维奈托克联合奥滨尤妥珠单抗治疗伴有合并症的 CLL 患者

Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions.

机构信息

From Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf, University Hospital Cologne and University of Cologne (K.F., O.A.-S., J.B., A.-M.F., S. Robrecht, B.E., K.-A.K., M.H.), the Oncogeriatric Unit, Department of Geriatric Medicine, St. Marien Hospital (V.G.), CECAD (Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases) (M.H.), Center for Molecular Medicine Cologne (M.H.), Cologne, Department III of Internal Medicine, University Hospital Rostock, Rostock (S.B.), Department III of Internal Medicine, Ulm University, Ulm (E.T., S.S.), the Departments of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases, and Tropical Medicine, Klinikum Schwabing, Munich (C.-M.W.), Department II of Internal Medicine, Campus Kiel, University of Schleswig-Holstein, Kiel (M.R.), and the Department of Hematology, Oncology, and Rheumatology, Saarland University Medical School, Homburg (S.S.) - all in Germany; Roche Products, Welwyn Garden City, United Kingdom (M.T., M.D., S.W., K.H.); Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod, Russia (O.S.); the Division of Onco-Hematology, Santa Maria Terni Hospital, University of Perugia, Perugia, Italy (A.M.L.); the Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (J.P.-I.); the Haematology Department, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia (S.O.); First Internal Department, Multiprofile Hospital for Active Treatment Hristo Botev, Vratsa, Bulgaria (L.S.); the Hematology Department, Clinique Victor Hugo, Le Mans, France (K.L.D.); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (L.M.F.); the Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen (C.U.N.); Wellington Blood and Cancer Centre, Capital and Coast District Health Board, and Malaghan Institute of Medical Research, Wellington, New Zealand (R.W.); Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada (S. Robinson); Moores Cancer Center, University of California San Diego, San Diego (T.J.K.), and Genentech, South San Francisco (M.M.) - both in California; AbbVie, North Chicago, IL (R.H.); and the Department of Immunology, Laboratory Medical Immunology, Erasmus MC, Rotterdam, the Netherlands (A.W.L.).

出版信息

N Engl J Med. 2019 Jun 6;380(23):2225-2236. doi: 10.1056/NEJMoa1815281. Epub 2019 Jun 4.

DOI:10.1056/NEJMoa1815281

PMID:31166681

Abstract

BACKGROUND

The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.

METHODS

In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.

RESULTS

In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with deletion, mutation, or both and in patients with unmutated immunoglobulin heavy-chain genes. Grade 3 or 4 neutropenia occurred in 52.8% of patients in the venetoclax-obinutuzumab group and in 48.1% of patients in the chlorambucil-obinutuzumab group, and grade 3 or 4 infections occurred in 17.5% and 15.0%, respectively. All-cause mortality was 9.3% in the venetoclax-obinutuzumab group and 7.9% in the chlorambucil-obinutuzumab group. These differences were not significant.

CONCLUSIONS

Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).

摘要

背景

BCL2 抑制剂 venetoclax 已在慢性淋巴细胞白血病（CLL）患者中显示出活性，但它在 CLL 合并症患者中与其他药物联合使用的疗效尚不清楚。

方法

在这项开放标签、3 期试验中，我们研究了 venetoclax 和 obinutuzumab 在未经治疗的 CLL 合并症患者中的固定疗程治疗。累积疾病严重程度评分（评分范围为 0 至 56，分数越高表示器官系统功能受损越严重）大于 6 分或计算出的肌酐清除率小于 70ml/min 的患者被随机分配接受 venetoclax-obinutuzumab 或氯苯丁酸-obinutuzumab 治疗。主要终点是研究者评估的无进展生存期。还评估了每种方案的安全性。

结果

共有 432 名患者（中位年龄 72 岁；中位累积疾病严重程度评分 8 分；中位肌酐清除率 66.4ml/min）接受了随机分组，每组 216 名患者。中位随访 28.1 个月后，venetoclax-obinutuzumab 组发生 30 次主要终点事件（疾病进展或死亡），氯苯丁酸-obinutuzumab 组发生 77 次（风险比，0.35；95%置信区间 [CI]，0.23 至 0.53；P<0.001）。Kaplan-Meier 估计 venetoclax-obinutuzumab 组 24 个月无进展生存率为 88.2%（95%CI，83.7 至 92.6），明显高于氯苯丁酸-obinutuzumab 组的 64.1%（95%CI，57.4 至 70.8）。这一获益在 del、mut 或两者均有的患者以及未突变免疫球蛋白重链基因的患者中也观察到了。venetoclax-obinutuzumab 组 52.8%的患者发生 3 级或 4 级中性粒细胞减少症，氯苯丁酸-obinutuzumab 组为 48.1%，venetoclax-obinutuzumab 组发生 3 级或 4 级感染的患者分别为 17.5%和 15.0%。venetoclax-obinutuzumab 组的全因死亡率为 9.3%，氯苯丁酸-obinutuzumab 组为 7.9%。这些差异无统计学意义。