Background

In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients.

Methods

We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up.

Findings

Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55–69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1–2 in months 1–9 and in 43 [33%] of 130 patients at grade 1–2 in months 9–15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1–2 in months 1–9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9–15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred.

Interpretation

Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed.

Funding

Roche, Janssen.

中文翻译：

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Obinutuzumab和ibrutinib诱导疗法后继之以最小残留疾病驱动策略治疗慢性淋巴细胞性白血病（ICLL07 FILO）：单臂，多中心，2期试验

背景

在患有慢性淋巴细胞性白血病的患者中，在骨髓中实现完全缓解和最小残留疾病小于0·01％（即每1万个白细胞少于1个慢性淋巴细胞性白血病细胞）与改善无进展生存率相关。我们的目的是探讨在先前未治疗的患者中使用obinutuzumab和ibrutinib进行9个月的诱导治疗的活性，并采取最小残留疾病驱动的治疗策略再进行6个月的随访。

方法

我们在法国的27家大学医院，综合医院和专科癌症中心进行了单臂2期试验。符合条件的患者至少年满18岁，之前未接受过治疗，并且具有免疫表型确认的B细胞慢性淋巴细胞性白血病；东部合作肿瘤小组（ECOG）的工作状态评分低于2；根据IWCLL 2008标准的Binet阶段C或活动性疾病的Binet A和B阶段；没有17p缺失或缺少p53突变; 并且被认为在医学上适合。在研究的第一阶段（诱导阶段），所有参与者在六个连续的4周周期内接受了8剂奥比妥珠单抗1000毫克的静脉输注，每天一次口服艾鲁替尼420毫克，共9个月。在第2部分中，在第9个月的第1天进行评估后，完全缓解且骨髓最小残留疾病小于0·01％的患者每天仅口服一次口服ibrutinib 420 mg，连续6个月。具有部分缓解或完全缓解且骨髓最小残留病为0·01％或更高的患者，每4个4周周期接受6个月的静脉注射氟达拉滨，环磷酰胺和奥比妥珠单抗1000 mg的治疗，同时继续使用依鲁替尼420 mg每天一次。主要终点指标是根据治疗意向（ITT）评估，在16个月的第1天获得完全缓解且骨髓最小残留疾病小于0·01％的患者比例。该试验已在ClinicalTrials.gov上注册（编号NCT02666898），并且仍在接受随访。

发现

在2015年10月27日至2017年5月16日之间，共招募135位患者。诱导治疗后（第9个月的第1天），可评估130例患者，其中十例（8％）达到完全缓解，骨髓最小残留病小于0·01％，被分配给依鲁替尼，120例（92 ％）被分配给ibrutinib加上氟达拉滨，环磷酰胺和obinutuzumab。经过最小残留疾病指导治疗（第16个月的第1天）后，135例患者（ITT人群）中的84名（62％，90％CI 55-69）达到了完全缓解，骨髓最小残留疾病小于0·01 ％。最常见的血液学不良事件是血小板减少症（在1-9个月的1-2级133例患者中有45 [34％]，在9-15个月的1-2级的130例患者中有43 [33％]）。最常见的非血液学不良事件是与输液有关的反应（在1-9个月中有83 [62％] 1-2级患者）和胃肠道疾病（在62和48％的患者中在1和2个月内有胃肠道疾病） 9-15）。发生了49次严重不良事件，最常见的是感染（十次），心脏事件（八次）和血液学事件（八次）。没有发生与治疗有关的死亡。

解释

对于以前未经治疗的慢性淋巴细胞性白血病患者，奥比妥珠单抗和依鲁替尼诱导治疗后采用最小残留病驱动策略是安全且有效的。如果需要维持更长的随访时间，包括评估最小残留病的进展，如果能够维持反应，那么该策略可能是一线治疗慢性淋巴细胞性白血病患者的一种选择，尽管需要随机证据。

资金

罗森，詹森。