Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study.
Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study.
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DOI：
10.1016/s1470-2045(14)70335-3
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发表时间：
2014-09
期刊：
影响因子：
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通讯作者：
O'Brien S
中科院分区：
文献类型：
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作者：
Burger JA;Keating MJ;Wierda WG;Hartmann E;Hoellenriegel J;Rosin NY;de Weerdt I;Jeyakumar G;Ferrajoli A;Cardenas-Turanzas M;Lerner S;Jorgensen JL;Nogueras-González GM;Zacharian G;Huang X;Kantarjian H;Garg N;Rosenwald A;O'Brien S
伊布替尼是一种口服的布鲁顿酪氨酸激酶（BTK）共价抑制剂，是治疗复发性慢性淋巴细胞白血病（CLL）的有效药物。我们研究了伊鲁替尼与单克隆抗体利妥昔单抗（iR）联合治疗高危CLL患者的活性和安全性。在这项单组、2期研究中，我们在美国德克萨斯州休斯顿的MD安德森癌症中心招募了40例高危CLL患者。需要治疗的症状性CLL患者接受28天周期的每日一次伊鲁替尼420 mg，以及利妥昔单抗（周期1期间每周一次，然后每个周期一次，直到周期6），然后连续单药伊鲁替尼。主要终点是意向治疗人群的无进展生存期（PFS）。本研究在ClinicalTrials.gov注册，编号NCT 01520519，不再招募患者。在2012年2月28日至2012年9月11日期间，我们招募了40名具有高危疾病特征的CLL患者。20例患者有del 17 p或TP 53突变（16例既往接受过治疗，4例未经治疗），13例患者有del 11 q复发性CLL，7例患者一线化疗免疫治疗后PFS < 36个月。毒性主要为轻度至中度（1-2级）。10例（25%）患者发生腹泻（9例[22.5%]患者为1级，1例[2.5%]患者为2级），14例（35%）患者发生出血事件（8例[20%]患者为1级，5例[12.5%]患者为2级，1例[2.5%]患者为3级），15例患者发生恶心37.5例患者（10例[25%] 1级，5例[12.5%] 2级），7例（17.5%）患者疲乏（4例[10%] 1级，3例[7.5%] 2级）。4例患者（10%）发生3级感染，无4级或5级感染。18个月时，Kaplan Meier估计的无进展生存期为78%（95% CI 60.6-88.5）（del[17 p]或TP 53突变：72%，95% CI：45.6-87.6），伊鲁替尼联合利妥昔单抗是一种耐受性良好的治疗方案，适用于高危CLL患者。它诱导高缓解率，并对这一难治性患者人群的生活质量产生积极影响。这些令人鼓舞的数据值得在一项正在进行的随机试验中进一步研究利妥昔单抗作为伊鲁替尼的联合伴侣的额外获益，该试验将伊鲁替尼单药与iR联合治疗进行比较（NCT 02007044）。Pharmacyclics，Inc.，得克萨斯州癌症预防和研究所（CPRIT），白血病和淋巴瘤协会，NCI赠款P30 CA 016672，MD安德森的CLL登月计划，和MD安德森癌症中心支持赠款CA 016672。
Ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), is an effective therapy for patients with relapsed chronic lymphocytic leukemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab (iR) in patients with high-risk CLL. In this single-arm, phase 2 studywe enrolled 40 patients with high-risk CLL at MD Anderson Cancer Center, Houston, Texas, USA. Patients with symptomatic CLL requiring therapy received 28 day cycles of once-daily ibrutinib 420 mg , together with rituximab (weekly during cycle 1, then once per cycle until cycle 6), followed by continuous single-agent ibrutinib. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01520519 and is no longer accruing patients. Between February 28, 2012 and September 11, 2012, we enrolled 40 CLL patients with high-risk disease features. 20 patients had del17p or TP53 mutations (16 previously treated, 4 untreated), 13 had relapsed CLL with del11q, and 7 patients a PFS < 36 months after frontline chemo-immunotherapy. Toxicity was mainly of mild to moderate severity (grade 1–2). 10 (25%) patients had diarrhea (grade 1 in 9 [22.5%] patients, grade 2 in 1 [2.5%]), bleeding events occurred in 14 (35%) patients (8 [20%] patients with grade 1, 5 [12.5%] patients grade 2, and 1 [2.5%] grade 3), nausea in 15 (37.5) patients (10 [25%] grade 1, 5 [12.5%] grade 2), and fatigue in 7 (17.5%) patients (4 [10%] grade 1, 3 [7.5%] grade 2). Grade 3 infections occurred in 4 patients (10%), no grade 4 or 5 infections occurred. At 18 months, the Kaplan Meier estimate of progression-free survival was 78% (95% CI 60.6–88.5) (del[17p] or TP53 mutation: 72%, 95% CI: 45.6–87.6) Ibrutinib in combination with rituximab is a well-tolerated regimen for patients with high-risk CLL. It induces high rates of remissions and has positive impact on QOL in this difficult-to-treat patient population. These encouraging data merit further investigation of the added benefit of rituximab as combination partner for ibrutinib in an ongoing randomized trial, in which single-agent ibrutinib is compared to iR combination therapy (NCT02007044). Pharmacyclics, Inc., Cancer Prevention and Research Institute of Texas (CPRIT), Leukemia & Lymphoma Society, NCI Grant P30 CA016672, MD Anderson’s Moon Shot Program in CLL, and MD Anderson Cancer Center Support Grant CA016672.