Title: 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).
Funder: Medical Research Council

Abstract: What is CLL and how is it treated? Chronic lymphocytic leukaemia ('CLL') is a blood cancer that affects the white blood cells called lymphocytes. It is the commonest adult leukaemia, with 3,800 people diagnosed each year in the UK. It is more common in people aged over 60. Currently some 31,900 people have CLL in the UK. CLL develops slowly and there is no cure. People with CLL have a weakened immune system and are susceptible to infections. These infections can be severe and life-threatening. New drugs called Bruton Tyrosine Kinase inhibitors (BTKi) have transformed the outlook for CLL patients, however they stop the immune response to vaccination. They need to be taken daily and continuously. They are sometimes paused if a patient needs an operation. In the UK, they are used at all stages of treatment. What question will the study answer? Does pausing BTKi inhibitor drugs for a total of three weeks before and after having the COVID vaccine improve the antibody response and is this well tolerated? Why is this study important? In March 2020 everyone with CLL was advised to shield. To date, most people with CLL continue to shield as best they can. Advice from haematologists is to be as careful as possible. This means they are largely trapped in their homes, feeling increasingly left behind as the rest of society moves on. It is now COVID-19 that is restricting life for people with CLL and their families, rather than their CLL. The problem is people with CLL have very poor responses to COVID-19 vaccines in comparison to the general population. For those on BTKi inhibitor drugs, it is a double whammy as the drugs make it even more unlikely that patient will responsd to COVID-19 vaccination. As COVID-19 is here to stay, further vaccine doses are likely to be recommended for clinically vulnerable patients. A study is needed because improving the response to COVID-19 vaccination would help protect people with CLL and allow them to resume a more normal life. Also, the results of this study will hopefully be relevant to other recommended vaccinations for CLL patients, such as ‘flu and pneumococcus. What type of study is IMPROVE, and who will take part? We will invite adults with well-controlled CLL who have been taking a BTKi inhibitor for at least a year, and are due to have a COVID vaccine, to take part in IMPROVE. We will recruit 120 people at six hospital sites. Half (60) will be asked to pause their treatment for three weeks: one week before their vaccine, and two weeks after. The other half (60) will continue their treatment as usual. We will take blood samples to check everyone’s vaccine response three weeks and 12 weeks after vaccination. We will also monitor their CLL and ask participants to complete questionnaires about their quality of life. How are patients and members of the public involved? Improving vaccination responses has been a hot topic between clinicians and the CLL community for many years. COVID-19 has made this a priority. People with CLL have co-designed the IMPROVE study and will be partners in governing, managing and advising throughout the study. How and to whom will the results be communicated? We will publish results in academic journals, and share them with clinicians, policy makers, and people with CLL and their families by email or post. Working with the blood cancer charities, we will communicate our research findings to people with CLL, using newsletters, websites, social media and webinars.

Lay abstract: 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: • Anti-spike-RBD-specific antibody titre 3 weeks post vaccination Secondary: • Anti-spike-RBD-specific antibody titre at 12 weeks post vaccination • T cell ELISpot response at baseline and 3 weeks post vaccination • Neutralising titre at 50% and 90% against Wuhan and the current dominant variant • Disease activity at baseline, week 3 and 12 post vaccination • Quality of life at baseline and weeks 3 and 12 weeks post vaccination. • Adherence (self-report) Mechanistic: • 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.

Research activity codes: 3.4 VACCINES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS;INFECTION