Mayo Clinic Cancer Center, Jacksonville, FL, USA.
Department I of Internal Medicine and German CLL Study Group, University of Cologne, Cologne, Germany.
Lancet Oncol. 2016 Feb;17(2):200-211. doi: 10.1016/S1470-2045(15)00465-9. Epub 2015 Dec 5.
Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma.
The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m(2) intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m(2) on day 1 of cycle 1, and 500 mg/m(2) on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090.
Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted.
In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile.
Janssen Research & Development.
大多数慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者在初始治疗后会复发。苯达莫司汀联合利妥昔单抗常用于复发或难治性疾病。我们评估了伊布替尼（一种 Bruton 酪氨酸激酶（BTK）的口服共价抑制剂）联合苯达莫司汀和利妥昔单抗在先前接受过治疗的慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者中的疗效和安全性。
HELIOS 试验是一项国际性、双盲、安慰剂对照的 3 期研究，纳入了年龄≥18 岁、有可测量的淋巴结疾病（CT 扫描时>1.5 cm）、既往接受过至少两周期化疗联合利妥昔单抗治疗的慢性淋巴细胞白血病或小淋巴细胞淋巴瘤患者，ECOG 体能状态为 0-1，骨髓、肝和肾功能充足。由于已知对苯达莫司汀联合利妥昔单抗反应不佳，因此排除了存在 17p 缺失的患者。先前接受过伊布替尼或其他 BTK 抑制剂治疗、在含有苯达莫司汀的方案中 24 个月内复发或难治、或进行过造血干细胞移植的患者也被排除在外。患者通过基于网络的系统按 1:1 比例随机分配接受苯达莫司汀联合利妥昔单抗治疗，每 4 周为一个周期（苯达莫司汀：第 1 周期第 2-3 天 70mg/m²，第 2-6 周期第 1-2 天 70mg/m²；利妥昔单抗：第 1 周期第 1 天 375mg/m²，第 2-6 周期第 1 天 500mg/m²，最多 6 个周期），联合伊布替尼（420mg 每日口服）或安慰剂，直至疾病进展或出现不可耐受的毒性。根据患者对嘌呤类似物的耐药情况和先前的治疗线数进行分层。主要终点是 IRC 评估的无进展生存期。对于 IRC 确认疾病进展的安慰剂组患者，允许交叉至伊布替尼治疗。分析按意向治疗进行，目前正在进行进一步的长期随访。该试验在 ClinicalTrials.gov 注册，编号为 NCT01611090。
2012 年 9 月 19 日至 2014 年 1 月 21 日，纳入了 578 名符合条件的患者，随机分配至伊布替尼或安慰剂联合苯达莫司汀和利妥昔单抗组（每组 289 名）。主要终点在预定的中期分析（2015 年 3 月 10 日）时达到。中位随访 17 个月（IQR 13.7-20.7）时，与安慰剂组相比，伊布替尼组的无进展生存期显著改善（伊布替尼组未达到（95%CI 无法评估），安慰剂组 13.3 个月（11.3-13.9）（HR 0.203，95%CI 0.150-0.276；p<0.0001）。IRC 评估的 18 个月无进展生存期，伊布替尼组为 79%（95%CI 73-83），安慰剂组为 24%（18-31）（HR 0.203，95%CI 0.150-0.276；p<0.0001）。最常见的所有级别不良反应为中性粒细胞减少和恶心。伊布替尼组 287 名患者中有 222 名（77%）和安慰剂组 287 名患者中有 212 名（74%）报告发生 3-4 级事件；两组中最常见的 3-4 级不良事件均为中性粒细胞减少（伊布替尼组 154 名[54%]，安慰剂组 145 名[51%]）和血小板减少（每组各 43 名[15%]）。与单独使用伊布替尼和苯达莫司汀联合利妥昔单抗时报告的安全性特征相似。
在有苯达莫司汀联合利妥昔单抗治疗适应证的患者中，与单独使用该方案相比，伊布替尼联合该方案可显著改善预后，且未发现新的安全性信号，安全性特征可管理。
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