From the Department of Clinical Haematology, Alfred Hospital, and the Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia (A.H.W.); the Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany (H. Döhner); Kent and Canterbury Hospital, Canterbury, United Kingdom (C.P.); Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, and Hospital Universitari i Politècnic La Fe, Valencia - both in Spain (P.M.); Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology, and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia (B.A.); the Department of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, and Institut de Recherche Saint-Louis, Université de Paris, Paris (H. Dombret); the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston (F.R.); Indiana University Cancer Center, Indianapolis (H.S.); Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (J.H.J.); Hospital District of Helsinki and Uusimaa (HUS) Comprehensive Cancer Center, Hematology Research Unit Helsinki and iCAN Digital Precision Cancer Center Medicine Flagship, University of Helsinki, Helsinki (K.P.); AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium (D.S.); University of Alberta Hospital, Edmonton, Canada (I.S.); Ondokuz Mayis University, Samsun (M.T.), and Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara (M.K.C.) - both in Turkey; Antonio e Biagio e Cesare Arrigo Hospital, Alessandria (V.G.), Città della Salute e della Scienza, Turin (C.F.), Ospedale San Gerardo Monza, Monza (L.B.), and Ospedale Policlinico San Martino, Genoa (G.B.) - all in Italy; Rambam Medical Center and Faculty of Medicine Technion, Haifa, Israel (Y.O.); Hospital dos Capuchos, Centro Hospitalar Universitário de Lisboa Central, Lisbon, Portugal (A.B.S.); Wroclaw Medical University, Wroclaw, Poland (J.R.); Ústav Hematologie a Krevní Transfuze, Prague, Czech Republic (J.C.); Amsterdam University Medical Center, Location VUMC (Vrije Universiteit Medical Center), Amsterdam (G.J.O.); Celgene (Bristol Myers Squibb), Boudry, Switzerland (I.L.T.); Bristol Myers Squibb, Princeton, NJ (B.S., K.K., Q.D., C.L.B.); University of Kansas Medical Center, Kansas City (B.S.); and Weill Cornell Medicine and New York Presbyterian Hospital, New York (G.J.R.).
N Engl J Med. 2020 Dec 24;383(26):2526-2537. doi: 10.1056/NEJMoa2004444.
Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor.
We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bioequivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life.
A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment.
CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZAR AML-001 ClinicalTrials.gov number, NCT01757535.).
虽然诱导化疗可使许多老年急性髓系白血病（AML）患者缓解，但复发很常见，总生存情况较差。
我们开展了一项 3 期、随机、双盲、安慰剂对照试验，以评估口服阿扎胞苷（CC-486，一种低甲基化药物，与注射用阿扎胞苷不具有生物等效性）作为强化化疗后处于缓解期的 AML 患者的维持治疗药物。入组患者年龄 55 岁及以上，完全缓解，有或无完全血细胞计数恢复，且不适合造血干细胞移植。患者被随机分配接受 CC-486（300 mg）或安慰剂，每天一次，28 天为一个周期，连用 14 天。主要终点为总生存情况。次要终点包括无复发生存情况和健康相关生活质量。
共 472 例患者接受了随机分组；238 例患者被分入 CC-486 组，234 例患者被分入安慰剂组。中位年龄为 68 岁（范围：55 岁至 86 岁）。从随机分组开始，CC-486 组的中位总生存时间明显长于安慰剂组（分别为 24.7 个月和 14.8 个月；P<0.001）。CC-486 组的中位无复发生存时间也明显长于安慰剂组（分别为 10.2 个月和 4.8 个月；P<0.001）。CC-486 组在根据基线特征定义的大多数亚组中均显示出总生存情况和无复发生存情况获益。两组中最常见的不良事件均为 1 级或 2 级胃肠道事件。常见的 3 级或 4 级不良事件为中性粒细胞减少（CC-486 组 41%的患者，安慰剂组 24%的患者）和血小板减少（分别为 22%和 21%）。CC-486 治疗期间，总体健康相关生活质量得以维持。
在化疗后缓解的老年 AML 患者中，CC-486 维持治疗与安慰剂相比，总生存情况和无复发生存情况明显更长。副作用主要为胃肠道症状和中性粒细胞减少。治疗期间，生活质量评估指标保持稳定。（由 Celgene 公司资助；QUAZAR AML-001 临床试验.gov 注册号：NCT01757535.）。
