初治慢性淋巴细胞白血病的维奈托克联合治疗方案。
First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.
机构信息
From the Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne (B.E., M.F., C.Z., S.R., F.S., A.-M.F., J.B., K.F., K.A.K., M. Hallek), the Clinic for Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen (J.T.), the Division of Chronic Lymphocytic Leukemia, Department of Internal Medicine III, University of Ulm, Ulm (C.S., E.T., S.S.), Group Practice for Hematology and Oncology, Dresden (T.I.); the Hematology-Oncology Center, Würzburg (B.S.), Specialist Medical Practice of Hematology and Oncology, Mutlangen (H.H.), the Department of Hematology, Clinic for Hematology and Oncology, Centrum of Oncology, Brüderhospital St. Josef, Paderborn (T.G.), the Munich Clinic Schwabing, Academic Teaching Hospital, Ludwig Maximilian University, Munich (C.-M.W.); and the Department of Hematology, University Hospital Schleswig-Holstein, Campus Kiel (M.R., M. Brüggemann), Kiel - all in Germany; the Department of Hematology, Odense Rigshospitalet, Copenhagen University Hospital (C.U.N., C.C.-B., C.G.), and the Department of Hematology, Center for Cancer and Organ Diseases, Rigshospitalet (L.E.),Copenhagen, the Department of Hematology, Faculty of Medicine, Aalborg University Hospital, Aalborg (I.C.), the Department of Hematology, Zealand University Hospital, Roskilde (C.B.P.), and the Department of Hematology, Odense University Hospital, Odense (H.F.) - all in Denmark; the Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam (A.P.K., M.O.), the Department of Internal Medicine, Amphia Hospital, Breda (M.K.), the Department of Hematology, Maasstad Ziekenhuis, Rotterdam (M.B.L.L.), the Department of Hematology and Oncology, Medical Center Leeuwarden, Leeuwarden (M. Hoogendoorn), the Department of Hematology, St. Antonius Hospital Utrecht, Utrecht (H.K.), the Department of Hematology, Meander Medical Center, Amersfoort (J.C.R.), and the Department of Hematology, Albert Schweitzer Hospital, Dordrecht (M.-D.L.) - all in the Netherlands; the Department of Hematology, Luzerner Kantonsspital, Lucerne (M.G.), the Department of Hematology, Kantonsspital St. Gallen, St. Gallen (M. Baumann), the Department of Hematology, Clinic for Medical Oncology and Hematology, Kantonsspital Hospital Winterthur, Winterthur (J.G.), and the Department of Medical Oncology and Hematology Clinic, University Hospital Zürich, Zürich (A.W.) - all in Switzerland; the Department of Hematology, Lund University Cancer Center, Lund (G.J.), and the Department of Hematology, Linköping University Hospital, Linköping (K.L.) - both in Sweden; the Department of Hematology, Blackrock Health Member Hospitals, Hermitage Clinic, Dublin (P.T.); the Department of Medicine I, Division of Hematology and Hemostaseology (P.B.S.), the Department of Internal Medicine, University Hospital for Internal Medicine, Clinical Department of Hematology and Hemostaseology (U.J.), and the Comprehensive Cancer Center Vienna, Vienna General Hospital (P.B.S.), Medical University of Vienna, and the Department of Hematology and Oncology, Hanusch Hospital (T.N.) - both in Vienna; the Department of Hematology and Blood Bank, Bnai Zion Medical Center, Haifa, Israel (T.T.); the Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital, Helsinki (V.L.); the Department of Oncology, Universitair Ziekenhuis Leuven, Leuven, Belgium (A.J.); and the Department of Hematology, University College London, London (N.D.S.).
出版信息
N Engl J Med. 2023 May 11;388(19):1739-1754. doi: 10.1056/NEJMoa2213093.
BACKGROUND
Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking.
METHODS
In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival.
RESULTS
A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).
CONCLUSIONS
Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).
背景
在适合的（即合并症负担低的）晚期慢性淋巴细胞白血病（CLL）患者中，作为一线治疗，联合抗 CD20 抗体的维奈托克与化疗方案的随机临床试验尚缺乏。
方法
在一项 3 期、开放性试验中，我们按照 1:1:1:1 的比例，随机分配不伴有异常的适合的 CLL 患者，接受 6 个周期的化疗免疫治疗（氟达拉滨-环磷酰胺-利妥昔单抗或苯达莫司汀-利妥昔单抗）或 12 个周期的维奈托克-利妥昔单抗、维奈托克-奥滨尤妥珠单抗或维奈托克-奥滨尤妥珠单抗-伊布替尼。伊布替尼在两次连续检测到微小残留病（MRD）不可检测（灵敏度<10，即 10,000 个白细胞中<1 个 CLL 细胞）或可延长后停药。主要终点是在第 15 个月时通过外周血流式细胞术评估的不可检测的微小残留病（敏感性<10）和无进展生存期。
结果
共有 926 例患者被分配到四种治疗方案之一（229 例接受化疗免疫治疗，237 例接受维奈托克-利妥昔单抗，229 例接受维奈托克-奥滨尤妥珠单抗，231 例接受维奈托克-奥滨尤妥珠单抗-伊布替尼）。在第 15 个月时，与化疗免疫治疗组（52.0%，97.5%CI，44.4 至 59.5）相比，维奈托克-奥滨尤妥珠单抗组（86.5%，97.5%CI，80.6 至 91.1）和维奈托克-奥滨尤妥珠单抗-伊布替尼组（92.2%，97.5%CI，87.3 至 95.7）的患者中有不可检测的微小残留病的比例显著更高（P<0.001），但维奈托克-利妥昔单抗组（57.0%，97.5%CI，49.5 至 64.2）差异无统计学意义（P=0.32）。维奈托克-奥滨尤妥珠单抗-伊布替尼组和化疗免疫治疗组的 3 年无进展生存期分别为 90.5%和 75.5%（疾病进展或死亡的风险比，0.32；97.5%CI，0.19 至 0.54；P<0.001）。在 3 年时，维奈托克-奥滨尤妥珠单抗（风险比，0.42；97.5%CI，0.26 至 0.68；P<0.001）而非维奈托克-利妥昔单抗（风险比，0.79；97.5%CI，0.53 至 1.18；P=0.18）也有更高的无进展生存期。与化疗免疫治疗（18.5%）和维奈托克-奥滨尤妥珠单抗-伊布替尼（21.2%）相比，化疗免疫治疗（10.5%）和维奈托克-奥滨尤妥珠单抗（13.2%）更常见 3 级和 4 级感染。
结论
在适合的 CLL 患者中，与化疗免疫治疗相比，联合奥滨尤妥珠单抗或奥滨尤妥珠单抗-伊布替尼的维奈托克作为一线治疗更具优势。（由 AbbVie 等资助；GAIA-CLL13 临床试验注册编号，NCT02950051；EudraCT 编号，2015-004936-36。）
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