BACKGROUND Patients with chronic lymphocytic leukaemia who progress to Richter transformation (diffuse large B-cell lymphoma morphology) have few therapeutic options. We analysed data from the Richter transformation cohort of a larger, ongoing, phase 1-2, single-arm study evaluating the safety and activity of the selective, irreversible Bruton's tyrosine kinase inhibitor acalabrutinib for the treatment of chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS For this open-label, single-arm, phase 1-2 study, patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) were assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. Patients were enrolled across seven centres from four countries. Safety and pharmacokinetics were assessed as primary endpoints; secondary endpoints were overall response rate, duration of response, and progression-free survival. Safety was assessed in the all-treated population (patients who received ≥1 dose), and activity was assessed in the all-treated population (for progression-free survival) and efficacy-evaluable population (for response rate; patients in the all-treated population with ≥1 response assessment after the first dose). This trial is registered with ClinicalTrials.gov (NCT02029443). FINDINGS Between Sept 2, 2014, and April 25, 2016, 25 patients with Richter transformation were enrolled; 12 (48%) were male and 23 (92%) were White. As of data cutoff (March 1, 2021), two (8%) of 25 patients remained on acalabrutinib. The median time on study was 2·6 months (IQR 1·8-8·4). The most common adverse events (all grades) were diarrhoea (12 [48%] of 25 patients), headache (11 [44%]), and anaemia (eight [32%]). The most common grade 3-4 adverse events were neutropenia (seven [28%] of 25) and anaemia (five [20%]). The most common reason for treatment discontinuation was disease progression (17 [68%] of 25 patients). 11 (44%) deaths were reported within 30 days of the last acalabrutinib dose; none was considered treatment-related. Acalabrutinib was rapidly absorbed and eliminated, with similar day 1 and day 8 exposures. The overall response rate was 40·0% (95% CI 21·1-61·3), with two (8%) of 25 patients having a complete response and eight (32%) having a partial response; the median duration of response was 6·2 months (95% CI 0·3-14·8). Median progression-free survival in the overall cohort was 3·2 months (95% CI 1·8-4·0). INTERPRETATION Acalabrutinib appears to be generally well tolerated, although progression-free survival was relatively poor in this cohort of patients with Richter transformation. On the basis of these findings, the use of acalabrutinib monotherapy in this setting is limited; however, further assessment of acalabrutinib as part of combination-based regimens for patients with Richter transformation is warranted. FUNDING Acerta Pharma, a member of the AstraZeneca Group.

中文翻译：

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Acalabrutinib 单药治疗慢性淋巴细胞白血病 (ACE-CL-001)：一项开放标签、单臂、1-2 期研究的 Richter 转化队列分析。

背景进展为 Richter 转化（弥漫性大 B 细胞淋巴瘤形态）的慢性淋巴细胞白血病患者几乎没有治疗选择。我们分析了一项更大的、正在进行的 1-2 期单臂研究的 Richter 转化队列的数据，该研究评估了选择性、不可逆的布鲁顿酪氨酸激酶抑制剂 acalabrutinib 治疗慢性淋巴细胞白血病或小淋巴细胞淋巴瘤的安全性和活性。方法 对于这项开放标签、单臂、1-2 期研究，年龄在 18 岁或以上且经活检证实未经治疗或既往接受过治疗的弥漫性大 B 细胞淋巴瘤（Richter 转化）或幼淋巴细胞白血病转化（东部肿瘤协作组体能状态≤2）的患者被分配接受口服 acalabrutinib 200 mg 每天两次作为单一疗法直到疾病进展或毒性。患者在来自四个国家的七个中心入组。安全性和药代动力学被评估为主要终点；次要终点是总反应率、反应持续时间和无进展生存期。在所有治疗人群（接受≥1剂的患者）中评估安全性，并在所有治疗人群（无进展生存期）和疗效可评估人群（缓解率；在第一次给药后有≥1 次反应评估的所有治疗人群中的患者）。该试验已在 ClinicalTrials.gov (NCT02029443) 注册。结果 2014 年 9 月 2 日至 2016 年 4 月 25 日，25 名 Richter 转化患者入组；12 人（48%）为男性，23 人（92%）为白人。截至数据截止（2021 年 3 月 1 日），25 名患者中有 2 名（8%）仍在使用阿卡布替尼。中位学习时间为 2·6 个月（IQR 1·8-8·4）。最常见的不良事件（所有级别）是腹泻（25 名患者中的 12 名 [48%]）、头痛（11 名 [44%]）和贫血（8 名 [32%]）。最常见的 3-4 级不良事件是中性粒细胞减少（25 例中的 7 例 [28%]）和贫血（5 例 [20%]）。停止治疗的最常见原因是疾病进展（25 名患者中的 17 名 [68%]）。11 例（44%）在最后一次阿卡布替尼给药后 30 天内报告死亡；没有一个被认为与治疗有关。Acalabrutinib 被迅速吸收和消除，第 1 天和第 8 天的暴露量相似。总体反应率为 40·0% (95% CI 21·1-61·3)，25 名患者中有 2 名 (8%) 完全反应，8 名 (32%) 部分反应；中位缓解持续时间为 6·2 个月 (95% CI 0·3-14·8)。整个队列的中位无进展生存期为 3·2 个月（95% CI 1·8-4·0）。解释 Acalabrutinib 似乎一般耐受性良好，尽管在这组 Richter 转化患者中无进展生存期相对较差。基于这些发现，在这种情况下使用阿卡拉布替尼单药治疗是有限的；然而，有必要进一步评估acalabrutinib作为Richter转化患者联合治疗方案的一部分。资助 Acerta Pharma，阿斯利康集团的成员。