PDF(Pubmed)
Abstract：
UNASSIGNED: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children\'s Oncology Group study, AAML1421.
UNASSIGNED: Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%.
UNASSIGNED: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF.
UNASSIGNED: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).
UNASSIGNED: Subjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%.
UNASSIGNED: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF.
UNASSIGNED: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).
摘要：
■蒽环类药物可有效治疗急性髓性白血病（AML），但受心脏毒性的限制。CPX-351，一种脂质体柔红霉素和阿糖胞苷，可以提供治疗益处，心脏毒性较小。在1/2期儿童肿瘤学组研究中，在CPX-351治疗的复发性AML患儿中，评估了左心室收缩功能和心脏生物标志物的急性变化。AAML1421.
■受试者在第1、3和5天接受135单位/m2/剂量的CPX-351作为第1周期。在基线和第1周期结束时(第29+/-1周)进行超声心动图并集中定量。高敏肌钙蛋白（hs-cTnT）和N末端B型利钠肽原（NT-proBNP）在基线和连续到第1周期结束时（第5、8、15、22和29天）进行测量。使用Wilcoxon符号秩检验分析基线和CPX-351后回声/生物标志物测量值之间的差异。在每个时间点使用cTnT/NT-proBNP对CPX-351后左心室射血分数（LVEF）进行线性回归建模，控制基线LVEF。癌症治疗相关的心功能不全（CTRCD）定义为LVEF下降≥10％-<50％。
■在AAML1421上登记的38名重度蒽环类药物预处理(中位数348mg/m2柔红霉素当量)受试者中的25名被包括在心脏分析中。在基线,25名受试者中有8名(32%)的中央定量LVEF<50%,LVEF中位数为53.8%[48.0,56.9].CPX-351后，LVEF显着下降（ΔLVEF-3.3％[-7.8，0]），25名受试者中有6名（24％）经历了CTRCD。在所有科目中，与基线相比，第1周期结束时hs-cTnT略有增加[基线hs-cTnT7.2（3，10.6）；ΔcTnT1.80（0，6.1），p=0.03]。NT-proBNP保持稳定升高，无明显变化。NT-proBNP或cTnT水平与CPX-351后LVEF之间没有显著关联。
■在这项暴露于CPX-351的蒽环类药物预处理儿童的单臂研究中，心血管功能的基线异常普遍存在。CPX-351后，LVEF下降，cTnT增加，NT-proBNP没有变化。需要更长时间的随访以确定这些变化是否会导致临床上有意义的长期心脏功能下降。一项正在进行的CPX-351与标准蒽环类抗生素在蒽环类抗生素初治患者中的随机试验将进一步了解CPX-351的心脏效应（ClinicalTrials.gov;NCT04293562）。
■受试者在第1、3和5天接受135单位/m2/剂量的CPX-351作为第1周期。在基线和第1周期结束时(第29+/-1周)进行超声心动图并集中定量。高敏肌钙蛋白（hs-cTnT）和N末端B型利钠肽原（NT-proBNP）在基线和连续到第1周期结束时（第5、8、15、22和29天）进行测量。使用Wilcoxon符号秩检验分析基线和CPX-351后回声/生物标志物测量值之间的差异。在每个时间点使用cTnT/NT-proBNP对CPX-351后左心室射血分数（LVEF）进行线性回归建模，控制基线LVEF。癌症治疗相关的心功能不全（CTRCD）定义为LVEF下降≥10％-<50％。
■在AAML1421上登记的38名重度蒽环类药物预处理(中位数348mg/m2柔红霉素当量)受试者中的25名被包括在心脏分析中。在基线,25名受试者中有8名(32%)的中央定量LVEF<50%,LVEF中位数为53.8%[48.0,56.9].CPX-351后，LVEF显着下降（ΔLVEF-3.3％[-7.8，0]），25名受试者中有6名（24％）经历了CTRCD。在所有科目中，与基线相比，第1周期结束时hs-cTnT略有增加[基线hs-cTnT7.2（3，10.6）；ΔcTnT1.80（0，6.1），p=0.03]。NT-proBNP保持稳定升高，无明显变化。NT-proBNP或cTnT水平与CPX-351后LVEF之间没有显著关联。
■在这项暴露于CPX-351的蒽环类药物预处理儿童的单臂研究中，心血管功能的基线异常普遍存在。CPX-351后，LVEF下降，cTnT增加，NT-proBNP没有变化。需要更长时间的随访以确定这些变化是否会导致临床上有意义的长期心脏功能下降。一项正在进行的CPX-351与标准蒽环类抗生素在蒽环类抗生素初治患者中的随机试验将进一步了解CPX-351的心脏效应（ClinicalTrials.gov;NCT04293562）。
