Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Department of Oncology, University of Oxford, Oxford, UK.
Lancet Haematol. 2021 Dec;8(12):e912-e921. doi: 10.1016/S2352-3026(21)00305-7. Epub 2021 Nov 1.
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.
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).
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).
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.
Acerta Pharma, a member of the AstraZeneca Group.
进展为里希特转化（弥漫大 B 细胞淋巴瘤形态）的慢性淋巴细胞白血病患者治疗选择有限。我们分析了一项更大规模、正在进行的、1-2 期、单臂研究中里希特转化队列的数据，该研究评估了选择性、不可逆布鲁顿酪氨酸激酶抑制剂阿卡鲁替尼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。
在这项开放标签、单臂、1-2 期研究中，年龄在 18 岁及以上、经活检证实未经治疗或先前经治的弥漫大 B 细胞淋巴瘤（里希特转化）或前淋巴细胞白血病转化（东部合作肿瘤学组表现状态≤2）的患者被分配接受口服阿卡鲁替尼 200mg，每日两次，作为单药治疗，直至疾病进展或毒性。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是主要终点；次要终点是总缓解率、缓解持续时间和无进展生存期。在所有治疗人群（接受了至少 1 剂治疗的患者）中评估安全性，在所有治疗人群（无进展生存期）和疗效可评估人群（缓解率；所有治疗人群中至少有 1 次缓解评估的患者）中评估疗效。该试验在 ClinicalTrials.gov 注册（NCT02029443）。
在 2014 年 9 月 2 日至 2016 年 4 月 25 日期间，共有 25 例里希特转化患者入组；12 例（48%）为男性，23 例（92%）为白人。截至数据截止日期（2021 年 3 月 1 日），25 例患者中有 2 例（8%）仍在接受阿卡鲁替尼治疗。研究中位时间为 2.6 个月（IQR 1.8-8.4）。最常见的不良事件（所有级别）为腹泻（25 例患者中的 12 例[48%]）、头痛（11 例[44%]）和贫血（8 例[32%]）。最常见的 3-4 级不良事件为中性粒细胞减少症（25 例患者中的 7 例[28%]）和贫血（5 例[20%]）。治疗停止的最常见原因是疾病进展（25 例患者中的 17 例[68%]）。在最后一次阿卡鲁替尼给药后 30 天内报告了 11 例（44%）死亡；无死亡被认为与治疗有关。阿卡鲁替尼吸收迅速，消除迅速，第 1 天和第 8 天的暴露量相似。总缓解率为 40.0%（95%CI 21.1-61.3），25 例患者中有 2 例（8%）达到完全缓解，8 例（32%）达到部分缓解；缓解持续时间的中位数为 6.2 个月（95%CI 0.3-14.8）。在整个队列中，无进展生存期的中位数为 3.2 个月（95%CI 1.8-4.0）。
阿卡鲁替尼似乎耐受性良好，尽管在这组里希特转化患者中无进展生存期相对较差。基于这些发现，阿卡鲁替尼单药治疗在这种情况下受到限制；然而，需要进一步评估阿卡鲁替尼作为里希特转化患者联合治疗方案的一部分。
阿卡塔制药，隶属于阿斯利康集团。
