Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study
Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study
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DOI：
10.1182/blood-2014-12-617522
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发表时间：
2015-08-13
期刊：
影响因子：
20.3
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Jaglowski, Samantha M.;Jones, Jeffrey A.;Byrd, John C.
伊曲替尼代表了慢性淋巴细胞白血病（CLL）的治疗进展，但作为单一疗法，在既往治疗的患者中几乎没有完全缓解。抗CD20抗体与化疗联合使用可改善缓解和无进展生存期（PFS）。我们评估了在3种不同给药序列中将奥法木单抗添加至伊曲替尼的安全性和活性。招募了患有CLL/小淋巴细胞性淋巴瘤（SLL）、前淋巴细胞性白血病或Richter转化且先前治疗失败>= 2次的患者。患者在3个方案中接受了每日420 mg伊鲁替尼和12剂奥法木单抗300/2000 mg：伊鲁替尼导入（第1组; n = 5 27）、同时开始（第2组; n = 20）或奥法木单抗导入（第3组; n = 24）。71例患者接受了治疗;大多数患者患有高危疾病，包括del（17）（p13.1）（44%）或del（11）（q22.3）（31%）。最常见的不良事件（任何级别）为腹泻（70%）、输注相关反应（45%）和外周感觉神经病变（44%）。CLL/SLL患者（n 5 - 66）的总体缓解率分别为100%，79%和71%，第1，2和3组，分别。所有患者的估计12个月PFS分别为89%、85%和75%。第3组中有4例患者在接受伊鲁替尼治疗前发生疾病进展。这项研究证明了这种组合的耐受性和临床活性，与单药伊曲替尼相比，达到最佳缓解的时间更快，并且具有持久的缓解。
Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed >= 2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n 5 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n 5 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses.