Review Emphasizes 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 must be proactively and closely monitored, even as the clinicians managing them implement prophylactic measures, the authors declared. 

Respiratory tract infections may occur in patients with CLL taking BTK inhibitors | image credit: Worldillustrator - stock.adobe.com

These tactics can include anything from the utilization of prophylactic antibiotics to vaccinations against prevalent pathogens, and certainly educating patients on hygiene practices to minimize exposure to infection. It’s also important to identify patient subgroups whose risk of infection is even further elevated, noted the authors, necessitating further refinement of BTK inhibitor treatment plans.

B-cell lymphomas include 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 hat does not dissipate the possibility of off-target effects—including those that can compromise immune system integrity and raise susceptibility to infection.² 

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

By the Numbers

The patients’ median age across studies ranged between 64 and 73 years. The authors calculated risk ratio (RR) using a random‐effects model in R Statistical Software.

The overall pooled RR for URTIs of any grade that were associated with BTK inhibitor treatment was statistically significant 1.55 (95% CI, 1.22-1.97; P < .05). Of 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 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 were statistically significant.

Why They’re Susceptible

BTK inhibitors undeniably offer targeted therapeutic benefits against B-cell lymphomas, disrupting the proliferation and survival of cancer cells. Yet instigating the modulation of BTK—a critical enzyme for B-cell development and for both innate and adaptive immune functions—means being 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 could be impaired, potentially facilitating both infection onset and progression.

BTK also has a regulatory influence on cytokine production, which is crucial to the orchestration of effective immune responses. Another result of its inhibition, then, could be that cytokine signaling is disrupted, further damaging the immune system’s capability to ward off infections, according to the authors.

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

Identifying the biomarkers that predict infection susceptibility would be a wise goal of future research, they stated. Another goal would be elucidating the specific molecular mechanisms that underpin increased infection risks in patients taking BTK inhibitors.

Of course, next-generation BTK inhibitors would ideally be characterized by enhanced specificity and fewer off-target effects—including those that affect infection risk. For now, balancing the benefits of BTK inhibition with the increased infection risk is an intricate, judicious process, the team acknowledged, particularly in the context of long-term therapy.

References

1. Zuber M, Borate 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