Effect of Dexrazoxane on Heart Function Among Long-Term Survivors of Childhood Leukemia and Lymphoma: A Report from the Children's Oncology Group (COG)
Authors: Chow Eric J , Doody David R. , Armenian Saro H. , Aggarwal Sanjeev , Baker K. Scott , Bhatia Smita , Blythe Nancy A. , Constine Louis S. , Freyer David R. , Kopp Lisa M. , Leisenring Wendy M. , Sasaki Nao , Vrooman Lynda M. , Asselin Barbara L. , Schwartz Cindy L. , Lipshultz Steven E. 
Published: October 2019

Abstract
Background:Dexrazoxane (DRZ) has been shown to have cardioprotective effects among doxorubicin-treated childhood cancer survivors up to 5-years after therapy completion, including effects on fractional shortening (FS%) and other parameters of left ventricular anatomy and function. However, data on longer-term effects are lacking.
Methods: COG protocols P9404 (T-cell acute lymphoblastic leukemia/lymphoma; cumulative doxorubicin 360 mg/m2), P9425 (advanced stage Hodgkin lymphoma; cumulative doxorubicin 180-300 mg/m2), and P9426 (low/intermediate stage Hodgkin; cumulative doxorubicin 100-200 mg/m2) were phase 3 randomized clinical trials conducted between 1996 and 2001. Patients were randomly assigned to treatment with or without DRZ (10:1 mg dose ratio of DRZ:doxorubicin); DRZ was given as an intravenous bolus before each doxorubicin dose. Beginning in 2014, a subset of COG institutions began prospectively reassessing the cardiovascular health of long-term survivors in first complete remission treated on these 3 protocols, including echocardiography and selected blood biomarkers (e.g., high-sensitivity troponins, b-type natriuretic peptides [BNP], N-terminal [NT] proBNP). Echocardiograms and blood analytes were all processed centrally, with DRZ status masked.
Results: To date, 94 participants (54% DRZ+; 57% male; average doxorubicin dose 279 mg/m2; current mean age 28 years and 16 years since cancer diagnosis) have been recruited from 30 institutions. Participants were similar with respect to demographic and treatment characteristics when compared by DRZ status. Overall, compared with DRZ+ participants, DRZ- participants had non-significantly reduced FS% (mean±SD: 33.0±4.8 vs. 34.8±4.6; p=0.10), but greater myocardial wall stress and dysfunction as measured by BNP (mean±SD: 18.3±14.7 vs. 11.3±10.6 pg/mL; p=0.02) and NT-proBNP (64.8±55.5 vs. 44.5±39.0 pg/mL; p=0.06). When the analysis was restricted to those who received the greatest doxorubicin exposure (P9404 participants, n=41), differences all became statistically significant (FS%: 31.3±3.9 vs. 34.9±3.7, p<0.01; BNP and NT-proBNP: p=0.03 for both). Only a subset of participants (n=43) had ejection fraction evaluable, but DRZ+ patients also were more likely to have greater values (mean±SD: 56.8±6.3 vs. 61.2±6.4; p=0.03). Among all participants, the effects of DRZ on FS% appeared to vary by sex, with females showing significant differences (DRZ- 31.7±2.2 vs. DRZ+ 36.3±4.2; p<0.001) but not males (DRZ- 34.0±6.0 vs. DRZ+ 34.0±4.6; p=0.99). DRZ status was significantly associated with FS% and both BNP and NT-proBNP in multivariate analyses that adjusted for sex, original protocol, race/ethnicity, current age, and age at cancer diagnosis (p<0.05). Other parameters of systolic dysfunction and myocardial injury including wall thickness/dimension ratio and high-sensitivity troponins were similar across study arms, both overall and in subanalyses. Overall, only 3 participants had FS% <28 (DRZ+, n=2). Two other participants reported a history of clinical cardiomyopathy (both DRZ+, one currently on medications). Globally, regardless of DRZ status, participants had a high burden of comorbid cardiovascular conditions: 57% overweight/obese, 37% pre-/hypertensive, 50% with dyslipidemia, and 11% pre-/diabetic.
Conclusion: In this preliminary analysis, long-term survivors of childhood cancer treated with doxorubicin and DRZ appeared to have more preserved systolic function and reduced myocardial wall stress compared with survivors treated with doxorubicin alone. Secondary prevention efforts should be directed at treating common but potentially modifiable cardiovascular risk factors in this high-risk young adult population. Accrual of remaining eligible study participants is ongoing and may provide more refined estimates of DRZ's cardioprotective effects in the future.

Disclosures
Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Lipshultz:Clinigen Group: Consultancy, Other: Travel/accommodations for consulting related meeting; Pfizer: Research Funding; Roche Diagnostics: Research Funding.