Hôpital Mignot, Université Versailles-Saint Quentin, Le Chesnay, France.
Lancet. 2012 Apr 21;379(9825):1508-16. doi: 10.1016/S0140-6736(12)60485-1. Epub 2012 Apr 5.
The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity.
In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36.
280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity.
The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia.
Wyeth (Pfizer).
在 3 期临床试验中，添加抗 CD33 抗体偶联物 gemtuzumab ozogamicin 到急性髓系白血病的标准治疗中的结果是相互矛盾的。我们研究了在标准一线化疗中添加低分数剂量 gemtuzumab ozogamicin 是否会改善这种白血病患者的预后，而不会导致过度毒性。
在法国 26 个血液学中心进行的 3 期、开放标签研究中，年龄在 50-70 岁之间的未经治疗的初发性急性髓系白血病患者以计算机生成的序列以 1:1 的比例与四组块大小随机分配至标准治疗（对照组），或标准治疗加五次静脉 gemtuzumab ozogamicin（诱导期第 1、4 和 7 天以及两个巩固化疗疗程的第 1 天各 3mg/m2）。主要终点是无事件生存（EFS）。次要终点是无复发（RFS）、总生存（OS）和安全性。分析采用意向治疗。这项研究在 EudraCT 注册，编号为 2007-002933-36。
280 名患者随机分配至对照组（n=140）和 gemtuzumab ozogamicin 组（n=140），每组 139 名患者进行分析。诱导后完全缓解伴或不伴不完全血小板恢复的患者，对照组为 104 例（75%），gemtuzumab ozogamicin 组为 113 例（81%）（比值比 1.46，95%CI 0.20-2.59；p=0.25）。2 年时，对照组 EFS 估计为 17.1%（10.8-27.1），gemtuzumab ozogamicin 组为 40.8%（32.8-50.8）（风险比 0.58，0.43-0.78；p=0.0003），OS 分别为 41.9%（33.1-53.1）和 53.2%（44.6-63.5）（0.69，0.49-0.98；p=0.0368），RFS 分别为 22.7%（14.5-35.7）和 50.3%（41.0-61.6）（0.52，0.36-0.75；p=0.0003）。对照组（22 [16%]）比 gemtuzumab ozogamicin 组（4 [3%]）更常见血液学毒性，特别是持续性血小板减少症（p<0.0001），但毒性导致死亡的风险并未增加。
使用分割的较低剂量 gemtuzumab ozogamicin 可以安全地给予更高的累积剂量，并显著改善急性髓系白血病患者的预后。这些发现值得重新评估 gemtuzumab ozogamicin 作为急性髓系白血病的一线治疗。
惠氏（辉瑞）。
