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.
Jonathan A Cook, Piers E M Patten, Nicholas Peckham, Paul Moss, Neil Phillips, Abhishek Abhishek, Thomas Roberts, Marie Hodges, Georgina Talbot, Vicki Barber, Anne Francis, Adrian M Shields, Lelia Duley, Robbert Hoogeboom, Brian J Willett, Sam Scott, Nilima Parry-Jones, Toby A Eyre, Gareth Plested, Gratian Vandici, Farooq Ahmad Wandroo, Claire Hutchinson, Shankara Paneesha, Duncan J Murray, Nicolas Martinez-Calle, Stephen Jenkins, Earnest Heartin, Helen M Parry
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引用次数: 0
Abstract
Background: Chronic lymphocytic leukaemia is the commonest leukaemia and is associated with profound immunosuppression. Bruton tyrosine kinase inhibitors (BTKi) have revolutionised chronic lymphocytic leukaemia management; however, therapy impairs vaccine-induced immunity. 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.
Methods: We performed an open-label, two-arm, parallel-group, randomised trial in secondary-care haematology clinics in 11 UK hospitals. 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. 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. 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. 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. This trial is registered with ISRCTN, 14197181, and has been completed.
Findings: 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. 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. The only serious adverse event during the 12-week follow-up was the death of one participant in the pause group due to COVID-19 infection 2 months after randomisation.
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.
Funding: National Institute for Health and Care Research.
期刊介绍：
Launched in autumn 2014, The Lancet Haematology is part of the Lancet specialty journals, exclusively available online. This monthly journal is committed to publishing original research that not only sheds light on haematological clinical practice but also advocates for change within the field. Aligned with the Lancet journals' tradition of high-impact research, The Lancet Haematology aspires to achieve a similar standing and reputation within its discipline. It upholds the rigorous reporting standards characteristic of all Lancet titles, ensuring a consistent commitment to quality in its contributions to the field of haematology.
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