Cytarabine Dose for Acute Myeloid Leukemia
Cytarabine Dose for Acute Myeloid Leukemia
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DOI：
10.1056/nejmoa1010222
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发表时间：
2011-03-17
影响因子：
158.5
通讯作者：
Ossenkoppele, Gert J.
中科院分区：
文献类型：
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作者：
Lowenberg, Bob;Pabst, Thomas;Ossenkoppele, Gert J.
背景阿糖胞苷（ara-C）是治疗急性髓系白血病（AML）的重要药物。高剂量阿糖胞苷（每平方米体表面积2000至3000毫克）具有毒性，但与每平方米100至400毫克的常规剂量相比，无复发生存率更高。中间剂量水平尚未得到彻底评估。 方法我们对 18 至 60 岁（中位数 49 岁）新诊断 AML 患者的两种诱导方案进行了比较。中剂量组共431名患者，在诱导治疗第1周期期间接受阿糖胞苷200 mg/m2连续静脉输注24小时，在诱导治疗第2周期期间接受阿糖胞苷1000 mg/m2持续3小时每天2次静脉输注。高剂量组共有 429 名患者，在第 1 周期中每 12 小时接受 1000 mg 阿糖胞苷每平方米 1000 mg/平方米的剂量递增方案，在第 2 周期中每平方米每天两次 2000 mg 的阿糖胞苷。完全缓解的患者没有接受额外的阿糖胞苷，但在第三个化疗周期中接受巩固治疗（米托蒽醌-依托泊苷）或接受自体或同种异体干细胞移植。评估每个治疗组的完全缓解率、生存率和毒性反应。 结果在中位随访 5 年时，中剂量组和高剂量组在完全缓解率（分别为 80% 和 82%）、复发概率、5 年无事件生存率（34% 和 35%）或总生存率（40% 和 42%）方面没有显着差异。高剂量阿糖胞苷在任何预后亚组中都没有提供明显的优势。高剂量治疗导致 3 级和 4 级毒性反应（第 1 周期）发生率较高、住院时间延长、中性粒细胞恢复（第 2 周期）和血小板恢复（第 2 和 3 周期）延迟。 结论 较低剂量的阿糖胞苷诱导治疗已对所有反应终点产生了最大的抗白血病作用，表明高于此剂量水平的剂量-反应关系达到平台期。高剂量阿糖胞苷会导致过度的毒性作用，而无治疗效果。
BACKGROUNDCytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated.METHODSWe compared two induction regimens in patients 18 to 60 years of age (median, 49) who had newly diagnosed AML. The intermediate-dose group, totaling 431 patients, received cytarabine at a dose of 200 mg per square meter given by continuous intravenous infusion for 24 hours during cycle 1 of induction therapy and 1000 mg per square meter by infusion for 3 hours twice daily during cycle 2 of induction therapy. The high-dose group, totaling 429 patients, received a dose-escalated regimen of 1000 mg of cytarabine per square meter every 12 hours in cycle 1 and 2000 mg per square meter twice daily in cycle 2. Patients with a complete response did not receive additional cytarabine but received consolidation therapy in a third cycle of chemotherapy (mitoxantrone-etoposide) or underwent autologous or allogeneic stem-cell transplantation. Complete remission rates, survival rates, and toxic effects were assessed for each treatment group.RESULTSAt a median follow-up of 5 years, no significant differences were noted between the intermediate-dose group and the high-dose group with respect to complete remission rates (80% and 82%, respectively), probability of relapse, event-free survival at 5 years (34% and 35%), or overall survival (40% and 42%). High-dose cytarabine provided no clear advantage in any prognostic subgroup. The high-dose treatment resulted in higher incidences of grade 3 and grade 4 toxic effects (in cycle 1), prolonged hospitalization, and delayed neutrophil recovery (in cycle 2) and platelet recovery (in cycles 2 and 3).CONCLUSIONSInduction therapy with cytarabine at the lower dose already produced maximal antileukemic effects for all response end points, suggesting a plateau in the dose-response relationship above this dose level. High-dose cytarabine results in excessive toxic effects without therapeutic benefit.