Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes

Abstract

Purpose: 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.

Patients and 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.

Conclusion: 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.

Fig 1.

CONSORT diagram shows allocation and disposition of patients with high-risk acute lymphoblastic leukemia in the Dana-Farber Cancer Institute Childhood Acute Lymphoblastic Leukemia Consortium Protocol 95-01 randomized controlled trial. CR, complete remission.

Fig 2.

(A) Model-based estimated probability of having an increased cardiac troponin T (cTnT) level at each depicted time point in patients treated with doxorubicin, with or without dexrazoxane. The doxorubicin-dexrazoxane group is indicated by the blue line, the doxorubicin group by the gold line. Vertical bars show 95% CIs. Increased cTnT is defined as a value greater than 0.01 ng/mL. *P value versus dexrazoxane group ≤ .05; †P value versus dexrazoxane group ≤ .001. An overall test for dexrazoxane effect during treatment was significant (P < .001). (B) Model-based estimated probability of having an increased N-terminal pro-brain natriuretic peptide (NT-proBNP) level at each depicted time point in patients treated with doxorubicin with or without dexrazoxane. The dexrazoxane group is indicated by the blue line, the doxorubicin group by the gold line. Vertical bars show 95% CIs. Increased NT-proBNP is defined as a value ≥ 150 pg/mL for children younger than 1 year old and a value ≥ 100 pg/mL for children age ≥ 1 year. *P value versus dexrazoxane group ≤ .05; †P value versus dexrazoxane group ≤ .001. An overall test for dexrazoxane effect during treatment was significant (P < .001) and after treatment was not significant (P = .24). (C) Model-based estimated probability of having an increased high-sensitivity C-reactive protein (hsCRP) level at each depicted time point in patients treated with doxorubicin with or without dexrazoxane. The dexrazoxane group is indicated by the blue line, the doxorubicin group by the gold line. Vertical bars show 95% CIs. Increased hsCRP is defined as a level ≥ 1.9 mg/L. *P value versus dexrazoxane group ≤ .05. Overall tests for dexrazoxane effect during treatment (P = .08) and after treatment (P = .49) were not significant.

Fig 3.

Median serum cardiac troponin I (cTnI) levels during doxorubicin therapy of a 40-sample subset from 18 children with high-risk acute lymphoblastic leukemia. The dexrazoxane group is indicated by the blue line, the doxorubicin group by the gold line. Vertical bars show 95% CIs. *P value versus dexrazoxane-doxorubicin group ≤ .05; †P value versus dexrazoxane group ≤ .001.