Background

Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax–obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions.

Methods

In this open-label, single-arm, investigator-sponsored, phase 2 study, patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma were recruited from two academic hospitals in Boston, MA, USA. Eligible patients were aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0–2, and were treatment naive. Patients were treated in 28 day cycles. Acalabrutinib monotherapy was given orally at 100 mg twice daily for cycle 1, then combined for six cycles with intravenous obinutuzumab (100 mg on cycle 2 day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 and on day 1 of cycles 3–7); and from the beginning of cycle 4, oral venetoclax was dosed daily using an accelerated ramp-up from 20 mg on day 1 to 400 mg by day 22 and continued at this dose thereafter. Patients continued on acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until day 1 of cycle 16 or day 1 of cycle 25. If the patient had undetectable MRD in the bone marrow they were given the option to discontinue therapy at the start of cycle 16 (if also in complete remission) or at the start of cycle 25 (if at least in partial remission). The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined as <1 chronic lymphocytic leukaemia cell per 10 000 leucocytes as measured by four-colour flow cytometry), at cycle 16 day 1. Safety and activity endpoints were assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT03580928, and is ongoing.

Findings

Between Aug 2, 2018, and May 23, 2019, 37 patients with chronic lymphocytic leukaemia were enrolled and all received at least one dose of any study drug. The median age of patients was 63 years (IQR 57–70), and ten (27%) were female and 27 (73%) were male. Median follow-up was 27·6 months (IQR 25·1–28·2). At cycle 16 day 1, 14 (38% [95% CI 22–55]) of 37 participants had a complete remission with undetectable MRD in the bone marrow. The most common grade 3 or 4 haematological adverse event was neutropenia (16 [43%] of 37 patients). The most common grade 3–4 non-haematological adverse events were hyperglycaemia (three [8%]) and hypophosphataemia (three [8%]). Serious adverse events occurred in nine (24%) patients; the most common was neutropenia in three (8%) patients. There have been no deaths on study.

Interpretation

Acalabrutinib, venetoclax, and obinutuzumab is a highly active and well tolerated frontline therapy for chronic lymphocytic leukaemia. Although the primary endpoint of this study was not met, the high proportion of patients who had undetectable MRD in the bone marrow supports further investigation of this regimen, which is being tested against acalabrutinib–venetoclax and chemoimmunotherapy in an ongoing phase 3 study (NCT03836261).

Funding

AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award.

中文翻译：

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Acalabrutinib、venetoclax 和 obinutuzumab 作为慢性淋巴细胞白血病的一线治疗：一项单臂、开放标签、2 期研究

背景

acalabrutinib 的连续治疗和 venetoclax-obinutuzumab 的固定疗程治疗均对先前未治疗的慢性淋巴细胞白血病有效。我们假设前线时间有限、微小残留病 (MRD) 指导的阿卡布替尼、venetoclax 和 obinutuzumab 的三联疗法将诱导深度（即，更多患者检测不到 MRD）和持久缓解。

方法

在这项开放标签、单臂、研究者赞助的 2 期研究中，从美国马萨诸塞州波士顿的两家学术医院招募了慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者。符合条件的患者年龄在 18 岁或以上，东部肿瘤协作组的体能状态为 0-2，并且未接受过治疗。患者以 28 天为周期接受治疗。Acalabrutinib 单药在第 1 周期每天两次口服 100 mg，然后与静脉注射 obinutuzumab 联合 6 个周期（第 2 周期第 1 天 100 mg、第 2 天 900 mg、第 8 天 1000 mg 和第 15 天 1000 mg 和在第 3-7 个周期的第 1 天）；从第 4 周期开始，每天口服维奈托克，从第 1 天的 20 毫克加速增加到第 22 天的 400 毫克，此后继续以该剂量给药。患者继续服用 acalabrutinib 100 mg 每天两次和 venetoclax 400 mg 每天一次，直到第 16 个周期的第 1 天或第 25 个周期的第 1 天。如果患者在骨髓中检测不到 MRD，他们可以选择在周期开始时停止治疗16（如果也完全缓解）或在第 25 个周期开始时（如果至少部分缓解）。主要终点是在第 16 个周期的第 1 天完全缓解，骨髓中检测不到 MRD（定义为 <1 个慢性淋巴细胞白血病细胞/10 000 个白细胞，通过四色流式细胞术测量）。安全性和活性终点在所有接受至少一剂任何研究药物的患者。该研究已在 ClinicalTrials.gov 注册，NCT03580928，并且正在进行中。如果患者在骨髓中检测不到 MRD，他们可以选择在第 16 个周期开始时（如果也完全缓解）或在第 25 个周期开始时（如果至少部分缓解）停止治疗。主要终点是在第 16 个周期第 1 天完全缓解，骨髓中检测不到 MRD（定义为 <1 个慢性淋巴细胞白血病细胞/10 000 个白细胞，通过四色流式细胞术测量）。安全性和活性终点在所有接受至少一剂任何研究药物的患者。该研究已在 ClinicalTrials.gov 注册，NCT03580928，并且正在进行中。如果患者在骨髓中检测不到 MRD，他们可以选择在第 16 个周期开始时（如果也完全缓解）或在第 25 个周期开始时（如果至少部分缓解）停止治疗。主要终点是在第 16 个周期第 1 天完全缓解，骨髓中检测不到 MRD（定义为 <1 个慢性淋巴细胞白血病细胞/10 000 个白细胞，通过四色流式细胞术测量）。安全性和活性终点在所有接受至少一剂任何研究药物的患者。该研究已在 ClinicalTrials.gov 注册，NCT03580928，并且正在进行中。

发现

在 2018 年 8 月 2 日至 2019 年 5 月 23 日期间，招募了 37 名慢性淋巴细胞白血病患者，并且均接受了至少一剂任何研究药物的治疗。患者的中位年龄为 63 岁（IQR 57-70），其中女性 10 人（27%），男性 27 人（73%）。中位随访时间为 27·6 个月（IQR 25·1–28·2）。在第 16 个周期的第 1 天，37 名参与者中有 14 名（38% [95% CI 22–55]）完全缓解，骨髓中未检测到 MRD。最常见的 3 级或 4 级血液学不良事件是中性粒细胞减少症（37 名患者中的 16 名 [43%]）。最常见的 3-4 级非血液学不良事件是高血糖（三个 [8%]）和低磷血症（三个 [8%]）。9 名 (24%) 患者发生严重不良事件；最常见的是三名 (8%) 患者的中性粒细胞减少症。没有在学习中死亡。

解释

Acalabrutinib、venetoclax 和 obinutuzumab 是一种高活性且耐受性良好的慢性淋巴细胞白血病一线疗法。尽管未达到本研究的主要终点，但骨髓中检测不到 MRD 的患者比例很高，支持对该方案的进一步研究，该方案​​正在一项正在进行的 3 期研究 (NCT03836261) 中针对 acalabrutinib-venetoclax 和化学免疫疗法进行测试.

资金

阿斯利康 (AstraZeneca) 和 Dana-Farber 癌症研究所合作奖。