Stein Eytan M, Fathi Amir T, DiNardo Courtney D, Pollyea Daniel A, Roboz Gail J, Collins Robert, Sekeres Mikkael A, Stone Richard M, Attar Eyal C, Frattini Mark G, Tosolini Alessandra, Xu Qiang, See Wendy L, MacBeth Kyle J, de Botton Stéphane, Tallman Martin S, Kantarjian Hagop M
Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
Massachusetts General Hospital Cancer Center, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Lancet Haematol. 2020 Apr;7(4):e309-e319. doi: 10.1016/S2352-3026(19)30284-4. Epub 2020 Mar 5.
Mutations in isocitrate dehydrogenase-2 (IDH2) occur in around 5% of patients with myelodysplastic syndromes. Neomorphic activity of mutant IDH2 proteins results in hypermethylation of DNA and histones, leading to blocked haemopoietic differentiation. Enasidenib, an inhibitor of mutated IDH2 proteins, induces responses in patients with IDH2-mutated, relapsed or refractory acute myeloid leukaemia. We aimed to establish the clinical outcomes of enasidenib monotherapy in a subgroup of patients with myelodysplastic syndromes harbouring mutations in IDH2 from the AG221-C-001 trial.
The multicentre, open-label, phase 1-2 AG221-C-001 trial enrolled patients with advanced haematological malignancies (2008 WHO criteria) harbouring an IDH2 mutation. The present study is a subgroup analysis of patients with IDH2-mutated myelodysplastic syndromes in the phase 1 dose-escalation and expansion portions of the trial. Patients with myelodysplastic syndromes were aged 18 years or older with an ECOG performance status score of 2 or lower, and were relapsed or refractory to, or ineligible for, standard treatments. Patients received oral doses of enasidenib at 60-300 mg per day in repeated 28-day treatment cycles. In this subgroup analysis, we focused on the safety and activity of enasidenib as main outcomes. Overall response rate, duration of response, and overall and event-free survival analyses were by intention-to-treat. Safety was assessed in all participants who received at least one dose of study drug in terms of treatment-emergent adverse events. The AG221-C-001 trial is registered on ClinicalTrials.gov, NCT01915498, status ongoing but closed to recruitment.
17 patients with myelodysplastic syndromes harbouring an IDH2 mutation (median age, 67·0 years [IQR 60·5-73·0]) were enrolled between Feb 18, 2014, and Sept 1, 2015. At data cutoff (Oct 1, 2018), after a median follow-up of 11·0 months (IQR 6·8-23·0), all patients had discontinued enasidenib, with a median of 3 treatment cycles (2-15) for all patients (five [29%] received ≥12 cycles). At entry, three (18%) patients had relapsed after allogeneic stem-cell transplants, 13 (76%) had previously received therapy with hypomethylating agents, and ten (59%) had received at least two previous therapies. No dose-limiting toxicities were reported. The most common treatment-emergent adverse events were diarrhoea and nausea (in nine [53%] patients each). Most common grade 3-4 treatment-emergent adverse events were indirect hyperbilirubinaemia (in six [35%] patients), pneumonia (in five [29%] patients), and thrombocytopaenia (in four [24%] patients). Serious treatment-emergent adverse events in more than one patient were pneumonia (in five [29% patients); tumor lysis syndrome (in three [18%] patients); and sepsis, atrial flutter, indirect hyperbilirubinaemia, cerebral hemorrhage, and mental status change (in two [12%] patients each). No treatment-related deaths occurred. An overall response was achieved in 9 patients (53% [95% CI 28-77]), with a median duration of response of 9·2 months (95% CI 1·0-not reached). Six (46%) of 13 patients previously treated with hypomethylating agents responded. Median overall survival was 16·9 months (95% CI 1·5-32·3), and median event-free survival was 11·0 months (1·5-16·7).
