Review highlights potential infection risks with BTK inhibitors

Patients with B-cell lymphomas receiving Bruton tyrosine kinase (BTK) inhibitor monotherapy have a statistically significant increased risk of infections, particularly upper respiratory tract infections (URTIs), according to a recent publication in Hematological oncology.¹ These patients should be monitored proactively and closely, even if the physicians treating them implement prophylactic measures, the authors explain.

These tactics can include everything from the use of prophylactic antibiotics to vaccinations against common pathogens, and certainly educating patients on hygiene practices to minimize exposure to infections. It is also important to identify subgroups of patients whose risk of infection is even further increased, the authors noted, necessitating further refinement of BTK inhibitor treatment plans.

include B-cell lymphomas chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, follicular lymphoma, multiple myeloma and Waldenström macroglobulinemia. BTK inhibitors target malignant cells in these diseases, but this does not eliminate the possibility of off-target effects, including effects that may compromise the integrity of the immune system and increase susceptibility to infections.²

In their review/meta-analysis, the team included 18 reports on 12 studies (one phase 2, the rest phase 3). All studies were randomized controlled trials: each included patients with B-cell lymphoma treated with BTK inhibitor monotherapy, and each reported on infections in those patients.

By the numbers

The median age of patients in the studies ranged between 64 and 73 years. The authors calculated the risk ratio (RR) using a random effect model in R Statistical Software.

The overall pooled RR for URTIs of any grade associated with BTK inhibitor treatment was statistically significant: 1.55 (95% CI: 1.22-1.97; P <.05). Of the 1046 patients, 14 developed a URTI of grade 3 or higher, yielding an RR of 1.46 (95% CI, 0.61-3.54), which the authors noted was not statistically significant. For pneumonia, the pooled RR of any grade of infection was 1.20 (95% CI: 0.68-2.10) and for grade 3 or higher it was 1.12 (95% CI: 0.67-1.85 ); neither was statistically significant.

Why they are sensitive

BTK inhibitors provide distinctly targeted therapeutic benefits against B-cell lymphomas, disrupting cancer cell proliferation and survival. But directing modulation of BTK – a crucial enzyme for B cell development and for both innate and adaptive immune functions – means we need to be aware of its broader immunological implications.

BTK is involved in the signaling pathways of macrophages, neutrophils and dendritic cells. When BTK is inhibited, critical functions such as pathogen recognition and clearance may be compromised, potentially facilitating both initiation and progression of infection.

BTK also has a regulatory influence on cytokine production, which is crucial for the orchestration of effective immune responses. Thus, another consequence of its inhibition could be to disrupt cytokine signaling, further damaging the immune system’s ability to fend off infections, the authors said.

Infection rates and severity varied across the studies analyzed, the team noted. This “accentuates the heterogeneity of patient responses to BTK inhibitor therapy and underlines the multifaceted nature of infection risk, which may be influenced by factors such as disease characteristics, duration of treatment, and patient-specific demographics,” they wrote.

Identifying the biomarkers that predict susceptibility to infections would be a sensible goal of future research, she said. Another goal would be to elucidate the specific molecular mechanisms underlying increased infection risks in patients taking BTK inhibitors.

Of course, next-generation BTK inhibitors would ideally be characterized by increased specificity and fewer off-target effects, including effects that influence infection risk. For now, balancing the benefits of BTK inhibition with the increased risk of infection is a complicated, judicious process, the team acknowledged, especially in the context of long-term therapy.

References

1. Zuber M, Boraat SN, Gokhale P, et al. Bruton tyrosine kinase inhibitor monotherapy in B-cell lymphoma and risk of infection: a systematic review and meta-analysis of randomized controlled trials. Hematol Oncol. 2024;42(5):e3308. doi:10.1002/hon.3308

2. McDonald C, Xanthopoulos C, Kostareli E. The role of Bruton’s tyrosine kinase in the immune system and disease. Immunology. 2021;164(4):722-736. doi:10.1111/imm.13416