title: Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes.
abstract: OBJECTIVE
  Doxorubicin causes cardiac injury and cardiomyopathy in children with acute lymphoblastic leukemia (ALL). Measuring biomarkers during therapy might help individualize treatment by immediately identifying cardiac injury and cardiomyopathy.
  
  
  METHODS
  Children with high-risk ALL were randomly assigned to receive doxorubicin alone (n = 100; 75 analyzed) or doxorubicin with dexrazoxane (n = 105; 81 analyzed). Echocardiograms and serial serum measurements of cardiac troponin T (cTnT; cardiac injury biomarker), N-terminal pro-brain natriuretic peptide (NT-proBNP; cardiomyopathy biomarker), and high-sensitivity C-reactive protein (hsCRP; inflammatory biomarker) were obtained before, during, and after treatment.
  
  
  RESULTS
  cTnT levels were increased in 12% of children in the doxorubicin group and in 13% of the doxorubicin-dexrazoxane group before treatment but in 47% and 13%, respectively, after treatment (P = .005). NT-proBNP levels were increased in 89% of children in the doxorubicin group and in 92% of children in the doxorubicin-dexrazoxane group before treatment but in only 48% and 20%, respectively, after treatment (P = .07). The percentage of children with increased hsCRP levels did not differ between groups at any time. In the first 90 days of treatment, detectable increases in cTnT were associated with abnormally reduced left ventricular (LV) mass and LV end-diastolic posterior wall thickness 4 years later (P < .01); increases in NT-proBNP were related to an abnormal LV thickness-to-dimension ratio, suggesting LV remodeling, 4 years later (P = .01). Increases in hsCRP were not associated with any echocardiographic variables.
  
  
  CONCLUSIONS
  cTnT and NT-proBNP may hold promise as biomarkers of cardiotoxicity in children with high-risk ALL. Definitive validation studies are required to fully establish their range of clinical utility.
authors.affiliation: University of Miami Miller School of Medicine, Miami, FL 33101, USA. slipshultz@med.miami.edu
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.forename: Tracie L
authors.initials: TL
authors.lastname: Miller
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Scully
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Lipsitz
authors.forename: Nader
authors.initials: N
authors.lastname: Rifai
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Steven D
authors.initials: SD
authors.lastname: Colan
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Henkel
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Asselin
authors.forename: Uma H
authors.initials: UH
authors.lastname: Athale
authors.forename: Luis A
authors.initials: LA
authors.lastname: Clavell
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.forename: Bruno
authors.initials: B
authors.lastname: Michon
authors.forename: Marshall A
authors.initials: MA
authors.lastname: Schorin
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D011929:Razoxane / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D020107:Troponin T / Q000097:blood*; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D002316:Cardiotonic Agents; D010446:Peptide Fragments; D020107:Troponin T; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D011929:Razoxane; D004317:Doxorubicin; D002097:C-Reactive Protein