Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial.
Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial.
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DOI：
10.1016/s1470-2045(14)71182-9
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发表时间：
2015-02
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影响因子：
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通讯作者：
Wiestner A
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作者：
Farooqui MZ;Valdez J;Martyr S;Aue G;Saba N;Niemann CU;Herman SE;Tian X;Marti G;Soto S;Hughes TE;Jones J;Lipsky A;Pittaluga S;Stetler-Stevenson M;Yuan C;Lee YS;Pedersen LB;Geisler CH;Calvo KR;Arthur DC;Maric I;Childs R;Young NS;Wiestner A
具有TP53突变的慢性淋巴细胞白血病(CLL)患者对一线化疗免疫治疗的反应较差，导致早期复发和短期生存。我们研究了伊布鲁替尼在有TP53异常的初治和复发或难治性CLL中的安全性和活性。在这项由研究人员发起的单臂第2阶段研究中，我们在美国国立卫生研究院临床中心(美国马里兰州贝塞斯达)招募了符合条件的患有活动性CLL且存在TP53异常的成年患者。患者接受伊布鲁替尼420 mg的28天周期口服，每天一次，直到疾病进展或发生限定性毒性反应。主要终点是所有可评估患者在24周时对治疗的总体反应。这项研究已在ClinicalTrials.gov注册，编号NCT01500733，并已完全注册。在2011年12月22日至2014年1月2日期间，我们招募了51名患者；47名CLL患者缺失17p13.1，4名患者携带TP53突变，无17p13.1缺失。所有患者都有需要治疗的活动性疾病。35名入选患者以前没有接受过治疗，16名患者复发或难治性疾病。中位随访时间为24个月(IQR12.9~27.0)。33名未经治疗的患者和15名复发或难治性CLL患者在24周时可评估疗效。33例初治患者中32例(97%；95%可信区间86~100)达到客观缓解，其中部分缓解18例(55%)，部分缓解伴淋巴细胞增多14例(42%)。1例在术后0·4个月出现进展性疾病。15例复发或难治性CLL患者中有12例(80%；95%可信区间52~96)有客观反应：6例(40%)部分缓解，6例(40%)部分缓解伴淋巴细胞增多，其余3例(20%)病情稳定。与治疗相关的3级或更严重的不良事件有12例(24%)患者中性粒细胞减少(1例4级患者[2%])，7例贫血(14%)患者，5例(10%)患者(4级患者1例[2%])。3级肺炎3例(6%)，3级皮疹1例(2%)。单药伊布鲁替尼在具有TP53异常的慢性淋巴细胞白血病中的活性和安全性状况令人鼓舞，并支持其作为这种高危疾病患者的一线和二线环境下的新治疗选择。国家心肺血液研究所和国家癌症研究所、丹麦癌症学会、诺和诺德基金会、国家卫生研究院医学研究学者计划和药物环类公司的壁内研究计划。
Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations. In this investigator-initiated, single-arm phase 2 study we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov number NCT01500733, and is fully enrolled. Between Dec 22, 2011 and Jan 2, 2014 we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12·9-27·0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0·4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and thrombocytopenia in five (10%) patients (grade 4 in one [2%] patient). Grade 3 pneumonia occurred in three (6%) patients, and grade 3 rash in one (2%) patient. The activity and safety profile of single-agent ibrutinib in CLL with TP53 aberrations is encouraging and supports its consideration as a novel treatment option for patients with this high-risk disease in both first-line and second-line settings Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute, Danish Cancer Society, Novo Nordisk Foundation, National Institutes of Health Medical Research Scholars Program, and Pharmacyclics Inc.