背景:许多患有急性髓性白血病的老年患者由于强化化疗引起的毒性而死亡或不能接受异基因造血干细胞移植(HSCT)。我们假设用地西他滨单药治疗替代强化化疗可以改善预后。
方法:这个开放标签,随机化,控制,3期试验在9个欧洲国家的54家医院进行.新诊断为急性髓性白血病且尚未接受治疗的60岁及以上患者,如果他们的东部肿瘤协作组表现状态为2或更低,并且有资格接受强化化疗。患者被随机分配(1:1)接受地西他滨或标准化疗(称为3+7)。对于地西他滨组,在第一个28天周期的前10天给予地西他滨(20mg/m2),接下来是28天的周期,包括5天或10天的地西他滨。对于3+7组,柔红霉素(60mg/m2)在前3天和阿糖胞苷(200mg/m2)在前7天,随后是1-3个额外的化疗周期。强烈鼓励同种异体HSCT。意向治疗人群的总生存期是主要终点。在接受分配治疗的所有患者中评估安全性。该试验在ClinicalTrials.gov注册,NCT02172872,并对新参与者关闭。
结果:在2014年12月1日至2019年8月20日之间,606例患者被随机分配到地西他滨(n=303)或3+7(n=303)组。在一项中期分析显示徒劳之后,IDMC于2019年5月22日建议,考虑到参与研究的患者的风险和获益,研究按计划继续进行.此处显示的最终分析的截止日期是2021年6月30日。在中位随访4·0年(IQR2·9-4·8)时,地西他滨组4年总生存率为26%(95%CI21-32),3+7组为30%(24-35)(死亡风险比1·04[95%CI0·86-1·26];p=0·68)。方案中同种异体HSCT的比率在组间相似(地西他滨303例患者中的122[40%]和3+7例患者中的118[39%])。地西他滨组302例患者中的3-5级不良事件发生率为254例(84%),3+7组298例患者中的279例(94%)。3-5级感染率(41%[302中的125]对53%[298中的158]),与3+7组相比,地西他滨组的口腔黏膜炎(2%[302中的7]vs10%[298中的31])和腹泻(1%[302中的3]vs8%[298中的24])较低.据报道,地西他滨组中有12%(302例中的35例)的患者死亡,3+7组中有14%(298例中的41例)的患者死亡。
结论:在符合强化化疗条件的老年急性髓性白血病患者中,与3+7化疗相比,10天地西他滨没有改善总生存率,但显示出更好的安全性。在没有有利遗传学的老年急性髓性白血病患者中,地西他滨可以被认为是37诱导的耐受性更好且足够有效的替代方案。
背景:扬森制药。
BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.
METHODS: This open-label, randomised, controlled, phase 3
trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group,
daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This
trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants.
RESULTS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the
study continued as planned considering the risks and benefits for the patients participating in the
study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group.
CONCLUSIONS: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics.
BACKGROUND: Janssen Pharmaceuticals.