Enasidenib is generally well tolerated and can induce responses in patients with mutant IDH2 myelodysplastic syndromes, including in those who have had previous therapy with hypomethylating agents. Testing for IDH2 mutations in myelodysplastic syndromes is essential for identifying patients who might benefit from enasidenib therapy, including those patients in whom conventional treatments have been unsuccessful.
Celgene and Agios Pharmaceuticals.
异柠檬酸脱氢酶-2（IDH2）突变发生在约5%的骨髓增生异常综合征患者中。突变IDH2蛋白的新功能活性导致DNA和组蛋白的高甲基化，从而导致造血分化受阻。恩杂鲁胺是一种突变IDH2蛋白抑制剂，可诱导IDH2突变、复发或难治性急性髓系白血病患者产生反应。我们旨在通过AG221-C-001试验确定恩杂鲁胺单药治疗在一组携带IDH2突变的骨髓增生异常综合征患者中的临床疗效。
多中心、开放标签的1-2期AG221-C-001试验纳入了患有晚期血液系统恶性肿瘤（按照2008年世界卫生组织标准）且携带IDH2突变的患者。本研究是对该试验1期剂量递增和扩展部分中携带IDH2突变的骨髓增生异常综合征患者的亚组分析。骨髓增生异常综合征患者年龄在18岁及以上，东部肿瘤协作组（ECOG）体能状态评分为2或更低，且对标准治疗复发、难治或不适用。患者接受口服恩杂鲁胺，剂量为每日60 - 300毫克，每28天为一个重复治疗周期。在该亚组分析中，我们将恩杂鲁胺的安全性和活性作为主要研究结果。总缓解率、缓解持续时间、总生存期和无事件生存期分析均采用意向性分析。根据治疗中出现的不良事件对所有接受至少一剂研究药物的参与者进行安全性评估。AG221-C-001试验已在ClinicalTrials.gov注册，注册号为NCT01915498，状态为正在进行但已停止招募。
2014年2月18日至2015年9月1日期间，共纳入17例携带IDH2突变的骨髓增生异常综合征患者（中位年龄67.0岁[四分位间距60.5 - 73.0]）。在数据截止时（2018年10月1日），中位随访11.0个月（四分位间距6.8 - 23.）后，所有患者均已停用恩杂鲁胺，所有患者的中位治疗周期数为3个（2 - 15个）（5例[29%]接受≥12个周期）。入组时，3例（18%）患者在异基因干细胞移植后复发，13例（76%）患者此前接受过去甲基化药物治疗，10例（59%）患者此前至少接受过两种治疗。未报告剂量限制性毒性。最常见的治疗中出现的不良事件是腹泻和恶心（各有9例[53%]患者）。最常见的3 - 4级治疗中出现的不良事件是间接胆红素血症（6例[35%]患者）、肺炎（5例[29%]患者）和血小板减少症（4例[24%]患者）。不止1例患者出现的严重治疗中出现的不良事件是肺炎（5例[29%]患者）；肿瘤溶解综合征（3例[18%]患者）；以及败血症、心房颤动、间接胆红素血症、脑出血和精神状态改变（各有2例[12%]患者）。未发生与治疗相关的死亡。9例患者（53%[95%置信区间28 - 77]）获得总体缓解，中位缓解持续时间为9.2个月（95%置信区间1.0 - 未达到）。13例此前接受过去甲基化药物治疗的患者中有6例（46%）有反应。中位总生存期为16.9个月（95%置信区间1.5 - 32.3），中位无事件生存期为11.0个月（1.5 - 16.7）。
恩杂鲁胺总体耐受性良好，可诱导携带突变IDH2的骨髓增生异常综合征患者产生反应，包括那些此前接受过去甲基化药物治疗的患者。检测骨髓增生异常综合征中的IDH2突变对于识别可能从恩杂鲁胺治疗中获益的患者至关重要，包括那些常规治疗未成功的患者。
新基公司和阿吉奥斯制药公司。
