基于微小残留病灶评估的慢性淋巴细胞白血病治疗策略

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease.

机构信息

From the Department of Clinical Hematology (T.M., P.H.) and the Hematological Malignancy Diagnostic Service (N.W., S.D., R.T., A.R.), Leeds Cancer Centre, and the Leeds Cancer Research UK Clinical Trials Unit (D.A.C., D.H., A.H., S.J., N.G., S.G., S.B., J.M.B.) and Leeds Institute of Medical Research (N.W., S.D., P.H.), University of Leeds, Leeds, the Christie Hospital NHS Foundation Trust and the University of Manchester, Manchester (A.B.), Hull University Teaching Hospitals NHS Trust, Hull (D.A.), University College London Hospitals NHS Foundation Trust (K.C.), the Comprehensive Cancer Centre, King's College London (P.E.M.P.), King's College Hospital NHS Foundation Trust (P.E.M.P.), and Barts Health NHS Trust (J.G.), London, the Clatterbridge Cancer Centre NHS Foundation Trust and the University of Liverpool, Liverpool (A.P.), University Hospitals Birmingham NHS Foundation Trust, Birmingham (S.P.), Nottingham University Hospitals NHS Trust, Nottingham (C.P.F), Oxford University Hospitals NHS Foundation Trust, Oxford (T.A.E., A.S.), Cancer Sciences, Faculty of Medicine, University of Southampton and the Hematology Department, Cancer Care Directorate, University Hospital Southampton NHS Foundation Trust, Southampton (F.F.), University Hospital of Wales, Cardiff (N.E.), University Hospitals of Leicester NHS Trust, Leicester (B.K.), Worcestershire Acute Hospitals NHS Trust, Worcester (N.P.), Belfast City Hospital, Belfast (O.S.), Aberdeen Royal Infirmary, Aberdeen (G.P.), University Hospitals Dorset NHS Foundation Trust, Bournemouth (R.W.), and CLL Support, Chippenham (L.D.) - all in the United Kingdom.

出版信息

N Engl J Med. 2024 Jan 25;390(4):326-337. doi: 10.1056/NEJMoa2310063. Epub 2023 Dec 10.

DOI:10.1056/NEJMoa2310063

PMID:38078508

Abstract

BACKGROUND

The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear.

METHODS

In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety.

RESULTS

A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%).

CONCLUSIONS

MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

摘要

背景

与化疗免疫治疗相比，伊布替尼联合维奈托克可改善慢性淋巴细胞白血病（CLL）患者的预后。伊布替尼-维奈托克联合治疗以及根据可测量残留疾病（MRD）确定的治疗持续时间的个体化是否比氟达拉滨-环磷酰胺-利妥昔单抗（FCR）更有效尚不清楚。

方法

在这项涉及未经治疗的 CLL 患者的 3 期、多中心、随机、对照、开放标签平台试验中，我们比较了伊布替尼-维奈托克和伊布替尼单药与 FCR。在伊布替尼-维奈托克组中，在伊布替尼治疗 2 个月后，添加维奈托克进行长达 6 年的治疗。伊布替尼-维奈托克治疗的持续时间根据外周血和骨髓中检测到的 MRD 定义，并双倍于达到不可检测的 MRD 所需的时间。主要终点是与 FCR 组相比，伊布替尼-维奈托克组的无进展生存期，这是本次报告的结果。关键次要终点是总生存期、反应、MRD 和安全性。

结果

共有 523 名患者被随机分配至伊布替尼-维奈托克组或 FCR 组。在中位随访 43.7 个月时，伊布替尼-维奈托克组中有 12 例患者和 FCR 组中有 75 例患者发生疾病进展或死亡（风险比，0.13；95%置信区间[CI]，0.07 至 0.24；P<0.001）。伊布替尼-维奈托克组中有 9 例患者死亡，FCR 组中有 25 例患者死亡（风险比，0.31；95%CI，0.15 至 0.67）。在 3 年时，伊布替尼-维奈托克组中有 58.0%的患者因无法检测到 MRD 而停止治疗。在接受 5 年伊布替尼-维奈托克治疗后，65.9%的患者骨髓中无法检测到 MRD，92.7%的患者外周血中无法检测到 MRD。伊布替尼-维奈托克组和 FCR 组的感染风险相似。伊布替尼-维奈托克组发生心脏严重不良事件的患者比例高于 FCR 组（10.7%比 0.4%）。