Correspondence
Biventricular Cardiac Thrombosis during Interleukin-2 Infusion
N Engl J Med 2001; 344:859-860March 15, 2001
- Article
To the Editor:
We report on the phenomenon of intracardiac thrombosis with features of Löffler's syndrome observed in conjunction with interleukin-2 therapy.
Patient 1, a 26-year-old woman with stage IV Hodgkin's disease, began to receive a continuous infusion of recombinant human interleukin-2 (aldesleukin; Proleukin, Chiron) in an experimental outpatient protocol; the initial dose was 75,000 IU per kilogram of body weight per day and was increased weekly, as tolerated, to a maximum of 150,000 IU per kilogram per day. The patient had a corresponding increase in eosinophils in peripheral blood to a maximum of 11,400 cells per cubic millimeter.
On day 27 of therapy, she presented with a two-day history of increasing fatigue. Her heart rate was 120 beats per minute, her blood pressure was 79/50 mm Hg, her respiratory rate was 16 per minute, and her temperature was 97.7°F. The oxygen saturation while the patient was breathing room air was 95 percent. The patient had normal findings on cardiac auscultation, clear lungs, an enlarged, tender liver that was palpable 10 cm below the right costal margin, no ascites, and no pedal edema. Laboratory evaluation revealed leukocytosis (white-cell count, 15,900 per cubic millimeter) with eosinophilia (33 percent; absolute count, 5300 per cubic millimeter), a hematocrit of 27 percent, and a platelet count of 17,000 per cubic millimeter.
Interleukin-2 treatment was discontinued, but the patient's condition deteriorated. Surface echocardiography showed bilateral intraventricular masses. The patient died on day 29. An autopsy showed biventricular thrombi, normal coronary arteries, and prominent eosinophilic infiltration of the endomyocardium (Figure 1Figure 1
Pathological Evaluation of the Heart of Patient 1.).Subsequent patients were monitored by surface echocardiography during the study. Patient 2 (the 11th patient treated and the 2nd with findings), a 33-year-old woman with stage IV Hodgkin's disease, was treated with a continuous infusion of interleukin-2 at 75,000 to 234,000 IU per kilogram per day, and had a maximal eosinophil count of 5000 per cubic millimeter. An asymptomatic change in cardiac function developed during a three-week period of exposure to interleukin-2 (week 6 to week 8), with gradual thickening of the apical left ventricular and right ventricular walls, which was interpreted as early thrombus formation, focal abnormalities of apical motion, and a reduction in the ejection fraction from 55 percent to 40 percent, without elevations in creatine kinase. Treatment with interleukin-2 was discontinued. Prompt normalization of the ejection fraction was followed later by spontaneous resolution of thrombus and wall-motion abnormalities.
Interleukin-2 therapy is associated with increased peripheral eosinophilia; the eosinophil count may exceed 5000 to 10,000 per cubic millimeter.1 In turn, hypereosinophilia has been associated with cardiac fibrosis, ventricular thrombosis, and death in diverse disorders collectively known as Löffler's syndrome (as well as eosinophilic endomyocardial disease and tropical endomyocardial fibrosis),2 but these findings have not been associated with interleukin-2 therapy.3 Released eosinophil cationic proteins have been proposed as the mechanism of damage to the endocardium that initiates thrombus development.4 Typically, symptomatic cardiac disease occurs after periods of hypereosinophilia lasting several months to years.2 Hence, death due to thrombosis in Patient 1 was unusually rapid for any cause.
This catastrophic event prompted us to perform prospective serial echocardiography on subsequent patients receiving prolonged infusion of interleukin-2. We observed early signs of thrombosis in 1 additional (asymptomatic) patient among the next 10 (Patient 2), for an incidence of 1 in 10, or 10 percent (95 percent confidence interval, 0.5 percent to 45 percent; the index case is not included in the statistical analysis). The signs fully reversed after the withdrawal of interleukin-2. The reversal of thrombus and improved cardiac function in Patient 2 are in accord with prior reports on the reversal of eosinophilia in Löffler's syndrome from other causes.5
The long history of clinical applications of interleukin-2, and the lack of clinical recognition of an association with intracardiac thrombosis with features of Löffler's syndrome,3 both strongly support the safety of interleukin-2 as it is currently used. For newer regimens employing longer, uninterrupted schedules of infusion, however, this report may serve to create awareness of a potentially important alternative in the differential diagnosis of symptoms that occur during interleukin-2 therapy.
5 ReferencesR.P. Junghans, Ph.D., M.D.
W. Manning, M.D.
M. Safar, M.D.
W. Quist, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 022151
Lotze MT ,Matory YL ,Rayner AA , et al. Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer 1986;58:2764-2772
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Endomyocardial fibrosis. In: Spry CJF. Eosinophils: a comprehensive review and guide to the scientific and medical literature. Oxford, England: Oxford University Press, 1988:232-58.
3
Rosenberg SA. Principles of cancer management: biologic therapy. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven, 1997:349-73.
4
Sasano H ,Virmani R ,Patterson RH ,Robinowitz M ,Guccion JG . Eosinophilic products lead to myocardial damage. Hum Pathol 1989;20:850-857
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Presti C ,Ryan T ,Armstrong WF . Two-dimensional and Doppler echocardiographic findings in hypereosinophilic syndrome. Am Heart J 1987;114:172-175
CrossRef | Web of Science | Medline
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