From Ohio State University Comprehensive Cancer Center, Columbus (J.A.W., A.S.R., N.A.H., W.Z., K.A.R., G.L., J.S.B., H.G.O., J.C.B.); the Alliance Statistics and Data Center (A.S.R., A.M.B., B.M.-E., B.F., S.J.M.), Mayo Clinic (W.D., S.A.P., M.L.), Rochester, MN; Washington University School of Medicine, St. Louis (N.L.B.); Duke Cancer Institute, Duke University Medical Center, Durham (D.M.B., H.E.), and First Health of the Carolinas Cancer Center, Pinehurst (C.K.) - both in North Carolina; the University of Rochester Medical Center, Rochester, NY (P.M.B.); Stanford University School of Medicine, Stanford (S.C.), and the City of Hope Comprehensive Cancer Center, Duarte (A.H.) - both in California; Dana-Farber Partners CancerCare (J.R.B., R.M.S.) and the Massachusetts General Hospital Cancer Center (J.S.A.) - both in Boston; Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN (S.N.); University of Chicago Comprehensive Cancer Center (R.A.L.) and Loyola University Chicago (S.E.S.) - both in Chicago; the University of Calgary, Tom Baker Cancer Centre, Calgary, AB, Canada (C.O.); and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD (R.F.L.).
N Engl J Med. 2018 Dec 27;379(26):2517-2528. doi: 10.1056/NEJMoa1812836. Epub 2018 Dec 1.
Ibrutinib has been approved by the Food and Drug Administration for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) since 2016 but has not been compared with chemoimmunotherapy. We conducted a phase 3 trial to evaluate the efficacy of ibrutinib, either alone or in combination with rituximab, relative to chemoimmunotherapy.
Patients 65 years of age or older who had untreated CLL were randomly assigned to receive bendamustine plus rituximab, ibrutinib, or ibrutinib plus rituximab. The primary end point was progression-free survival. The Alliance Data and Safety Monitoring Board made the decision to release the data after the protocol-specified efficacy threshold had been met.
A total of 183 patients were assigned to receive bendamustine plus rituximab, 182 to receive ibrutinib, and 182 to receive ibrutinib plus rituximab. Median progression-free survival was reached only with bendamustine plus rituximab. The estimated percentage of patients with progression-free survival at 2 years was 74% with bendamustine plus rituximab and was higher with ibrutinib alone (87%; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.26 to 0.58; P<0.001) and with ibrutinib plus rituximab (88%; hazard ratio, 0.38; 95% CI, 0.25 to 0.59; P<0.001). There was no significant difference between the ibrutinib-plus-rituximab group and the ibrutinib group with regard to progression-free survival (hazard ratio, 1.00; 95% CI, 0.62 to 1.62; P=0.49). With a median follow-up of 38 months, there was no significant difference among the three treatment groups with regard to overall survival. The rate of grade 3, 4, or 5 hematologic adverse events was higher with bendamustine plus rituximab (61%) than with ibrutinib or ibrutinib plus rituximab (41% and 39%, respectively), whereas the rate of grade 3, 4, or 5 nonhematologic adverse events was lower with bendamustine plus rituximab (63%) than with the ibrutinib-containing regimens (74% with each regimen).
Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival. (Funded by the National Cancer Institute and Pharmacyclics; ClinicalTrials.gov number, NCT01886872 .).
伊布替尼于 2016 年被美国食品药品监督管理局批准用于治疗未经治疗的慢性淋巴细胞白血病（CLL）患者，但尚未与化疗免疫治疗进行比较。我们进行了一项 3 期试验，以评估伊布替尼单独使用或与利妥昔单抗联合使用相对于化疗免疫治疗的疗效。
65 岁及以上未经治疗的 CLL 患者被随机分配接受苯达莫司汀联合利妥昔单抗、伊布替尼或伊布替尼联合利妥昔单抗治疗。主要终点是无进展生存期。在达到协议规定的疗效阈值后，联盟数据和安全监测委员会决定发布数据。
共有 183 例患者接受苯达莫司汀联合利妥昔单抗治疗，182 例患者接受伊布替尼治疗，182 例患者接受伊布替尼联合利妥昔单抗治疗。仅苯达莫司汀联合利妥昔单抗达到无进展生存期。预计 2 年无进展生存率为 74%，伊布替尼单独治疗为 87%（疾病进展或死亡的风险比，0.39；95%置信区间[CI]，0.26 至 0.58；P<0.001），伊布替尼联合利妥昔单抗为 88%（风险比，0.38；95%CI，0.25 至 0.59；P<0.001）。伊布替尼联合利妥昔单抗组与伊布替尼组在无进展生存率方面无显著差异（风险比，1.00；95%CI，0.62 至 1.62；P=0.49）。中位随访 38 个月时，三组总生存率无显著差异。苯达莫司汀联合利妥昔单抗组（61%）与伊布替尼或伊布替尼联合利妥昔单抗组（分别为 41%和 39%）相比，3 级、4 级或 5 级血液学不良事件发生率较高，而苯达莫司汀联合利妥昔单抗组（63%）与伊布替尼组相比，3 级、4 级或 5 级非血液学不良事件发生率较低（每个方案的发生率均为 74%）。
在未经治疗的老年 CLL 患者中，伊布替尼治疗的无进展生存期优于苯达莫司汀联合利妥昔单抗。伊布替尼与伊布替尼联合利妥昔单抗在无进展生存率方面无显著差异。（由美国国立癌症研究所和 Pharmacyclics 资助；临床试验.gov 编号，NCT01886872）。
