Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial
Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial
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DOI：
10.1016/s1470-2045(12)70200-0
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发表时间：
2012-07-01
期刊：
影响因子：
51.1
通讯作者：
Romaguera, Jorge
中科院分区：
文献类型：
--
作者：
Wang, Michael;Fayad, Luis;Romaguera, Jorge
背景利妥昔单抗和来那度胺联合治疗套细胞淋巴瘤（MCL）的临床前研究显示出前景。我们的目的是确定来那度胺与利妥昔单抗联合应用时的最大耐受剂量（MTD），并在复发性或难治性MCL.Methods复发性或难治性MCL患者中评估该联合应用的疗效和安全性。在MD安德森癌症中心进行的1/2期试验。在1期研究中，为了确定来那度胺的MTD，4个患者队列在每个28天周期的第1-21天接受递增剂量（10、15、20和25 mg）的每日口服来那度胺。利妥昔单抗375 mg/m2静脉给药，每周4次，仅在第1周期给药。在第2阶段，患者接受利妥昔单抗加来那度胺的MTD，遵循与第1阶段相同的周期。两个阶段的治疗持续到疾病进展、干细胞移植或严重毒性。主要疗效终点为总体缓解（完全或部分缓解）。次要疗效终点为生存期。我们使用Kaplan-Meier方法估计缓解持续时间、无进展生存期和总生存期。本研究注册于ClinicalTrials.gov，编号NCT 00294632。结果52例患者于2006年2月10日至2009年7月30日期间入组，14例在I期，44例在II期（包括6例在I期部分接受来那度胺MTD的患者）。MTD为20 mg来那度胺。1例接受25 mg来那度胺治疗的患者发生4级非血小板减少性感染并死亡。在研究的II期部分，3-4级血液学毒性包括中性粒细胞减少症（29例患者）、淋巴细胞减少症（16例患者）、白细胞减少症（13例患者）和血小板减少症（10例患者）。仅发生了2次发热性中性粒细胞减少症。在II期的44例患者中，25例（57%）总体缓解：16例（36%）完全缓解，9例（20%）部分缓解。中位缓解持续时间为18.9个月（95% CI 17.0个月至未达到[NR]）。中位无进展生存期为11.1个月（95% CI 8.3至24.9个月），中位总生存期为24.3个月（19.8个月至NR）。五14例谁接受硼替佐米治疗前enrollment. Interpretation实现了整体responsibility. Oral来那度胺加利妥昔单抗是耐受性良好，有效的复发性或难治性MCL患者。
Background The combination of rituximab and lenalidomide has shown promise for the treatment of mantle-cell lymphoma (MCL) in preclinical studies. We aimed to identify the maximum tolerated dose (MTD) of lenalidomide when combined with rituximab in a phase 1 trial and to assess the efficacy and safety of this combination in a phase 2 trial in patients with relapsed or refractory MCL.Methods Patients with relapsed or refractory MCL who had received one to four previous lines of treatment were enrolled in this single-arm, open-label, phase 1/2 trial at MD Anderson Cancer Center. In phase 1, to identify the MTD of lenalidomide, four patient cohorts received escalating doses (10, 15, 20, and 25 mg) of daily oral lenalidomide on days 1-21 of each 28-day cycle. 375 mg/m(2) intravenous rituximab was also administered in four weekly doses during cycle 1 only. In phase 2, patients received rituximab plus the MTD of lenalidomide, following the same cycles as for phase 1. Treatment in both phases continued until disease progression, stem-cell transplantation, or severe toxicity. The primary efficacy endpoint was overall response (complete or partial response). The secondary efficacy endpoint was survival. We used the Kaplan-Meier method to estimate response duration, progression-free survival, and overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00294632.Findings 52 patients were enrolled between Feb 10, 2006 and July 30, 2009, 14 in phase 1 and 44 (including six patients who received the MTD of lenalidomide in the phase 1 portion) in phase 2. The MTD was 20 mg lenalidomide. One patient who was treated with 25 mg lenalidomide developed a grade 4 non-neutropenic infection and died. In the phase 2 portion of the study, grade 3-4 haematological toxicities included neutropenia (29 patients), lymphopenia (16 patients), leucopenia (13 patients), and thrombocytopenia (ten patients). There were only two episodes of febrile neutropenia. Among 44 patients in phase 2, 25 (57%) had an overall response: 16 (36%) had a complete response and nine (20%) had a partial response. The median response duration was 18.9 months (95% CI 17.0 months to not reached [NR]). The median progression-free survival was 11.1 months (95% CI 8.3 to 24.9 months), and the median overall survival was 24.3 months (19.8 months to NR). Five of 14 patients who had received bortezomib treatment before enrolment achieved an overall response.Interpretation Oral lenalidomide plus rituximab is well tolerated and effective for patients with relapsed or refractory MCL.