奥滨尤妥珠单抗联合苯丁酸氮芥治疗伴有合并症的 CLL 患者。

Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.

机构信息

From the German CLL Study Group, Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne (V.G., K.F., A.E., B.E., C.M.W., K.-A.K., M.H.), the Department for Geriatric Medicine and Research, St. Marien Hospital and University of Cologne, Cologne (V.G.), Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich (R.B.), Klinikum Schwabing, Munich (C.M.W.), private oncology practice, Dresden (T.I.), Medical Department II, University of Schleswig-Holstein, City Hospital Kiel, Kiel (M.R., M.K.), the Department of Internal Medicine III, Ulm University, Ulm (S.S., H.D.), and Cluster of Excellence "Cellular Stress Responses in Aging-Associated Diseases" (CECAD), University of Cologne, Cologne (M.H.) - all in Germany; Penza Regional Oncology Dispensary, Penza (T.C.), and Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod (O.S.) - both in Russia; Servicio De Hematologia, Hospital Universitario 12 De Octubre, Madrid (J.S.); Hôpital Haut Lévêque, Bordeaux, Pessac, France (M.-S.D.); the Department of Haematology, Monash Medical Centre, Clayton, Australia (S.O.); University of Calgary, Calgary, AB, Canada (C.J.O.); the Department of Immunology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands (A.W.L.); F. Hoffmann-La Roche, Basel, Switzerland (E.A.); F. Hoffmann-La Roche, Welwyn, United Kingdom (K.H.); and Genentech, South San Francisco, CA (M.W.).

出版信息

N Engl J Med. 2014 Mar 20;370(12):1101-10. doi: 10.1056/NEJMoa1313984. Epub 2014 Jan 8.

DOI:10.1056/NEJMoa1313984

PMID:24401022

Abstract

BACKGROUND

The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions.

METHODS

We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival.

RESULTS

The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased.

CONCLUSIONS

Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).

摘要

背景

单克隆抗 CD20 抗体利妥昔单抗联合化疗药物，已被证明可延长身体状况良好的初治慢性淋巴细胞白血病（CLL）患者的总生存期，但对同时存在合并症的患者无效。我们研究了与利妥昔单抗相比，糖基化工程抗体奥滨尤妥珠单抗（也称为 GA101）联合氯苯丁酸在患有初治 CLL 且同时存在合并症的患者中的获益。

方法

我们随机分配 781 名患有初治 CLL 和累积疾病评分量表（CIRS）评分高于 6 分（范围为 0 至 56，分数越高表示健康状况越差）或估计肌酐清除率为 30 至 69 ml/分钟的患者接受氯苯丁酸、奥滨尤妥珠单抗联合氯苯丁酸或利妥昔单抗联合氯苯丁酸治疗。主要终点是研究者评估的无进展生存期。

结果

患者的中位年龄为 73 岁，肌酐清除率为 62 ml/分钟，基线时 CIRS 评分为 8 分。与氯苯丁酸单药治疗相比，奥滨尤妥珠单抗联合氯苯丁酸或利妥昔单抗联合氯苯丁酸治疗可提高缓解率并延长无进展生存期（奥滨尤妥珠单抗联合氯苯丁酸治疗的无进展生存期中位数为 26.7 个月，氯苯丁酸单药治疗为 11.1 个月；进展或死亡风险比为 0.18；95%置信区间[CI]为 0.13 至 0.24；P<0.001；利妥昔单抗联合氯苯丁酸治疗的无进展生存期中位数为 16.3 个月，氯苯丁酸单药治疗为 11.1 个月；风险比为 0.44；95%CI 为 0.34 至 0.57；P<0.001）。与氯苯丁酸单药治疗相比，奥滨尤妥珠单抗联合氯苯丁酸治疗可延长总生存期（死亡风险比为 0.41；95%CI 为 0.23 至 0.74；P=0.002）。与利妥昔单抗联合氯苯丁酸治疗相比，奥滨尤妥珠单抗联合氯苯丁酸治疗可延长无进展生存期（风险比为 0.39；95%CI 为 0.31 至 0.49；P<0.001）和更高的完全缓解率（20.7%比 7.0%）和分子缓解率。奥滨尤妥珠单抗联合氯苯丁酸治疗比利妥昔单抗联合氯苯丁酸治疗更常见输注相关反应和中性粒细胞减少症，但感染风险并未增加。