Patients with B-cell lymphomas receiving Bruton’s 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 proactively and closely monitored, even if their managing clinicians are implementing prophylactic measures, the authors said.

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

These tactics can include anything from the use of prophylactic antibiotics to vaccinations against prevalent pathogens and certainly educating patients about hygiene practices to minimize exposure to infection. It is also important to identify subgroups of patients whose risk of infection is even higher, the authors noted, 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 eliminate the possibility of off-target effects, including those that may compromise the integrity of the immune system and increase 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 infections in these patients.

By the numbers

The mean age of patients in the studies ranged from 64 to 73 years. The authors calculated the risk ratio (RR) using a random effects model in R Statistical Software.

The pooled overall 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 grade 3 or higher URTI, 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 greater was 1.12 (95% CI, 0.67-1 .85); none were statistically significant.

Why are they susceptible?

BTK inhibitors undoubtedly provide targeted therapeutic benefit against B-cell lymphomas by disrupting cancer cell proliferation and survival. However, instigating modulation of BTK—an enzyme critical for B-cell development and for innate and adaptive immune functions—means being aware of its broader immunological implications.

BTK is involved in macrophage, neutrophil and dendritic cell signaling pathways. When BTK is inhibited, critical functions such as pathogen recognition and clearance could be impaired, facilitating both the onset and progression of infection.

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

Rates and severity of infection varied across the studies reviewed, the team noted. This “highlights 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, duration of treatment, and patient-specific demographics,” they wrote.

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

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

reference

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