A multi-centre randomised controlled trial examining the effects of temporarily pausing Bruton Tyrosine Kinase inhibitor therapy to coincide with SARS-CoV-2 vaccination and its impact on immune responses in patients with Chronic Lymphocytic Leukaemia (including a nested mechanistic sub-study).

Research question Does a three-week pause of Bruton Tyrosine Kinase inhibitor (BTKi) treatment improve immune responses to SARS-CoV-2 vaccination in people with Chronic Lymphocytic Leukaemia (CLL)? Background CLL is the most common adult leukaemia in the UK and is associated with profound immunosuppression. Patients show increased susceptibility to COVID-19 and display impaired SARS-CoV-2 vaccine responses. BTKi drugs have revolutionised the management of CLL and are also used in other malignancies and some autoimmune diseases. However BTKi therapy inhibits normal B cell responses and our recent UK-wide study of COVID-19 vaccine responses in CLL identified BTKi treatment as the strongest predictor of low antibody response. BTKi therapy is associated with increased bleeding risk and is routinely paused peri-operatively without clinical impact. Pausing BTKi around the time of vaccination could improve COVID-19 vaccine responses leading to better protection against infection and severe disease. Aims To assess if a three-week pause of BTKi treatment improves the immune response to SARS-CoV-2 vaccination in CLL patients whilst maintaining disease control. Method Design A prospective 2-arm parallel group, multicentre randomised controlled trial and nested mechanistic study. Setting: Secondary care. Population Patients aged 18 and over, diagnosed with CLL and taking BTKi therapy for more than 12 months. Randomisation 1:1 individual randomisation stratified by 1st or subsequent line of therapy. Intervention Advice to pause BTKi therapy for 3 weeks (starting 1 week before vaccination) Comparator Continue daily BTKi therapy as usual. Outcomes Primary: 'Ä¢ Anti-spike-RBD-specific antibody titre 3 weeks post vaccination Secondary: 'Ä¢ Anti-spike-RBD-specific antibody titre at 12 weeks post vaccination 'Ä¢ T cell ELISpot response at baseline and 3 weeks post vaccination 'Ä¢ Neutralising titre at 50% and 90% against Wuhan and the current dominant variant 'Ä¢ Disease activity at baseline, week 3 and 12 post vaccination 'Ä¢ Quality of life at baseline and weeks 3 and 12 weeks post vaccination. 'Ä¢ Adherence (self-report) Mechanistic: 'Ä¢ B cell receptor signalling assay assessment of adherence and relationship to antibody generation. Research contact: 1. Pre-vaccine: consent, research assessments, disease activity, blood collection. 2. Randomisation (phone): reconfirm eligibility. 3. Weeks 1, 2 (SMS/phone): adherence to intervention 4. Weeks 3 and 12 post vaccine: research assessment, blood collection. Analysis: Multi-level mixed effects models adjusted for randomisation factors and important prognostic factors using the as randomised population. Sample size: 120 participants (60 in each arm) will allow detection of an absolute difference of 0.65SD effect size (mean difference of 0.97 log10 scale), using 90%, 2-sided a=5% and 15% loss to follow up. 20 participants (10 in each arm) will participate in the mechanistic sub-study and provide additional blood samples for B cell receptor signalling. Timelines for delivery (months) Set up: 1-3 Recruitment: 4-11. Follow up and laboratory analysis: 4-14. Data analysis and write-up 13-18. Anticipated impact and dissemination The results will be disseminated to patients, the public and to our supporting charities. Findings will be published in high impact journals, presented at international conferences and relayed to the JCVI, the BCUK Vaccine Taskforce and BCSH guideline writing group.