美国斯坦福大学医学院、加州大学尔湾分校等机构的科学家在研究中取得新进展。他们分析了依鲁替尼-利妥昔单抗或化学免疫治疗慢性淋巴细胞白血病的疗效。 该项研究成果发表在2019年8月1日出版的《新英格兰医学杂志》上。

在第三阶段临床试验中，研究组随机分配(2:1的比率)70岁或70岁以前未经治疗的慢性淋巴细胞白血病患者，接受依鲁替尼和利妥昔单抗6周期(独单周期依鲁替尼之后)，然后经依鲁替尼治疗直到疾病进展,或接受六个周期与氟达拉滨化疗,环磷酰胺,利妥昔单抗。主要终点为无进展生存期，总生存期为次要终点。该课题组研究人员报告计划进行的中期分析的结果。 共有529例患者接受随机分组(354例为依鲁替尼-利妥昔单抗组，175例为化学免疫治疗组)。 在33.6个月的中位随访中，无进展生存期分析结果显示，依鲁替尼-利妥昔单抗优于化疗免疫疗法(3年时为89.4% vs. 72.9%;进展或死亡的危险比为0.35;95%置信区间[CI]， 0.22 ~ 0.56;P < 0.001)，符合方案规定的中期分析疗效阈值。总体生存分析的结果也支持依鲁替尼-利妥昔单抗优于化疗免疫治疗(3年为98.8% vs. 91.5%;死亡危险比为0.17;95% CI, 0.05 ~ 0.54;术中,0.001)。 在亚组分析中，未发生免疫球蛋白重链可变区(IGHV)突变的患者，依鲁替尼-利妥昔单抗的无进展生存率优于化疗免疫疗法(3年生存率为90.7% vs. 62.5%;进展或死亡的危险比为0.26;95% CI, 0.14 - 0.50)。 ibrutinib-rituximab组3年无进展生存率为87.7%，化疗免疫治疗组为88.0%(进展或死亡的危险比为0.44;95% CI, 0.14 - 1.36)。 3级或更高级别（不论归因）的不良事件发生率在两组中相似（在接受依鲁替尼 - 利妥昔单抗治疗的352例[80.1％]中有282例，接受化学免疫治疗的158例[79.7％]中有126例），使用依鲁替尼 - 利妥昔单抗的3级或更高级别的感染性并发症不如化学免疫疗法（37例患者[10.5％]对32例[20.3％]，P <0.001）。

据了解，与标准的氟达拉滨、环磷酰胺和利妥昔单抗化疗免疫治疗相比，依鲁替尼-利妥昔单抗治疗先前未治疗的慢性淋巴细胞白血病(CLL)的疗效数据有限。

附：英文原文

Title: Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia

Author: Tait D. Shanafelt, M.D., Xin V. Wang, Ph.D., Neil E. Kay, M.D., Curtis A. Hanson, M.D., Susan O’Brien, M.D., Jacqueline Barrientos, M.D., Diane F. Jelinek, Ph.D., Esteban Braggio, Ph.D., Jose F. Leis, M.D., Ph.D., Cong C. Zhang, M.D., Steven E. Coutre, M.D., Paul M. Barr, M.D., et al.

Issue&Volume:Vol.381 No.5, 2019

Abstract: 

        BACKGROUND

Data regarding the efficacy of treatment with ibrutinib–rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.

METHODS

In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.

RESULTS

A total of 529 patients underwent randomization (354 patients to the ibrutinib–rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib–rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib–rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib–rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib–rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib–rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib–rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001).

CONCLUSIONS

The ibrutinib–rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813opens in new tab.)

DOI: 10.1056/NEJMoa1817073

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1817073