来那度胺联合利妥昔单抗治疗复发或难治性套细胞淋巴瘤患者：一项 1/2 期临床试验。

Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial.

机构信息

Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

出版信息

Lancet Oncol. 2012 Jul;13(7):716-23. doi: 10.1016/S1470-2045(12)70200-0. Epub 2012 Jun 6.

DOI:10.1016/S1470-2045(12)70200-0

PMID:22677155

Abstract

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.

FUNDING

Celgene.

摘要

背景

利妥昔单抗联合来那度胺在临床前研究中显示出对套细胞淋巴瘤（MCL）的治疗潜力。我们旨在确定利来那度胺与利妥昔单抗联合使用的最大耐受剂量（MTD），并在复发或难治性 MCL 患者的 2 期试验中评估该联合用药的疗效和安全性。

方法

在 MD 安德森癌症中心进行的这项单臂、开放性、1/2 期试验中，招募了既往接受过 1-4 线治疗的复发或难治性 MCL 患者。在 1 期试验中，为了确定利来那度胺的 MTD，4 个患者队列接受了每日口服利来那度胺（剂量分别为 10、15、20 和 25 mg），每天一次，连续 21 天，每个 28 天周期。仅在第 1 周期中，每周给予 375 mg/m²静脉注射利妥昔单抗 4 次。在 2 期试验中，患者接受利妥昔单抗联合 1 期试验中确定的 MTD 利来那度胺，周期与 1 期相同。在疾病进展、干细胞移植或严重毒性发生之前，患者持续接受治疗。主要疗效终点是总缓解（完全或部分缓解）。次要疗效终点是生存。我们使用 Kaplan-Meier 法估计反应持续时间、无进展生存期和总生存期。分析采用意向治疗。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00294632。

结果

2006 年 2 月 10 日至 2009 年 7 月 30 日期间共纳入 52 例患者，其中 14 例在 1 期，44 例（包括 6 例在 1 期接受利来那度胺 MTD 的患者）在 2 期。MTD 为 20 mg 利来那度胺。1 例接受 25 mg 利来那度胺治疗的患者发生 4 级非中性粒细胞减少性感染并死亡。在研究的 2 期部分，3-4 级血液学毒性包括中性粒细胞减少（29 例）、淋巴细胞减少（16 例）、白细胞减少（13 例）和血小板减少（10 例）。仅发生 2 例发热性中性粒细胞减少症。在 44 例 2 期患者中，25 例（57%）有总体反应：16 例（36%）完全缓解，9 例（20%）部分缓解。反应持续时间的中位数为 18.9 个月（95%CI，17.0 个月至未达到[NR]）。无进展生存期的中位数为 11.1 个月（95%CI，8.3 个月至 24.9 个月），总生存期的中位数为 24.3 个月（19.8 个月至 NR）。在入组前接受硼替佐米治疗的 14 例患者中有 5 例获得了总体反应。