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高剂量阿糖胞苷诱导治疗可改善年龄<46 岁成人急性髓系白血病患者的预后：EORTC-GIMEMA AML-12 试验结果。

High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial.

机构信息

Roelof Willemze, Constantijn J.M. Halkes, and Erik W.A. Marijt, Leiden University Medical Center, Leiden; Petra Muus, Joop Jansen, and Theo de Witte, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands; Stefan Suciu and Liv Meert, European Organisation for Research and Treatment of Cancer Headquarters; Dominique Bron, Hôpital Universitaire, Bordet-Erasme, Brussels; Dominik L.D. Selleslag, Algemeen Ziekenhuis Sint-Jan, Brugge; Zwi Berneman, Universitair Ziekenhuis, Antwerpen; Georges Fillet, Centre Hospitalier Universitaire du Sart-Tilman, Liège; Anne Hagemeijer, Center for Human Genetics, University of Leuven, Leuven, Belgium; Giovanna Meloni, Marco Mancini, Silvia Maria Trisolini, and Franco Mandelli, "Sapienza" University; Sergio Amadori and Adriano Venditti, Tor Vergata University Hospital; Simona Sica, Università Cattolica del Sacro Cuore, Policlinico A. Gemelli; Paola Fazi and Marco Vignetti, Gruppo Italiano Malattie Ematologiche dell' Adulto Foundation, Central Office, Rome; Giorgina Specchia, Università degli Studi di Bari, Bari; Francesco Fabbiano, Ospedali Riuniti "Villa Sofia-Cervello"; Maria Enza Mitra, Policlinico "Paolo Giaccone," Palermo; Francesco Nobile, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria; Marco Sborgia, Azienda Unitá Sanitaria Locale di Pescara, Pescara; Andrea Camera, L'A.O. Universitaria-Università degli Studi di Napoli "Federico II," Napoli; Domenico Magro, A.O. Pugliese Ciaccio, Catanzaro; Nicola Cantore, A.O. San Giuseppe Moscati, Avellino; Lorella Melillo, Istituto Di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo; Pietro Leoni, A.O. Nuovo Ospedale Torrette, Ancona; Mario Luppi, A.O. Universitaria di Modena, Modena; Daniela Cilloni, University of Torino, Torino, Italy; Boris Labar, University Hospital Center-Rebro, Zagreb, Croatia; Jean-Pierre Marie, Saint-Antoine Hospital, Assistance Publique-Hopitaux de Paris and University Paris 6; Francois Lef

出版信息

J Clin Oncol. 2014 Jan 20;32(3):219-28. doi: 10.1200/JCO.2013.51.8571. Epub 2013 Dec 2.

DOI:10.1200/JCO.2013.51.8571

PMID:24297940

Abstract

PURPOSE

Cytarabine plays a pivotal role in the treatment of patients with acute myeloid leukemia (AML). Most centers use 7 to 10 days of cytarabine at a daily dose of 100 to 200 mg/m(2) for remission induction. Consensus has not been reached on the benefit of higher dosages of cytarabine.

PATIENTS AND METHODS

The European Organisation for Research and Treatment of Cancer (EORTC) and Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Leukemia Groups conducted a randomized trial (AML-12; Combination Chemotherapy, Stem Cell Transplant and Interleukin-2 in Treating Patients With Acute Myeloid Leukemia) in 1,942 newly diagnosed patients with AML, age 15 to 60 years, comparing remission induction treatment containing daunorubicin, etoposide, and either standard-dose (SD) cytarabine (100 mg/m(2) per day by continuous infusion for 10 days) or high-dose (HD) cytarabine (3,000 mg/m(2) every 12 hours by 3-hour infusion on days 1, 3, 5, and 7). Patients in complete remission (CR) received a single consolidation cycle containing daunorubicin and intermediate-dose cytarabine (500 mg/m(2) every 12 hours for 6 days). Subsequently, a stem-cell transplantation was planned. The primary end point was survival.

RESULTS

At a median follow-up of 6 years, overall survival was 38.7% for patients randomly assigned to SD cytarabine and 42.5% for those randomly assigned to HD cytarabine (log-rank test P = .06; multivariable analysis P = .009). For patients younger than age 46 years, survival was 43.3% and 51.9%, respectively (P = .009; multivariable analysis P = .003), and for patients age 46 to 60 years, survival was 33.9% and 32.9%, respectively (P = .91). CR rates were 72.0% and 78.7%, respectively (P < .001) and were 75.6% and 82.4% for patients younger than age 46 years (P = .01) and 68.3% and 74.8% for patients age 46 years and older (P = .03). Patients of all ages with very-bad-risk cytogenetic abnormalities and/or FLT3-ITD (internal tandem duplication) mutation, or with secondary AML benefitted from HD cytarabine.

CONCLUSION

HD cytarabine produces higher remission and survival rates than SD cytarabine, especially in patients younger than age 46 years.

摘要

目的

阿糖胞苷在急性髓系白血病（AML）患者的治疗中起着关键作用。大多数中心采用每天 100 至 200mg/m²的阿糖胞苷治疗 7 至 10 天来诱导缓解。尚未就更高剂量阿糖胞苷的益处达成共识。

患者和方法

欧洲癌症研究与治疗组织（EORTC）和意大利血液学协会成人白血病组（GIMEMA）进行了一项随机试验（AML-12；联合化疗、干细胞移植和白细胞介素-2治疗急性髓系白血病），共纳入 1942 名新诊断为 AML 的患者，年龄 15 至 60 岁，比较含柔红霉素、依托泊苷的缓解诱导治疗，阿糖胞苷标准剂量（SD；每天 100mg/m²，连续输注 10 天）或高剂量（HD；每天 3 次输注 3 小时，第 1、3、5 和 7 天给予 3000mg/m²）。完全缓解（CR）的患者接受含有柔红霉素和中剂量阿糖胞苷的单次巩固治疗（6 天，每天 12 小时给予 500mg/m²）。随后计划进行干细胞移植。主要终点是生存。

结果

中位随访 6 年后，随机分配至 SD 阿糖胞苷组的患者总体生存率为 38.7%，随机分配至 HD 阿糖胞苷组的患者为 42.5%（对数秩检验 P =.06；多变量分析 P =.009）。年龄小于 46 岁的患者的生存率分别为 43.3%和 51.9%（P =.009；多变量分析 P =.003），年龄为 46 至 60 岁的患者的生存率分别为 33.9%和 32.9%（P =.91）。CR 率分别为 72.0%和 78.7%（P <.001），年龄小于 46 岁的患者为 75.6%和 82.4%（P =.01），年龄为 46 岁及以上的患者为 68.3%和 74.8%（P =.03）。所有年龄组中，具有非常差的细胞遗传学异常和/或 FLT3-ITD（内部串联重复）突变的患者，或患有继发性 AML 的患者，均从 HD 阿糖胞苷中获益。