Background

Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma.

Methods

In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0–2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2–22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov, number NCT01582776, and is ongoing but closed to accrual.

Findings

Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2–2·8). 68 (79%) of 86 evaluable patients (95% CI 69–87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51–72), progression-free survival 65% (95% CI 54–74), duration of response 70% (95% CI 57–79), and overall survival 87% (95% CI 78–93). Complete response was achieved by 33 (38%, 95% CI 28–50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72–89) and 72 (84%, 74–91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia.

Interpretation

Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted.

Funding

Lymphoma Academic Research Organisation, and Celgene and Roche

中文翻译：

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奥比妥珠单抗联合来那度胺治疗复发性或难治性滤泡性B细胞淋巴瘤（GALEN）：一项多中心，单臂，2期研究

背景

来那度胺加利妥昔单抗被批准用于治疗复发性或难治性滤泡性淋巴瘤患者。已显示奥比妥单抗比利妥昔单抗更好地增强抗体依赖性细胞的细胞毒性，吞噬作用和直接B细胞杀伤作用。我们的目的是确定来那度胺加奥比妥单抗在先前治疗的复发性或难治性滤泡性淋巴瘤患者中的活性和安全性。

方法

在这项多中心单臂2期研究中，患者来自法国的24个淋巴瘤学术研究组织中心。符合条件的患者（年龄≥18岁）经组织学确认为WHO 1、2或3a级的CD20阳性复发性或难治性滤泡性淋巴瘤；ECOG绩效状态为0–2；并接受了至少一种先前的含利妥昔单抗治疗。患者接受口服来那度胺（20 mg）加上静脉输注奥比妥珠单抗作为诱导疗法（1000 mg；六个28天周期），来那度胺（10 mg； 12个28天周期； 2-22天）加上奥比妥单抗1年维持治疗（ 1000 mg；交替周期），以及使用obinutuzumab的1年维持治疗（1000 mg； 6个56天周期；第1天）。主要终点是根据研究者的评估，使用1999年国际工作组标准在诱导期达到总体缓解的患者比例。次要终点是无事件生存期，无进展生存期，总体生存期和安全性。分析是按照协议进行的；功效人群包括所有接受至少一剂奥比妥珠单抗和来那度胺治疗的患者，安全人群包括接受一剂两种研究药物的所有患者。这项研究已在ClinicalTrials.gov上注册，编号为NCT01582776，目前正在进行中，但尚未有任何结果。功效人群包括所有接受至少一剂奥比妥珠单抗和来那度胺治疗的患者，安全人群包括接受一剂两种研究药物的所有患者。这项研究已在ClinicalTrials.gov上注册，编号为NCT01582776，目前正在进行中，但尚未有任何结果。功效人群包括所有接受至少一剂奥比妥珠单抗和来那度胺治疗的患者，安全人群包括接受一剂两种研究药物的所有患者。这项研究已在ClinicalTrials.gov上注册，编号为NCT01582776，目前正在进行中，但尚未有任何结果。

发现

在2014年6月11日至2015年12月18日之间，共招募了89例患者，其中86例可评估疗效，88例评估安全性。中位随访时间为2·6年（IQR 2·2–2·8）。86名可评估患者中的68名（79％）（95％CI 69-87）在入院时达到了总体缓解，达到了预先设定的主要终点。在2年时，无事件生存率为62％（95％CI 51-72），无进展生存期为65％（95％CI 54-74），反应持续时间为70％（95％CI 57-79），并且总体生存率87％（95％CI 78-93）。诱导期末86例患者中有33例（38％，95％CI 28-50）达到了完全缓解，获得最佳总体缓解的患者比例分别为70（81％，95％CI 72-89）和72（ 86例患者在引产和治疗期间分别占84％，74-91）。最常见的不良事件是乏力（n = 54，61％），中性粒细胞减少症（n = 38，43％），支气管炎（n = 36，41％），腹泻（n = 35，40％）和肌肉痉挛（n = 34，39％）。中性粒细胞减少症是3级或以上的最常见毒性。四（5％）例患者出现发热性中性粒细胞减少。88例患者中有30例（34％）报告了57例严重不良事件。最常见的严重不良事件是基底细胞癌（n = 5，6％），发热性中性粒细胞减少（n = 4，5％）和输注相关反应（n = 3，3％）。一名患者因与治疗有关的发热性中性粒细胞减少症而死亡。

解释

我们的数据表明来那度胺加奥比妥珠单抗在先前治疗的复发或难治性滤泡性淋巴瘤患者（包括早期复发的患者）中具有活性，并且安全性可控。有必要对新的免疫调节方案（例如GALEN或以GALEN作为骨架）与来那度胺联合利妥昔单抗进行随机试验。

资金

淋巴瘤学术研究组织以及Celgene和Roche