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.

Publication Date

2025-03-31

Publication Title

The Lancet Haematology

Volume

12

Issue

4

ISSN

2352-3026

Acceptance Date

2025-01-01

Deposit Date

2025-04-11

Funding

This study was managed by the Oxford Clinical Trials Research Unit. We would like to thank the participants, patient advisory group, data monitoring committee, trial steering committee, support staff, Oxford Clinical Trials Research Unit colleagues, and Birmingham Biomedical Research Centre for their time and involvement in the study; UK Research and Innovation and Blood Cancer UK for funding HP and MH for the ongoing scientific work associated with this trial (MR/X006891/1); and the Lymphoma and Leukaemia Society for supporting PEMP with a research programme grant (6631-21). We would also like to thank Dr Graham Mcilroy for his help in recruitment at the University Hospitals Birmingham NHS Foundation Trust. This study was funded by the National Institute for Health and Care Research (151892). The views expressed are those of the author(s) and not necessarily those of the National Institute for Health and Care Research or the UK Department of Health and Social Care.

First Page

294

Last Page

303

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