Kantarjian Hagop M, Roboz Gail J, Kropf Patricia L, Yee Karen W L, O'Connell Casey L, Tibes Raoul, Walsh Katherine J, Podoltsev Nikolai A, Griffiths Elizabeth A, Jabbour Elias, Garcia-Manero Guillermo, Rizzieri David, Stock Wendy, Savona Michael R, Rosenblat Todd L, Berdeja Jesus G, Ravandi Farhad, Rock Edwin P, Hao Yong, Azab Mohammad, Issa Jean-Pierre J
University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA.
Weill Cornell Medicine, Division of Hematology and Oncology, the New York Presbyterian Hospital, New York, NY, USA.
Lancet Oncol. 2017 Oct;18(10):1317-1326. doi: 10.1016/S1470-2045(17)30576-4. Epub 2017 Aug 24.
The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy.
We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312.
Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m and 28 to 90 mg/m) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort).
More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m in a 5-day schedule versus standard of care.
Astex Pharmaceuticals and Stand Up To Cancer.
低甲基化药物阿扎胞苷和地西他滨已在骨髓增生异常综合征和急性髓系白血病中显示出疗效，但完全肿瘤缓解并不常见且持续时间短，这可能是由于药物半衰期短以及骨髓暴露不理想所致。新一代低甲基化药物胍地西他滨的半衰期和暴露时间比其活性代谢产物地西他滨更长。一项1期研究确定了28天治疗周期中第1 - 5天给予60mg/m²胍地西他滨共5天的有效治疗方案。在这项2期研究中，我们旨在评估两种剂量和方案的胍地西他滨在未接受过治疗、年龄较大（≥65岁）且不适合进行强化化疗的急性髓系白血病患者中的安全性和活性。
我们对胍地西他滨进行了一项多中心、随机、开放标签的1/2期研究，研究对象包括未接受过治疗的急性髓系白血病、复发或难治性急性髓系白血病以及骨髓增生异常综合征患者队列；在此我们报告未接受过治疗的急性髓系白血病患者队列的2期结果。我们纳入了来自美国14个医疗中心（医院和专科癌症诊所）的至少65岁且不适合进行强化化疗的患者，并使用计算机算法（动态随机化）将他们（1:1）随机分配至28天治疗周期第1 - 5天给予60或90mg/m²胍地西他滨（5天方案）。治疗分配未设盲。在方案修订后，我们还将另外的患者分配至28天治疗周期中10天方案的60mg/m²胍地西他滨治疗组。主要终点为复合完全缓解（完全缓解、血小板未完全恢复的完全缓解或中性粒细胞未完全恢复的完全缓解，无论血小板情况如何）。对所有接受至少一剂胍地西他滨的患者（按治疗方案）进行疗效评估。我们呈现最终分析结果，尽管在数据库锁定时，仍有15例患者处于总生存随访中。本研究已在ClinicalTrials.gov注册，编号为NCT01261312。
在2012年8月24日至2014年9月15日期间，共纳入107例患者：54例接受5天方案治疗（26例随机分配至60mg/m²，28例分配至90mg/m²），53例分配至10天方案治疗。中位年龄为77岁（范围62 - 92岁），中位随访时间为953天（IQR 721 - 1040）。所有接受治疗的患者均可评估疗效。在各剂量组或方案中，达到复合完全缓解的患者数量无差异（5天方案中60mg/m²组为13例[54%，95%CI 32.8 - 74.4]；5天方案中90mg/m²组为16例[59%；38.8 - 77.6]；10天方案中60mg/m²组为26例[50%，35.8 - 64.2]）。无论与治疗的关系如何，最常见的3级或更严重不良事件为发热性中性粒细胞减少（5天方案的51例患者中有31例[61%]，10天方案的52例患者中有36例[69%]）、血小板减少（25例[49%]对22例[42%]）、中性粒细胞减少（20例[39%]对18例[35%]）、肺炎（15例[29%]对19例[37%]）、贫血（15例[29%]对12例[23%]）和败血症（8例[16%]对14例[27%]）。5天和10天方案中，无论与治疗的关系如何，最常见的严重不良事件分别为发热性中性粒细胞减少（27例[53%]对25例[48%]）、肺炎（14例[27%]对16例[31%]）和败血症（8例[16%]对14例[27%]）。23例（22%）患者因不良事件死亡（主要死于败血症，8例[8%]；肺炎，5例[5%]）；4例死亡被认为与治疗相关的不良事件有关（肺炎，2例[2%]；多器官功能衰竭，1例[1%]；败血症，1例[1%]，均在10天方案队列中）。
在所有研究的药物剂量和方案中，超过一半未接受过治疗的老年急性髓系白血病患者使用胍地西他滨可达到复合完全缓解，且毒性可耐受。该人群推荐的胍地西他滨方案为5天方案，60mg/m²。针对该患者群体的一项3期研究正在进行（NCT02348489），以评估5天方案60mg/m²胍地西他滨与标准治疗的对比。
阿斯泰克斯制药公司和“勇敢抗癌”组织。
