The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia.
BACKGROUND
Doxorubicin chemotherapy is very effective in children with acute lymphoblastic leukemia (ALL) but also injures myocardial cells. Dexrazoxane, a free-radical scavenger, may protect the heart from doxorubicin-associated damage.


METHODS
To determine whether dexrazoxane decreases doxorubicin-associated injury of cardiomyocytes, we randomly assigned 101 children with ALL to receive doxorubicin alone (30 mg per square meter of body-surface area every three weeks for 10 doses) and 105 to receive dexrazoxane (300 mg per square meter) followed immediately by doxorubicin. Serial measurements of serum cardiac troponin T were obtained in 76 of 101 patients in the doxorubicin group and 82 of 105 patients in the group given dexrazoxane and doxorubicin. A total of 2377 serum samples (mean, 15.1 samples per patient) were obtained before, during, and after treatment with doxorubicin. Troponin T levels were evaluated in a blinded fashion to determine whether they were elevated (>0.01 ng per milliliter)--the primary end point--or extremely elevated (>0.025 ng per milliliter).


RESULTS
Elevations of troponin T occurred in 35 percent of the patients (55 of 158). Patients treated with doxorubicin alone were more likely than those who received dexrazoxane and doxorubicin to have elevated troponin T levels (50 percent vs. 21 percent, P<0.001) and extremely elevated troponin T levels (32 percent vs. 10 percent, P<0.001). The median follow-up was 2.7 years. The rate of event-free survival at 2.5 years was 83 percent in both groups (P=0.87 by the log-rank test).


CONCLUSIONS
Dexrazoxane prevents or reduces cardiac injury, as reflected by elevations in troponin T, that is associated with the use of doxorubicin for childhood ALL without compromising the antileukemic efficacy of doxorubicin. Longer follow-up will be necessary to determine the influence of dexrazoxane on echocardiographic findings at four years and on event-free survival.
Lipshultz
Steven E
SE
Department of Pediatrics, University of Miami School of Medicine, Holtz Children's Hospital of the University of Miami/Jackson Memorial Medical Center and the Sylvester Comprehensive Cancer Center, Miami 33101, USA. slipshultz@med.miami.edu
Rifai
Nader
N
Dalton
Virginia M
VM
Levy
Donna E
DE
Silverman
Lewis B
LB
Lipsitz
Stuart R
SR
Colan
Steven D
SD
Asselin
Barbara L
BL
Barr
Ronald D
RD
Clavell
Luis A
LA
Hurwitz
Craig A
CA
Moghrabi
Albert
A
Samson
Yvan
Y
Schorin
Marshall A
MA
Gelber
Richard D
RD
Sallan
Stephen E
SE
D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use; D009202:Cardiomyopathies / Q000097:blood / Q000139:chemically induced / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002614:Chelating Agents / Q000627:therapeutic use; D002648:Child; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000009:adverse effects* / Q000627:therapeutic use; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D016015:Logistic Models; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011379:Prognosis; D011929:Razoxane / Q000627:therapeutic use*; D020107:Troponin T / Q000097:blood*; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D002614:Chelating Agents; D020107:Troponin T; D011929:Razoxane; D004317:Doxorubicin