Pausing BTK Inhibitors Does Not Strengthen COVID Vaccination in CLL

Patients with chronic lymphocytic leukemia (CLL) who are taking Bruton tyrosine kinase (BTK) inhibitors do not need to pause their medications when getting vaccinated against coronavirus disease 2019 (COVID-19), a new report has found.¹

Previous research had suggested that taking a 3-week pause from BTK inhibitors would improve SARS-CoV-2 antibody responses to vaccination, but the new report indicates that such a pause provides no significant benefit. The findings were published in The Lancet Hematology.

People with CLL were hit hard by the COVID-19 pandemic, largely due to their immunocompromised state, corresponding author Helen M. Parry, PhD, of the University of Birmingham, in the United Kingdom, and colleagues explained.

A study published in 2022 noted that patients with CLL had generally poor responses to COVID-19 vaccines, though approximately one-quarter of patients (23.8%) responded to a third dose (one beyond the standard 2-dose mRNA vaccine regimen).² Yet, the investigators in that study found that patients were considerably more likely to respond to vaccination if they were treatment-naive or off therapy. Patients on active therapy had just a 12% antibody response rate to a third dose of vaccine, compared with 40% among treatment-naive patients and 40.6% among off-therapy patients. In patients receiving active therapy with BTK inhibitors, the response rate was just 15.3%.

Parry and colleagues noted that BTK inhibitors are routinely stopped around the time of surgery to reduce bleeding risk.¹ That led some to wonder whether a short pause before and after COVID-19 vaccination might improve immunity and create time for antigen presentation and germinal center reactions to take place, the authors noted.

In the new study, Parry and colleagues tested that hypothesis by having a cohort of patients stop BTK inhibitors a week before booster vaccination and for an additional 2 weeks following vaccination

“We proposed that by pausing BTK [inhibitors], both the strength and functional quality of the antibody response would improve as BTK signaling was restored,” they wrote.

The investigators constructed an open-label, parallel-group, randomized trial based at 11 hospitals in the United Kingdom. Between October 2022 and June 2023, 99 people with CLL who were taking a BTK inhibitor were randomly assigned to pause (n = 50) or continue (n = 49) their therapy in the time around their vaccination. Three weeks after vaccination, their anti-spike-RBD–specific antibody titers were analyzed to see if there was any difference between the 2 groups.

The investigators found that, at 3 weeks, the geometric mean (SD) anti–spike-RBD-specific antibody titer was 218.8 (122.9) U/mL in patients continuing therapy and 153.4 (103.2) U/mL in patients who paused therapy. At 12 weeks, the authors reported just one serious adverse event: a patient in the pause group died as a result of COVID-19 infection 2 months after being randomized into the trial.

“A 3-week pause in BTKi therapy did not improve the antibody titer elicited by SARS-CoV-2 booster vaccination at 3 weeks or 12 weeks after vaccination,” Parry and colleagues wrote. “Instead, a highly heterogeneous response was observed with similar proportions of nonresponders in both groups.”

The authors noted that most people in the overall cohort had already had at least 4 vaccination doses, suggesting that a plateau had been reached in some patients. Still, the authors said there were surprising findings, including a finding that antibody titers were actually lower in patients receiving first-line BTK inhibitor therapy.

Overall, Parry and colleagues concluded these data showed considerable heterogeneity in how patients responded and that the results are intriguing and warrant further study.

While pausing therapy did not affect response to vaccination, the investigators noted that participants who paused therapy did have higher rates of self-reported lymphadenopathy, though other features of disease flare were similar in both groups.

Parry and colleagues cautioned that their study was small and “slightly” underpowered, so a potential benefit to pausing therapy cannot be completely ruled out. For now, though, the investigators concluded that while other precautions should continue, pausing BTK inhibitor therapy is not recommended.

References

1. Cook JA, Patten PEM, Peckham N, et al. 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. Lancet Haematol. 2025;12(4):e294-e303. doi:10.1016/S2352-3026(25)00008-0
2. Herishanu Y, Rahav G, Levi S, et al. Efficacy of a third BNT162b2 mRNA COVID-19 vaccine dose in patients with CLL who failed standard 2-dose vaccination. Blood. 2022;139(5):678-685. doi:10.1182/blood.2021014085