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Chronic Progressive Cardiac Dysfunction Years After Doxorubicin Therapy for Childhood Acute Lymphoblastic Leukemia

From the Department of Pediatrics, Miller School of Medicine at the Univerity of Miami, Holtz Children's Hospital, and Sylvester Comprehensive Cancer Center, Miami, FL; Department of Pediatric Oncology and Department of Biostatistical Science, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Department of Cardiology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA; Department of Biometry and Epidemiology, Medical University of S Carolina, Charleston, SC

Address reprint requests to Steven E. Lipshultz, MD, Department of Pediatrics (D820), Miller School of Medicine at the University of Miami, PO Box 016820, Miami, FL 33101. Express mail address: Department of Pediatrics, Miller School of Medicine at the University of Miami, Medical Campus-MCCD-D820, 1601 NW 12th Ave, 9th Floor, Miami, FL 33136; e-mail: slipshultz{at}med.miami.edu

PURPOSE: Cross-sectional studies show that cardiac abnormalities are common in long-term survivors of doxorubicin-treated childhood malignancies. Longitudinal data, however, are rare.

METHODS: Serial echocardiograms (N = 499) were obtained from 115 doxorubicin-treated long-term survivors of childhood acute lymphoblastic leukemia (median age at diagnosis, 4.8 years; median follow-up after completion of doxorubicin, 11.8 years). Results were expressed as z scores to indicate the number of standard deviations (SDs) above (+) or below (–) the normal predicted value. Median individual and cumulative doxorubicin doses were 30 mg/m² per dose and 352 mg/m², respectively.

RESULTS: Left ventricular fractional shortening was significantly reduced after doxorubicin therapy, and the reduction was related to cumulative dose. z scores for fractional shortening transiently improved before falling to –2.76 more than 12 years after diagnosis. Reduced fractional shortening was related to impaired contractility and increasing afterload, consequences of a progressive reduction of ventricular mass, and wall thickness relative to body-surface area. Left ventricular contractility fell significantly over time and was depressed at last follow-up in patients receiving more than 300 mg/m² of doxorubicin. Systolic and diastolic blood pressures were below normal more than 9 years after diagnosis. Even patients receiving lower cumulative doxorubicin doses experienced reduced mass and dimension. Fractional shortening and dimension at the end of therapy predicted these parameters 11.8 years later.

CONCLUSION: Cardiac abnormalities were persistent and progressive after doxorubicin therapy. Inadequate ventricular mass with chronic afterload excess was associated with progressive contractile deficit and possibly reduced cardiac output and restrictive cardiomyopathy. The deficits were worst after highest cumulative doses of doxorubicin, but appeared even after low doses.

Supported by grants from the National Institutes of Health (CA 68484, CA 55576, CA 06516, CA 79060, HL 59837, HR 96041, HL 53392, HL 72705, and HL 69800).

This study was presented in part as an abstract at the American Society of Clinical and Oncology and the American Heart Association annual sessions.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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