Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial.
Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial.
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DOI：
10.1016/s1470-2045(10)70204-7
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发表时间：
2010-10
期刊：
影响因子：
51.1
通讯作者：
Colan, Steven D.
中科院分区：
文献类型：
--
作者：
Lipshultz, Steven E.;Scully, Rebecca E.;Lipsitz, Stuart R.;Sallan, Stephen E.;Silverman, Lewis B.;Miller, Tracie L.;Borry, Elly V.;Asselin, Barbara L.;Athale, Uma;Clavell, Luis A.;Larsen, Eric;Moghrabi, Albert;Samson, Yvan;Michon, Bruno;Schorin, Marshall A.;Cohen, Harvey J.;Neuberg, Donna S.;Orav, E. John;Colan, Steven D.
阿霉素化疗与心肌病有关。右雷佐生可减少急性淋巴细胞白血病（ALL）儿童多柔比星治疗期间的心脏损伤。我们旨在确定右雷佐生对完成多柔比星治疗5年后的儿童高危ALL幸存者心脏健康亚临床状态的长期影响。在1996年1月至2000年9月期间，从美国、加拿大和波多黎各的9个中心招募了高危ALL儿童。患者通过区组随机化分配接受10剂30 mg/m²阿霉素单独治疗，或在300 mg/m²右雷佐生之前接受相同剂量的阿霉素治疗。通过电话联系集中登记员获得治疗分配，以隐藏分配。研究者对治疗分配设盲，但治疗医生和患者不设盲;然而，研究者、医生和患者对研究血清心肌肌钙蛋白-T浓度和超声心动图测量设盲。主要终点是超声心动图评估的晚期左心室结构和功能异常;分析包括治疗完成后可获得数据的所有患者。本试验已完成，并在ClinicalTrials.gov注册，编号为NCT 00165087。100名儿童被分配到多柔比星组（分析了66名），105名儿童被分配到多柔比星+右雷佐生组（分析了68名）。阿霉素化疗结束后5年，单独接受阿霉素治疗的儿童平均左心室短轴缩短分数和收缩末期Z轴评分明显低于正常值（左心室缩短分数：−0·82，95% CI −1·31至−0·33;收缩末期内径：0.57，0.21 - 0.93），但对于那些也接受右雷佐生的人则没有（− 0.41，− 0.88至0.06; 0.15，− 0.20至0.51）。右雷佐生相对于单独使用多柔比星对左心室壁厚度（组间差异：0.47，0.46 - 0.48）和厚度-尺寸比（0.66，0.64 - 0.68）的保护作用是5年时唯一具有统计学意义的特征。亚组分析显示，右雷佐生对女孩5年时的左心室缩短分数（1·17，0·24-2·11）具有保护作用（p=0·04），但对男孩无保护作用（−0·10，−0·87 - 0·68）。同样，亚组分析显示右雷佐生对女孩5年时的左心室厚度-尺寸比（1·15，0·44-1·85）有保护作用（p=0·046），但对男孩无保护作用（0·19，−0·42 - 0·81）。复发和死亡的中位随访时间为8.7年（范围1.3 - 12.1），多柔比星单药组儿童的无事件生存率为77%（95%CI 67-84），多柔比星+右雷佐生组儿童为76%（67-84）（p= 0.99）。右雷佐生可为接受多柔比星治疗的高危ALL儿童提供长期心脏保护，而不影响肿瘤学疗效。右雷佐生对女孩的长期心脏保护作用大于男孩。美国国立卫生研究院、儿童心肌病基金会、迈阿密大学妇女癌症协会、兰斯阿姆斯特朗基金会、罗氏诊断公司、辉瑞公司和诺华公司。
Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: −0·82, 95% CI −1·31 to −0·33; end-systolic dimension: 0·57, 0·21–0·93) but not for those who also received dexrazoxane (−0·41, −0·88 to 0·06; 0·15, −0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46–0·48) and thickness-to-dimension ratio (0·66, 0·64–0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24–2·11), but not in boys (−0·10, −0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44–1·85), but not in boys (0·19, −0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3–12·1), event-free survival was 77% (95% CI 67–84) for children in the doxorubicin-alone group, and 76% (67–84) for children in the doxorubicin plus dexrazoxane group (p=0·99). Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. US National Institutes of Health, Children’s Cardiomyopathy Foundation, University of Miami Women’s Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.