has been recently reviewed by Gianni and coworkers.15 Putative mechanisms of anthracycline-mediated cardiotoxicity include not only reactive oxidative species but also mitochondrial DNA damage and acquired dystrophin mutations. Anthracycline toxicity is dose-dependant, with an average incidence of 5.1% at 400 mg/m2. Limitation of cumulative anthracycline exposure has worked as a strategy in the past; however, this approach has come into question lately in the setting of long-term survivors and in combination with newer therapies. Doses as low as 100 mg/m2 in childhood cancer survivors increase the risk of reduced fractional shortening and increased afterload.16,17 The targeted inhibitors, such as the anti-HER2 antibody trastuzumab (Herceptin, Genentech), unexpectedly synergize to cause cardiotoxicity.18 This activity suggests that trophic stimulation by tyrosine kinase growth factor pathways plays a role in overcoming anthracycline-mediated damage. Inhibition of the tyrosine kinase growth factor pathway may well have played a role in our patient. Cardiotoxicity seen with imatinib has been studied in vivo and in vitro. Electron microscopy revealed mitochondrial abnormalities and accumulation of membrane whorls in vacuoles and the endoplasmic reticulum, findings that suggest a toxic myopathy.6 Cardiomyocytes, when treated with imatinib in vitro, have shown activation of the endoplasmic reticulum stress response, activation of the intrinsic pathway of apoptosis, and, subsequently, cell death. Insertion of an imatinib-resistant c-ABL mutant reversed endoplasmic reticulum stress and rescued the cardiomyocytes.6

The mitochondrial damage with the BCR-ABL TKIs may be a downstream effect. Direct mitochondrial toxicity assays utilizing the multitargeted TKIs imatinib, dasatinib, sunitinib (Sutent, Pfizer), and sorafenib (Nexavar, Bayer Healthcare) have shown that only sorafenib induced direct mitochondrial dysfunction. 19 Recent reports also stated that cardiotoxicity may be noted in TKIs targeting pathways distinct from BCRABL. 20 Schmidinger and associates performed aggressive cardiac monitoring in 86 patients with metastatic renal cell carcinoma treated with sunitinib or sorafenib and found that cardiac dysfunction with these agents was highly underestimated: approximately 34% of patients experienced a cardiac event, 40% had electrocardiogram changes, and 18% were symptomatic.20 Clinical trials leading to the development of TKIs have not focused on exhaustive monitoring of cardiac safety, but have relied mostly on symptoms and cardiac events. Cardiac symptoms are unreliable in the oncology setting and are easily confounded by other explanations. Subclinical cardiac dysfunction is probably more prevalent than previously thought. The best way to monitor patients for cardiac dysfunction in the setting of TKI administration is not known. Reversibility was seen in our patient as well as in the larger case series with sunitinib and sorafenib reported by Schmidinger and associates,20 suggesting that cardiac dysfunction alone need not be an absolute contraindication for the use of such agents.


It is prudent to monitor cardiac function in a patient on treatment with TKIs over the long-term, and it is imperative to act immediately if the patient develops signs or symptoms of heart failure.13,21 Prior exposure to anthracyclines may increase susceptibility to TKI-mediated cardiotoxicity. It is reassuring that our patient recovered rapidly from all 3 episodes of severe cardiomyopathy with supportive care alone. Our patient’s unique history suggests that patients who are susceptible to cardiomyopathy with 1 TKI may be sensitive to others as a “class effect.”


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