Background

Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia.

Methods

We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m², days 1–3), cyclophosphamide (250 mg/m², days 1–3), and rituximab (375 mg/m² day 1 of cycle 1; 500 mg/m² day 1 of cycles 2–6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT02251548) and is ongoing.

Findings

Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50–58). At data cutoff, median follow-up was 16·5 months (IQR 10·6–34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23–0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%).

Interpretation

The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients.

Funding

Pharmacyclics and the Leukemia & Lymphoma Society.

中文翻译：

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依鲁替尼联合氟达拉滨、环磷酰胺和利妥昔单抗作为年轻慢性淋巴细胞白血病患者的初始治疗：一项单臂、多中心、2 期试验

 背景

氟达拉滨、环磷酰胺和利妥昔单抗 (FCR) 可以改善患有IGHV突变的年轻（年龄≤65 岁）健康的慢性淋巴细胞白血病患者的无病生存率。然而， IGHV未突变的患者很少有持久的反应。无论IGHV突变状态如何，依鲁替尼对慢性淋巴细胞白血病患者均有效，但需要持续治疗。我们假设限时的伊布替尼加 FCR 会在年轻健康的慢性淋巴细胞白血病患者中引起持久的反应。

 方法

我们在美国的七个地点进行了多中心、开放标签、非随机、单臂 2 期试验。我们招募了年龄为 65 岁或以下、患有先前未经治疗的慢性淋巴细胞白血病的患者。我们的初始队列（原始队列）不受预后标志物状态的限制，包括有 del(17p) 或TP53畸变的患者。方案修订后（2017 年 3 月 21 日），我们招募了一个额外的队列（扩展队列），其中包括没有 del(17p) 的患者。口服依鲁替尼（420 mg/天），持续 7 天，然后静脉注射氟达拉滨（25 mg/m ² ，第 1-3 天）、环磷酰胺（250 mg/m ² ，第 1 天），最多六个 28 天周期–3) 和利妥昔单抗（第 1 周期第 1 天 375 mg/ ^m2 ；第 2-6 周期第¹天 500 mg/m2）联合连续口服依鲁替尼（420 mg/天）。有反应者继续接受依鲁替尼维持治疗长达 2 年，2 年后骨髓中未检出微小残留病的患者能够停止治疗。主要终点是在最后一个周期的依鲁替尼加 FCR 治疗后 2 个月内达到完全缓解且骨髓中检测不到微小残留病的患者比例。根据方案对接受至少一剂研究治疗的所有患者进行分析。该试验已在 ClinicalTrials.gov (NCT02251548) 注册并正在进行中。

 发现

2014年10月23日至2018年4月23日期间，共有85名慢性淋巴细胞白血病患者入组。 83 名患者中的 4 名 (5%) 检测到 del(17p)，81 名患者中的 3 名 (4%) 发现TP53突变；两名患者同时具有 del(17p) 和TP53突变。患者的中位年龄为 55 岁 (IQR 50–58)。数据截止时，中位随访时间为 16·5 个月（IQR 10·6–34·1）。 85 名患者中，有 28 名患者 (33%, 95% CI 0·23–0·44) 在最后一个周期的依鲁替尼加 FCR 治疗后 2 个月内达到完全缓解且骨髓中未检出微小残留病（p=0·0035）仅 FCR 的历史价值为 20%）。在研究期间，85 名患者中有 71 名 (84%) 获得了骨髓中无法检测到的微小残留病的最佳缓解。一名患者出现疾病进展，一名患者死亡（依鲁替尼维持治疗 17 个月后心源性猝死，评估可能与依鲁替尼有关）。最常见的所有级别的毒性反应是血液学的，包括 63 名患者 (74%) 出现血小板减少、53 名患者 (62%) 出现中性粒细胞减少以及 41 名患者 (49%) 出现贫血。 3 级或 4 级非血液学严重不良事件包括 3 名患者 (4%) 发生 3 级心房颤动，以及 2 名患者 (2%) 发生 3 级耶氏肺孢子虫肺炎。

 解释

据我们所知，在不受预后标志物状态限制的慢性淋巴细胞白血病患者中，接受依鲁替尼加 FCR 治疗后骨髓中出现不可检测的微小残留病的患者比例是有史以来最高的。伊布替尼联合 FCR 有望作为一种限时联合治疗方案，用于年轻健康患者的慢性淋巴细胞白血病一线治疗。

 资金

药环学和白血病和淋巴瘤协会。