Burger Jan A, Keating Michael J, Wierda William G, Hartmann Elena, Hoellenriegel Julia, Rosin Nathalie Y, de Weerdt Iris, Jeyakumar Ghayathri, Ferrajoli Alessandra, Cardenas-Turanzas Marylou, Lerner Susan, Jorgensen Jeffrey L, Nogueras-González Graciela M, Zacharian Gracy, Huang Xuelin, Kantarjian Hagop, Garg Naveen, Rosenwald Andreas, O'Brien Susan
Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.
Lancet Oncol. 2014 Sep;15(10):1090-9. doi: 10.1016/S1470-2045(14)70335-3. Epub 2014 Aug 20.
Ibrutinib, an orally administered covalent inhibitor of Bruton's tyrosine kinase (BTK), is an effective treatment for relapsed chronic lymphocytic leukaemia (CLL). We investigated the activity and safety of the combination of ibrutinib with the monoclonal antibody rituximab in patients with high-risk CLL.
In this single-arm phase 2 study, we enrolled adult patients with high-risk CLL at the MD Anderson Cancer Center (Houston, TX, USA). All enrolled participants had high-risk cytogenetic abnormalities (deletion 17p, TP53 mutation, or deletion 11q) or a short progression-free survival (PFS <36 months) after previous first-line chemoimmunotherapy. Patients with symptomatic disease requiring therapy received 28-day cycles of once-daily ibrutinib 420 mg together with rituximab (375 mg/m(2), intravenously, every week during cycle 1, then once per cycle until cycle 6), followed by continuous daily single-agent ibrutinib 420 mg until disease progression or until toxicities or complications precluded further treatment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov number NCT01520519, and is no longer accruing patients.
Between Feb 28, 2012, and Sept 11, 2012, we enrolled 40 patients with CLL with high-risk disease features, 20 of whom had deletion 17p (del[17p]) or TP53 mutations (16 previously treated, four untreated), 13 had relapsed CLL with deletion 11q (del[11q]), and seven a PFS less than 36 months after first-line chemoimmunotherapy. 18-month PFS in all patients was 78·0% (95% CI 60·6-88·5), whereas in those with a del(17p) or TP53 mutation it was 72·4% (45·6-87·6) Toxicity was mainly mild to moderate in severity (grade 1-2). Diarrhoea occurred in ten (25%) patients (grade 1 in nine patients and grade 2 in one), bleeding events in 14 (33%) patients (eight grade 1 and five grade 2), nausea or vomiting in 15 patients (38%) (ten grade 1 and five grade 2), and fatigue in seven (18%) patients (four grade 1 and three grade 2). Five patients (13%) had grade 3 infections (two lung infections, one upper respiratory tract infection, one sepsis, and one mucositis), and no grade 4 or 5 infections occurred. One patient had grade 4 neutropenia.
The encouraging safety and activity of ibrutinib and rituximab in this population of patients with high-risk CLL merits further investigation of this combination.
Pharmacyclics Inc, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, National Cancer Institute, MD Anderson Cancer Center.
伊布替尼是一种口服的布鲁顿酪氨酸激酶（BTK）共价抑制剂，是复发慢性淋巴细胞白血病（CLL）的有效治疗方法。我们研究了伊布替尼与单克隆抗体利妥昔单抗联合应用于高危CLL患者的活性和安全性。
在这项单臂2期研究中，我们在美国德克萨斯州休斯顿市的MD安德森癌症中心招募了成年高危CLL患者。所有入组参与者都有高危细胞遗传学异常（17p缺失、TP53突变或11q缺失）或先前一线化疗免疫治疗后无进展生存期短（无进展生存期<36个月）。有症状且需要治疗的患者接受为期28天的疗程，每天一次口服伊布替尼420mg联合利妥昔单抗（375mg/m²，静脉注射，第1周期每周一次，然后每周期一次直至第6周期），随后持续每日单药伊布替尼420mg直至疾病进展或直至毒性或并发症妨碍进一步治疗。主要终点是意向性治疗人群的无进展生存期。本研究已在ClinicalTrials.gov注册，编号为NCT01520519，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例具有高危疾病特征的CLL患者，其中20例有17p缺失（del[17p]）或TP53突变（16例曾接受治疗，4例未治疗），13例复发CLL伴11q缺失（del[11q]），7例一线化疗免疫治疗后无进展生存期少于36个月。所有患者的18个月无进展生存率为78.0%（95%CI 60.6-88.5），而有del(17p)或TP53突变的患者为72.4%（45.6-87.6）。毒性主要为轻度至中度（1-2级）。腹泻发生在10例（25%）患者中（9例1级，1例2级），出血事件发生在14例（33%）患者中（8例1级，5例2级），恶心或呕吐发生在15例（38%）患者中（10例1级，5例2级），疲劳发生在7例（18%）患者中（4例1级，3例2级）。5例（13%）患者发生3级感染（2例肺部感染、1例上呼吸道感染、1例败血症和1例粘膜炎），未发生4级或5级感染。1例患者发生4级中性粒细胞减少。
伊布替尼和利妥昔单抗在该高危CLL患者群体中令人鼓舞的安全性和活性值得对这种联合用药进行进一步研究。
Pharmacyclics公司、德克萨斯州癌症预防与研究所、白血病与淋巴瘤协会、美国国立癌症研究所、MD安德森癌症中心。
