Jerkeman Mats, Eskelund Christian Winther, Hutchings Martin, Räty Riikka, Wader Karin Fahl, Laurell Anna, Toldbod Helle, Pedersen Lone Bredo, Niemann Carsten Utoft, Dahl Christina, Kuitunen Hanne, Geisler Christian H, Grønbæk Kirsten, Kolstad Arne
Department of Oncology, Institute of Clinical Sciences, Lund University and Skane University Hospital, Lund, Sweden.
Department of Haematology, Rigshospitalet, Copenhagen, Denmark; Biotech Research and Innovation Centre, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
Lancet Haematol. 2018 Mar;5(3):e109-e116. doi: 10.1016/S2352-3026(18)30018-8. Epub 2018 Jan 29.
Regimens based on ibrutinib alone and lenalidomide and rituximab in combination show high activity in patients with relapsed or refractory mantle cell lymphoma. We hypothesised that the combination of all three drugs would improve efficacy compared with previously published data on either regimen alone.
In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients aged 18 years or older with relapsed or refractory mantle cell lymphoma who had previously been treated with at least one rituximab-containing regimen, an Eastern Cooperative Oncology Group performance status score of 0-3, and at least one site of measurable disease, and who met criteria for several laboratory-assessed parameters. Treatment was divided into an induction phase of 12 cycles of 28 days with all three drugs and a maintenance phase with ibrutinib and rituximab only (cycle duration 56 days), given until disease progression or unacceptable toxicity. In the induction phase, patients received intravenous (375 mg/m) or subcutaneous (1400 mg) rituximab once a week during cycle 1 and then once every 8 weeks. Oral ibrutinib (560 mg once a day) was given to patients every day in the cycle, whereas oral lenalidomide (15 mg once a day) was given on days 1-21. The primary endpoint was overall response assessed in the intention-to-treat population according to Lugano criteria. Safety analysis included all patients who received the treatment, irrespective of eligibility or duration of treatment. The trial is ongoing, but is no longer accruing patients, and is registered with ClinicalTrials.gov, number NCT02460276.
Between April 30, 2015, and June 1, 2016, we enrolled 50 patients with relapsed or refractory mantle cell lymphoma at ten centres in Sweden, Finland, Norway, and Denmark. At a median follow-up of 17·8 months (IQR 14·7-20·9), 38 (76%, 95% CI 63-86) patients had an overall response, including 28 (56%, 42-69) patients who had a complete response and ten (20%, 11-33) who had a partial response. The most common grade 3-4 adverse events were neutropenia (in 19 [38%] of 50 patients), infections (in 11 [22%] patients), and cutaneous toxicity (in seven [14%] patients). There were three treatment-related deaths during the study, two due to sepsis and one due to embolic stroke.
Our results provide preliminary evidence that the triplet combination of ibrutinib, lenalidomide, and rituximab is an active regimen in patients with relapsed or refractory mantle cell lymphoma, and should be evaluated in a prospective randomised controlled trial.
Janssen and Celgene.
基于单药伊布替尼以及来那度胺与利妥昔单抗联合使用的治疗方案在复发或难治性套细胞淋巴瘤患者中显示出高活性。我们推测，与之前单独使用任一方案所公布的数据相比，三种药物联合使用将提高疗效。
在这项多中心、开放标签、单臂2期试验中，我们纳入了年龄在18岁及以上、复发或难治性套细胞淋巴瘤患者，这些患者先前至少接受过一种含利妥昔单抗的治疗方案，东部肿瘤协作组体能状态评分为0 - 3分，且至少有一个可测量病灶部位，并且符合多项实验室评估参数标准。治疗分为诱导期和维持期，诱导期为28天的12个周期，三种药物联合使用，维持期仅使用伊布替尼和利妥昔单抗（周期持续时间56天），持续至疾病进展或出现不可接受的毒性。在诱导期，患者在第1周期每周接受一次静脉注射（375 mg/m²）或皮下注射（1400 mg）利妥昔单抗，之后每8周一次。口服伊布替尼（每日一次，560 mg）在每个周期每日给予患者，而口服来那度胺（每日一次，15 mg）在第1 - 21天给予。主要终点是在意向性治疗人群中根据卢加诺标准评估的总缓解率。安全性分析包括所有接受治疗的患者，无论其是否符合入组标准或治疗持续时间。该试验正在进行，但不再招募患者，已在ClinicalTrials.gov注册，编号为NCT02460276。
在2015年4月30日至2016年6月1日期间，我们在瑞典、芬兰、挪威和丹麦的十个中心招募了50例复发或难治性套细胞淋巴瘤患者。在中位随访17.8个月（四分位间距14.7 - 20.9个月）时，38例（76%，95%置信区间63 - 86）患者有总缓解，包括28例（56%，42 - 69）完全缓解患者和10例（20%，11 - 33）部分缓解患者。最常见的3 - 4级不良事件是中性粒细胞减少（50例患者中有19例[38%]）、感染（11例[22%]患者）和皮肤毒性（7例[14%]患者）。研究期间有3例与治疗相关的死亡，2例因败血症，1例因栓塞性中风。
我们的结果提供了初步证据，表明伊布替尼、来那度胺和利妥昔单抗三联组合对复发或难治性套细胞淋巴瘤患者是一种有效的治疗方案，应在前瞻性随机对照试验中进行评估。
杨森和新基公司。
