title: Cardioprotection and Safety of Dexrazoxane in Patients Treated for Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia or Advanced-Stage Lymphoblastic Non-Hodgkin Lymphoma: A Report of the Children's Oncology Group Randomized Trial Pediatric Oncology Group 9404.
abstract: To determine the oncologic efficacy, cardioprotective effectiveness, and safety of dexrazoxane added to chemotherapy that included a cumulative doxorubicin dose of 360 mg/m(2) to treat children and adolescents with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic non-Hodgkin lymphoma (L-NHL).
  
  
  
  Patients were treated on Pediatric Oncology Group Protocol POG 9404, which included random assignment to treatment with or without dexrazoxane given as a bolus infusion immediately before every dose of doxorubicin. Cardiac effects were assessed by echocardiographic measurements of left ventricular function and structure.
  
  
  
  Of 573 enrolled patients, 537 were eligible, evaluable, and randomly assigned to an arm with or without dexrazoxane. The 5-year event-free survival (with standard error) did not differ between groups: 77.2% (2.7%) for the dexrazoxane group versus 76.0% (2.7%) for the doxorubicin-only group (P = .9). The frequencies of severe grade 3 or 4 hematologic toxicity, infection, CNS events, and toxic deaths were similar in both groups (P ranged from .26 to .64). Of 11 second malignancies, eight occurred in patients who received dexrazoxane (P = .17). The mean left ventricular fractional shortening, wall thickness, and thickness-to-dimension ratio z scores measured 3 years after diagnosis were worse in the doxorubicin-alone group (n = 55 per group; P ≤ .01 for all comparisons). Mean fractional shortening z scores measured 3.5 to 6.4 years after diagnosis remained diminished and were lower in the 21 patients who received doxorubicin alone than in the 31 patients who received dexrazoxane (-2.03 v -0.24; P ≤ .001).
  
  
  
  Dexrazoxane was cardioprotective and did not compromise antitumor efficacy, did not increase the frequencies of toxicities, and was not associated with a significant increase in second malignancies with this doxorubicin-containing chemotherapy regimen. We recommend dexrazoxane as a cardioprotectant for children and adolescents who have malignancies treated with anthracyclines.
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI. barbara_asselin@urmc.rochester.edu.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Asselin
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Vivian I
authors.initials: VI
authors.lastname: Franco
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Pullen
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borowitz
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hutchison
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Yaddanapudi
authors.initials: Y
authors.lastname: Ravindranath
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Saro H
authors.initials: SH
authors.lastname: Armenian
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Camitta
authors.affiliation: Barbara L. Asselin, University of Rochester School of Medicine and Wilmot Cancer Institute, Rochester; Robert E. Hutchison, State University of New York Upstate Medical Center, Syracuse, NY; Meenakshi Devidas, Children's Oncology Group and University of Florida, Gainesville, FL; Lu Chen, Children's Oncology Group, Monrovia; Saro H. Armenian, City of Hope National Medical Center, Duarte, CA; Vivian I. Franco, Yaddanapudi Ravindranath, and Steven E. Lipshultz, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI; Jeanette Pullen, University of Mississippi Medical Center and Children's Hospital, Jackson, MS; Michael J. Borowitz, Johns Hopkins University School of Medicine and Johns Hopkins Hospital, Baltimore, MD; and Bruce M. Camitta, Medical College of Wisconsin, Midwest Center for Cancer and Blood Disorders, Milwaukee, WI.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D066126:Cardiotoxicity / Q000097:blood / Q000209:etiology / Q000517:prevention & control; D002648:Child; D064730:Dexrazoxane / Q000008:administration & dosage*; D004317:Doxorubicin / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D016896:Treatment Outcome; D020107:Troponin T / Q000097:blood*
chemical_list: D002316:Cardiotonic Agents; D020107:Troponin T; D064730:Dexrazoxane; D004317:Doxorubicin