University of Miami Miller School of Medicine, Miami, FL 33101, USA.
J Clin Oncol. 2012 Apr 1;30(10):1042-9. doi: 10.1200/JCO.2010.30.3404. Epub 2012 Feb 27.
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.
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.
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.
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.
多柔比星会导致儿童急性淋巴细胞白血病（ALL）患者的心脏损伤和心肌病。在治疗过程中测量生物标志物可能有助于通过立即识别心脏损伤和心肌病来实现个体化治疗。
高风险 ALL 患儿被随机分配接受多柔比星单药治疗（n = 100；75 例分析）或多柔比星联合右雷佐生治疗（n = 105；81 例分析）。在治疗前、治疗中和治疗后，分别获得了超声心动图和心脏肌钙蛋白 T（cTnT；心脏损伤生物标志物）、N 末端脑利钠肽前体（NT-proBNP；心肌病生物标志物）和高敏 C 反应蛋白（hsCRP；炎症生物标志物）的连续血清测量值。
在治疗前，多柔比星组的 12%和多柔比星-右雷佐生组的 13%的患儿的 cTnT 水平升高，但在治疗后分别有 47%和 13%的患儿的 cTnT 水平升高（P =.005）。在治疗前，多柔比星组的 89%和多柔比星-右雷佐生组的 92%的患儿的 NT-proBNP 水平升高，但在治疗后，仅分别有 48%和 20%的患儿的 NT-proBNP 水平升高（P =.07）。在任何时间点，hsCRP 水平升高的患儿比例在两组之间均无差异。在治疗的前 90 天内，可检测到的 cTnT 升高与 4 年后左心室（LV）质量和 LV 舒张末期后侧壁厚度异常降低相关（P <.01）；NT-proBNP 的升高与 LV 厚度-直径比异常相关，提示 4 年后 LV 重构（P =.01）。hsCRP 的升高与任何超声心动图变量均无关。
cTnT 和 NT-proBNP 可能是儿童高危 ALL 患者心脏毒性的有希望的生物标志物。需要进行明确的验证研究，以充分确立其临床应用范围。
