Munir Talha, Girvan Sean, Cairns David A, Bloor Adrian, Allsup David, Varghese Abraham M, Gohil Satyen, Paneesha Shankara, Pettitt Andrew, Eyre Toby, Fox Christopher P, Forconi Francesco, Balotis Constantine, Pemberton Nicholas, Sheehy Oonagh, Gribben John, Elmusharaf Nagah, Gatto Simona, Preston Gavin, Schuh Anna, Walewska Renata, Duley Lelia, Webster Nichola, Dalal Surita, Rawstron Andrew, Howard Dena, Hockaday Anna, Jackson Sharon, Greatorex Natasha, Bell Sue, Stones David, Brown Julia M, Patten Piers E M, Hillmen Peter
Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
Leeds Cancer Research UK Clinical Trials Unit, University of Leeds, Leeds, United Kingdom.
N Engl J Med. 2025 Jun 15. doi: 10.1056/NEJMoa2504341.
An interim analysis of progression-free survival in this trial showed that ibrutinib-venetoclax was superior to fludarabine-cyclophosphamide-rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib-venetoclax is more effective than ibrutinib alone is unclear.
In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib-venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival.
A total of 172 of the 260 participants (66.2%) in the ibrutinib-venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib-venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib-venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib-venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib-venetoclax, ibrutinib-alone, and FCR groups, respectively.
With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib-venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).
本试验中无进展生存期的中期分析表明，在慢性淋巴细胞白血病（CLL）患者中，伊布替尼-维奈克拉优于氟达拉滨-环磷酰胺-利妥昔单抗（FCR）。伊布替尼-维奈克拉是否比单用伊布替尼更有效尚不清楚。
在这项3期、多中心、开放标签试验中，我们将CLL患者随机分配接受伊布替尼-维奈克拉、单用伊布替尼或FCR。主要终点是伊布替尼-维奈克拉组与单用伊布替尼组相比2年内骨髓中不可检测的可测量残留病（MRD），以及伊布替尼-维奈克拉组与FCR组相比的无进展生存期。一个有统计学效力的次要终点是伊布替尼-维奈克拉组与单用伊布替尼组相比的无进展生存期。其他次要终点包括总生存期。
伊布替尼-维奈克拉组260名参与者中有172名（66.2%）在2年内骨髓中MRD不可检测，相比之下，单用伊布替尼组的263名参与者中无一例（P<0.001），FCR组263名参与者中有127名（48.3%）。中位随访62.2个月时，伊布替尼-维奈克拉组有18名参与者（6.9%）发生疾病进展或死亡，相比之下，单用伊布替尼组有59名（22.4%）（风险比，0.29；95%置信区间[CI]，0.17至0.49；P<0.001），FCR组有112名（42.6%）（风险比，0.13；95%CI，0.08至0.21；P<0.001）。伊布替尼-维奈克拉组5年无进展生存率为93.9%，单用伊布替尼组为79.0%，FCR组为58.1%。伊布替尼-维奈克拉组有11名参与者（4.2%）死亡，相比之下，单用伊布替尼组有26名（9.9%）（风险比，0.41；95%CI，0.20至0.83），FCR组有39名（14.8%）（风险比，0.26；95%CI，0.13至0.50）。伊布替尼-维奈克拉组、单用伊布替尼组和FCR组分别有3名、8名和4名参与者猝死。
随着随访时间的延长和入组人数的增加，我们的试验表明，与单用伊布替尼或FCR相比，伊布替尼-维奈克拉更常出现不可检测的MRD和更长的无进展生存期。总生存期的结果也与伊布替尼-维奈克拉的益处一致。（由英国癌症研究基金会等资助；FLAIR国际标准随机对照试验注册号，ISRCTN01844152；欧盟临床试验注册号，2013-001944-76。）
