Immune response to COVID‐19 vaccination in patients with Waldenström macroglobulinaemia who pause their BTKi therapy

Abstract Patients with Waldenström macroglobulinaemia (WM) are at increased risk of severe COVID‐19 infection and have poor immune responses to COVID‐19 vaccination. This study assessed whether a closely monitored pause in Bruton's Tyrosine Kinase inhibitor (BTKi) therapy might result in an improved humoral response to a 3rd COVID‐19 vaccine dose. Improved response was observed in WM patients who paused their BTKi, compared to a group who did not pause their BTKi. However, the response was attenuated after BTKi recommencement. This data contributes to our understanding of vaccination strategies in this patient group and may help inform consensus approaches in the future.


INTRODUCTION
Patients with indolent lymphoma are at increased risk of severe COVID-19 disease [1]. Waldenström macroglobulinaemia (WM) is a rare type of non-Hodgkin's lymphoma characterised by malignant proliferation of lymphoplasmacytoid cells and monoclonal IgM secretion [2]. Patients with WM are at increased risk of SARS-CoV-2 infection due to underlying disease features and treatment related immunosuppression [3].
Bruton's Tyrosine Kinase inhibitors (BTKi) are utilised in the treatment of haematological malignancies including WM. These drugs irreversibly bind the BTK protein, impairing the B cell receptor signalling pathway and have a short therapeutic half-life [4]. It has been previously demonstrated that patients on BTKi therapy have reduced immunological responses to vaccination [5,6]. Several recent studies have shown poor response to COVID-19 vaccination in patients treated with BTKi for chronic lymphocytic leukaemia [7,8]. We previously reported poor generation of anti-spike IgG antibodies and low levels of live virus neutralisation in a prospective study of two doses of an mRNA COVID-19 vaccine in patients with WM on BTKi therapy [9].
Since our cohort was recruited, a 3rd COVID-19 vaccine was recommended to complete primary vaccination and provided further opportunity to assess, and potentially improve, vaccine immunogenicity. We hypothesised that a short pause in BTKi therapy might eventuate in a period of time where the patient's response to COVID-19 vaccination could be enhanced.

MATERIALS AND METHODS
The prospective TReatment Interruption of BTKi to Enhance COVID-19 Antibody response (TRIBECA) study was designed to assess anti-Spike IgG and virus neutralization responses to a 3rd COVID-19 vaccine dose in patients with WM willing to undergo a monitored pause in their BTKi therapy (N = 9) prior to and after the 3rd dose. The patients were originally recruited to a larger parent study commencing in 2021, which examined initial immune response to the first two COVID-19 vaccine doses. They were given information on the risks and benefits of pausing BTKi therapy and were subsequently given the option of participating in TRIBECA. We compared their response to WM patients in the parent study remaining on continuous BTKi (N = 8).
Patients with prior COVID-19 infection were not excluded. The study was approved by the Sydney Local Health District Human Research Ethics Committee and all subjects provided written informed consent prior to participation.
Immune response was measured prior to and up to 28 days after a 3rd vaccine dose, administered between October 2021 and February 2022. Immune response was also measured, in BTKi pause participants, up to 77 days after resuming BTKi. Humoral response to spike was measured by mean fluorescence intensity (MFI) of anti-SARS-CoV-2 spike antibodies (ASAb), obtained using a high-sensitivity flow cytom-etry cell assay, and live virus neutralization to a panel of SARS-CoV-2 variants of concern [12,13].

RESULTS
The median age in the BTKi pause group was 73 years, and six of nine were male. In the non-pause group, median age was 71 years, and seven of eight were male. In the BTKi pause group, six of nine were on zanubrutinib and three of nine on ibrutinib. In the non-pause group, five of eight were on zanubrutinib, and three of eight were on ibrutinib.

DISCUSSION
Our study demonstrates that patients with WM who paused their BTKi Despite these limitations, this study charts an improvement in humoral response to COVID vaccination after a pause in BTKi therapy.
While it may be reasonable to administer booster vaccination during scheduled BTKi pauses for other reasons, such as elective surgery, the declining humoral response on recommencement of BTKi in most patients suggests this may not be a worthwhile strategy to pursue a sustained immune response. Additionally, control of the patient's underlying haematological malignancy needs to be ensured as some studies have shown an increased risk of progressive disease associated with pauses in therapy [14].

CONCLUSION
A larger body of prospective data is warranted before any firm conclusions can be made and this study may lay a foundation for future research in maximising response to vaccination in this vulnerable patient cohort.