Immune Profiling May Help Gauge Infection Risk in Patients With CLL

Protein and RNA analysis can shed light on infection risk among people with chronic lymphocytic leukemia (CLL) receiving immune-based therapies, according to a new report.¹ The findings, which were published in Clinical & Translational Immunology, are based on a small cohort and need to be validated in a larger trial, the authors cautioned. If validated, the findings could have implications for patient monitoring and personalized care.

Corresponding author Benjamin W. Teh, MBBS, PhD, of the University of Melbourne, and colleagues noted that targeted therapies like Bruton tyrosine kinase (BTK) inhibitors have led to improved outcomes in patients with CLL. However, the authors added that such therapies can have a significant but variable impact on the immune system.

“With patients living longer and the nature of these therapeutics, infections remain a leading cause of morbidity and mortality,” they wrote.

One analysis, published in 2020, found that 26% of patients with CLL receiving first-line ibrutinib experienced grade 3 or above infections. The rate was significantly higher in patients with relapsed or refractory disease, 55% of whom experienced grade 3 or above infections.² 

Teh and colleagues added that the risk of infection appears to be highest within the first 12 months after initiating therapy.¹ While a significant amount of data show that infections are a major concern for people with CLL, there is not yet a clear method of identifying which individual patients are at the highest risk, they said.

Teh and colleagues hypothesized that comprehensive immune profiling might enable the creation of patient-specific risk profiles. Such profiles could then allow clinicians to come up with personalized infection-prevention strategies. The investigators noted that previous research has suggested that such profiling can be effective in the setting of multiple myeloma, though they said that immune signatures identified as meaningful in one hematologic malignancy are unlikely to be universally meaningful across all hematological malignancies.

The investigators constructed a pilot study in which 28 patients with relapsed or refractory CLL who were treated with ibrutinib were included. Peripheral blood mononuclear cells were collected from each participant at baseline and 3 and 6 months following the initiation of ibrutinib therapy. Those samples were analyzed using Luminex and RNA sequencing. The resulting Luminex and gene expression profiles were then compared to see if there were differences between patients who went on to develop an infection and patients who did not.

Over 9 months of monitoring, 13 patients developed an infection. There were 17 infection events, of which 18.1% were severe (grade 3 or above). Most of the infections (72.7%) were clinically diagnosed; 18.1% of infections were bacterial, and 9.2% were viral. Just over half of the infections (54.5%) involved the respiratory tract, and 36.3% involved the skin and soft tissue.

The analysis found that ibrutinib had no effect on relative cell populations in the 6 months included in the study. There did not appear to be a link between cell counts and infection risk. Yet, they also found that patients with an inflammatory transcriptome profile at 3 months had a greater risk of an infection. They also found that whole protein response to phorbol myristate acetate (PMA) stimulation was associated with infection risk.

The investigators said their findings suggest that protein and RNA analysis might help clinicians better assess individual patient risk. However, they noted that the findings were based on a small set of patients, and therefore their approach would need to be validated in larger, prospective studies.

References

1. Williams LJ, Li-Wai-Suen CS, Garnham AL, et al. Elucidating novel immune profiles for predicting infection in high-risk cohorts: a pilot study in patients with relapsed and refractory chronic lymphocytic leukaemia. Clin Transl Immunology. 2025;14(8):e70049. doi:10.1002/cti2.70049

2. Byrd JC, Furman RR, Coutre SE, et al. Ibrutinib treatment for first-line and relapsed/refractory chronic lymphocytic leukemia: final analysis of the Pivotal Phase Ib/II PCYC-1102 study. Clin Cancer Res. 2020;26(15):3918-3927. doi:10.1158/1078-0432.CCR-19-2856