Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial
Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial
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DOI：
10.1016/s1470-2045(15)00438-6
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发表时间：
2016-01-01
期刊：
影响因子：
51.1
通讯作者：
Zhang, Leo
中科院分区：
文献类型：
--
作者：
Wang, Michael L.;Lee, Hun;Zhang, Leo
背景：伊布替尼已在欧盟、美国和其他国家获批用于既往接受过一种治疗的套细胞淋巴瘤患者。在先前的单药伊曲替尼II期研究中，达到客观缓解的患者比例为68%; 111例患者中有38例（34%）出现一过性淋巴细胞增多。我们假设，加入利妥昔单抗可以靶向与再分布淋巴细胞增多相关的套细胞淋巴瘤细胞，从而产生更有效的抗肿瘤活性。（基于组织活检标本中的CD 20阳性和细胞周期蛋白D1阳性细胞），既往接受治疗次数无上限，并且东部肿瘤协作组体能状态评分为2或更低的患者入组这项单中心、开放标签、II期研究。患者每天接受连续口服伊克替尼（560 mg），直至出现疾病或不可接受的毒性作用。利妥昔单抗375 mg/m2在第1周期每周静脉给药1次，持续4周，然后在第3-8周期的第1天给药，此后每隔一个周期给药1次，持续2年。主要终点是意向治疗人群中达到客观缓解的患者比例和实际治疗人群中评估的安全性。该研究注册于ClinicalTrials.gov，编号NCT 01880567，并且仍在进行中，但不再累积patients.Findings在2013年7月15日和2014年6月30日之间，招募了50名患者。中位年龄为67岁（范围45-86），既往治疗方案的中位数量为3（范围1-9）。中位随访16.5个月（IQR 12.09-19.28）时，44例（88%，95% CI 75.7-95.5）患者达到客观缓解，22例（44%，30.0-58.7）患者达到完全缓解，22例（44%，30.0-58.7）患者达到部分缓解。在≥ 10%的患者中，唯一的3级不良事件是房颤，有6例（12%）患者出现房颤。各有1例患者发生4级腹泻和中性粒细胞减少症。不良事件导致5例（10%）患者停止治疗（3例[6%]患者发生房颤，1例[2%]患者发生肝脏感染，1例[2%]患者发生出血）。两名患者死于心脏骤停和脓毒性休克，而对研究，后者被认为可能与treatment.Interpretation伊替尼联合利妥昔单抗是积极的，并在复发性或难治性套细胞淋巴瘤患者的耐受性良好。我们的研究结果提供了初步的证据，这种组合在临床实践中的活动。3期试验需要更确切的数据。
Background Ibrutinib is approved in the EU, USA, and other countries for patients with mantle cell lymphoma who received one previous therapy. In a previous phase 2 study with single-agent ibrutinib, the proportion of patients who achieved an objective response was 68%; 38 (34%) of 111 patients had transient lymphocytosis. We hypothesised that adding rituximab could target mantle cell lymphoma cells associated with redistribution lymphocytosis, leading to more potent antitumour activity.Methods Patients with a confirmed mantle cell lymphoma diagnosis (based on CD20-positive and cyclin D1-positive cells in tissue biopsy specimens), no upper limit on the number of previous treatments received, and an Eastern Cooperative Oncology Group performance status score of 2 or less were enrolled in this single-centre, open-label, phase 2 study. Patients received continuous oral ibrutinib (560 mg) daily until progessive disease or unacceptable toxic effects. Rituximab 375 mg/m(2) was given intravenously once per week for 4 weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle up to 2 years. The primary endpoint was the proportion of patients who achieved an objective response in the intention-to-treat population and safety assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT01880567, and is still ongoing, but no longer accruing patients.Findings Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45-86), and the median number of previous regimens was three (range 1-9). At a median follow-up of 16.5 months (IQR 12.09-19.28), 44 (88%, 95% CI 75.7-95.5) patients achieved an objective response, with 22 (44%, 30.0-58.7) patients achieving a complete response, and 22 (44%, 30.0-58.7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment.Interpretation Ibrutinib combined with rituximab is active and well tolerated in patients with relapsed or refractory mantle cell lymphoma. Our results provide preliminary evidence for the activity of this combination in clinical practice. A phase 3 trial is warranted for more definitive data.