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Background: Doxorubicin (DOX) chemotherapy injures myocardial cells, leading to progressive cardiac dysfunction. Dexrazoxane (DZR), a free-radical scavenger, reduced troponin T (cTnT) elevation during therapy in children with acute lymphoblastic leukemia (ALL) on Dana-Farber Cancer Institute (DFCI) Protocol 95– 01. The long-term cardiac benefits of DZR are not yet known. Methods: We centrally remeasured echocardiograms from childhood ALL survivors who were randomly assigned to DOX (n =64; 30 mg/m 2 /dose for 10 doses) with or without DZR (n =58; 300 mg/m 2 /dose) during DFCI Protocol 95– 01. Results: Demographics and follow-up were similar in both arms (median f/u years: DOX 4.0 vs. DZR/DOX 3.7). Mean left ventricular (LV) end-systolic dimension was significantly abnormal for DOX vs. DZR/DOX at 3 years (mean Z-score: DOX 0.637 vs. DZR/DOX −0.0005, P=0.0164) and progressed at 3.5 years (0.800 vs. −0.006, P=0.0028) and 4 years (1.01 vs. 0.005, P=0.0013). DOX-group mean LV end-diastolic (ED) dimension was significantly dilated at 3.5 years (mean Z-score: DOX 0.223 vs. DZR/DOX −0.424, P=0.022) and 4 years (0.428 vs. −0.456, P=0.004). With 3.5 years follow-up, a number of non-significant trends showed DZR/DOX echo measures to be more normal: LV fractional shortening Z-score (DOX −2.092 vs. DZR/DOX −1.00); LV mass Z-score (−0.672 vs. −0.537); LVED posterior wall thickness Z-score (LVEDPWTz; −0.596 vs. −0.395). For DZR/DOX-patients, cTnT elevation (defined as >0.01 ng/ml) during DOX treatment correlated with thinner LVED posterior wall 3.5 years post treatment (mean LVEDPWTz: cTnT− =−0.011 vs. cTnT+= −1.200, P=0.0352). Conclusions: DZR is protective against late DOX cardiotoxicity with smaller LV dimensions, consistent with less LV remodeling. LV function, thickness, and mass trended to more normal among children who received DZR and all parameters trended toward a greater DZR effect over time. Further, cTnT elevation during therapy predicted late LV wall thinning. Table 1: Post-treatment Mean Differences in Dimension Z-Scores

Background: Doxorubicin damages heart muscle, placing long-term survivors of childhood cancer at elevated risk of cardiac dysfunction. N-terminal pro-brain natriuretic peptide (NT-proBNP), an independent predictor of mortality and cardiovascular events in other populations, may serve to indicate cardiomyopathy prior to irreversible damage in this population. Methods: To determine the diagnostic value of NT-proBNP in children receiving doxorubicin, the NCI Dana-Farber Cancer Institute ALL Consortium collected serial serum samples and echocardiograms from children with ALL between 1995 and 2000 randomized to receive doxorubicin alone (dox; n = 74; 1203 samples; median age = 6.4 yrs; 30 mg/m 2 /dose for 10 doses) or doxorubicin preceded by the cardioprotectant dexrazoxane (dex/dox; n = 80; 1338 samples; median age = 7.1 yrs; 300 mg/m 2 /dose). Results: Marked NT-proBNP elevation (NT-proBNP ≥ 100 pg/ml if age ≥ 1; proBNP ≥ 150 pg/ml if age > 1) was seen at baseline (treatment day 0; dox alone = 82.5% of patients abnormal; dex/dox = 87.4%; p = 0.527). During treatment, the percentage of patients with abnormal NT-proBNP levels fell to a minimum of 35.8% in the dox only group and 16.4% in the dex/dox group ( p < 0.001) before rising progressively at the end of treatment (treatment day 220; dox only = 70.8%; dex/dox = 5.3%; p < 0.001). After controlling for treatment, a patient with abnormal NT-proBNP six months after the start of doxorubicin had 2.39 times the odds of having myocardial injury as indicated by elevated cardiac troponin T (cTnT ≥0.01 ng/mL; OR = 2.39; 95%CI 1.156 - 4.946; p = 0.019). Further, at any given time and for either treatment, a patient with abnormal NT-proBNP had 2.36 times the odds of having abnormal LV fractional shortening (OR = 2.36; 95%CI 1.026 - 5.449; p = 0.047). Conclusion: Elevated serum NT-proBNP was significantly related to cumulative unprotected doxorubicin dose, left ventricular fractional shortening, and cTnT during doxorubicin therapy. A much higher percentage of patients exhibited levels of NT-proBNP suggestive of cardiomyopathy than showed death of cardiomyocytes as indicated by elevated cTnT levels. This might allow the testing of individualized preventative therapy for cancer patients at high risk for long-term cardiotoxicity.