伊布替尼用于早期慢性淋巴细胞白血病：随机、安慰剂对照、双盲、III期CLL12试验
Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial.
作者信息
Langerbeins Petra, Robrecht Sandra, Nieper Pascal, Cramer Paula, Fürstenau Moritz, Al-Sawaf Othman, Simon Florian, Fink Anna-Maria, Kreuzer Karl-Anton, Vehling-Kaiser Ursula, Tausch Eugen, Schneider Christof, Müller Lothar, Eckart Michael Josef, Schlag Rudolf, Freier Werner, Gaska Tobias, Balser Christina, Reiser Marcel, Stauch Martina, Zahn Mark-Oliver, Dörfel Steffen, Staib Peter, Behlendorf Timo, Hensel Manfred, Hebart Holger, Klaproth Holger, Block Andreas, Liersch Rüdiger, Hauch Ulrich, Heinrich Bernhard, Wendtner Clemens-Martin, Fischer Kirsten, Stilgenbauer Stephan, Eichhorst Barbara, Hallek Michael
机构信息
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
ÜBAG MVZ Dr Vehling-Kaiser GmbH, Landshut, Germany.
出版信息
J Clin Oncol. 2025 Feb;43(4):392-402. doi: 10.1200/JCO.24.00975. Epub 2024 Nov 27.
PURPOSE
The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies.
METHODS
The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments.
RESULTS
Ibrutinib significantly delayed progression to symptomatic disease ( < .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases ( = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group.
CONCLUSION
Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.
目的
CLL12试验在靶向治疗的背景下，重新评估了早期慢性淋巴细胞白血病（CLL）的观察等待共识。
方法
德国CLL研究组开展了一项随机、双盲、安慰剂对照的III期试验，363例无症状、未接受过治疗的Binet A期CLL患者，疾病进展风险增加，接受每日剂量420mg的依鲁替尼（n = 182）或安慰剂（n = 181）治疗。此外，152例低风险患者被分配到观察等待组。最终分析包括无事件生存期、无进展生存期、下次治疗时间、总生存期和安全性评估。
结果
依鲁替尼显著延迟了向有症状疾病的进展（P <.001；风险比，0.276 [95% CI，0.188至0.407]），但在中位观察时间69.3个月时，26例死亡病例未观察到生存获益（P =.562）。五年生存率极佳：依鲁替尼组为93.3%（95% CI，89.3至97.3），安慰剂组为93.6%（95% CI，89.5至97.7），观察等待队列中为97.9%（95% CI，95.6至100）。诊断后估计的10年生存率分别为：安慰剂组86.5%（95% CI，78.7至94.3），依鲁替尼组89.8%（95% CI，83.3至96.3），观察等待组95.3%（95% CI，91.1至99.4）。依鲁替尼组12例死亡中有1例与CLL相关，而安慰剂组14例CLL进展或Richter转化的致命病例中有4例。两个治疗组的不良事件和严重不良事件发生率分别为99.4%和60%。安全性分析表明依鲁替尼组心血管毒性增加。
结论
与安慰剂相比，依鲁替尼治疗早期CLL可延迟疾病进展。然而，在给定的观察时间和较少死亡病例的情况下，未显示出生存获益。在靶向治疗时代，无论风险因素如何，观察等待仍然是标准治疗方案。
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