A 3-week pause versus continued Bruton tyrosine kinase inhibitor use during COVID-19 vaccination in individuals with chronic lymphocytic leukaemia (IMPROVE trial): a randomised, open-label, superiority trial.

Bruton tyrosine kinase inhibitors (BTKi) have revolutionised chronic lymphocytic leukaemia management; however, therapy impairs vaccine-induced immunity.

Bruton酪氨酸激酶抑制剂（BTKi）彻底改变了慢性淋巴细胞白血病的管理；然而，治疗会损害疫苗诱导的免疫反应。

We evaluated whether a 3-week pause of BTKi treatment improved spike protein receptor binding domain (RBD) immunity to SARS-CoV-2 booster vaccination while maintaining disease control.

我们评估了在SARS-CoV-2加强疫苗接种期间暂停BTKi治疗3周是否能改善对刺突蛋白受体结合域（RBD）的免疫反应，同时保持疾病控制。

Methods

We performed an open-label, two-arm, parallel-group, randomised trial in secondary-care haematology clinics in 11 UK hospitals.

我们在英国11家医院的二级血液科诊所进行了一项开放标签、两臂、平行组、随机试验。

Participants aged 18 years or older, diagnosed with chronic lymphocytic leukaemia, and currently taking BTKi therapy (frontline or relapsed setting) for at least 12 months were eligible.

年龄在18岁或以上的参与者，被诊断为慢性淋巴细胞白血病，并且目前正在接受BTKi治疗（一线或复发设置）至少12个月，符合资格。

Participants were randomly allocated (1:1, by a centralised computer randomisation program, stratified by BTKi therapy line) to pause BTKi for 3 weeks, starting 6 days before their SARS-CoV-2 vaccination booster date, or to continue therapy as usual. Neither participants nor clinical staff were blinded but laboratory staff were.

参与者被随机分配（1:1，通过中央计算机随机化程序，按BTKi治疗线分层）在SARS-CoV-2疫苗加强剂接种日期前6天开始暂停BTKi治疗3周，或者继续按常规治疗。参与者和临床人员均未被蒙蔽，但实验室人员被蒙蔽。

Intramuscular injection of either original BA.1 or original BA.4/5 bivalent mRNA vaccine (50 μg mRNA-1273 or 30 μg BNT162b2), or 5 μg protein-based Vidprevtyn Beta (Sanofi Pasteur, Lyon, France) were received according to the national vaccination programme schedule.

受试者接受了原始BA.1或原始BA.4/5双价mRNA疫苗（50微克mRNA-1273或30微克BNT162b2）的肌肉注射，或按照国家疫苗接种计划接受了5微克基于蛋白的Vidprevtyn Beta（赛诺菲-巴斯德，法国里昂）的接种。

The primary outcome measure was anti-spike-RBD-specific antibody titre 3 weeks after vaccination and analysis performed by intention to treat (as randomly allocated, irrespective of compliance) following trial completion.

主要结果指标是接种疫苗后3周的抗刺突-RBD特异性抗体滴度，并在试验结束后按照意向治疗分析（按随机分配，无论是否遵守）进行分析。

This trial is registered with ISRCTN, 14197181, and has been completed.

该试验已在ISRCTN注册，编号为14197181，并已完成。

Results

Between Oct 10, 2022, and June 8, 2023, 99 individuals (71 [72%] male and 28 [28%] female, with 89 [90%] of White ethnicity) were randomly allocated to groups pausing (n=50 [51%]) or continuing (n=49 [49%]) their BTKi therapy, and followed up for 12 weeks.

在2022年10月10日至2023年6月8日期间，共有99名个体（男性71名[72%]，女性28名[28%]，其中89名[90%]为白人种族）被随机分配到暂停（n=50名[51%]）或继续（n=49名[49%]）BTKi治疗的组别，并进行了为期12周的随访。

At 3 weeks after vaccination, the geometric mean anti-spike-RBD-specific antibody titre was 218·8 U/mL (SD 122·9) in the continue group and 153·4 U/mL (103·2) in the pause group, with geometric mean ratio 1·104 (95% CI 0·565-2·158, p=0·77) using a mixed-effects model.

接种疫苗3周后，继续组的抗刺突-RBD特异性抗体几何平均滴度为218.8 U/mL（标准差122.9），暂停组为153.4 U/mL（标准差103.2），使用混合效应模型计算的几何平均比为1.104（95%置信区间0.565-2.158，p=0.77）。

The only serious adverse eventduring the 12-week follow-up was the death of one participant in the pause group due to COVID-19 infection 2 months after randomisation.

在12周的随访期间，唯一的严重不良事件是暂停组的一名参与者在随机分组后2个月因COVID-19感染死亡。

interpretation

Although the study was slightly underpowered, the results suggest that pausing BTKi around the time of vaccination is not beneficial for immunity and should not be recommended in clinical practice.

尽管该研究的统计功效略显不足，但结果表明，在接种疫苗期间暂停BTK抑制剂对免疫并无益处，因此不建议在临床实践中采用。

funding

National Institute for Health and Care Research.

国家健康与护理研究所