Low Serum IgE Levels Independently Associated With Increased CLL Risk

Adults with low serum immunoglobulin E (IgE) levels faced nearly double the hazard of developing chronic lymphocytic leukemia (CLL) compared with those with higher IgE levels. This association held after adjusting for a range of confounders, including hypogammaglobulinemia and atopy-related conditions, according to a study recently published in Frontiers in Immunology.¹

CLL is the most common adult leukemia in Western countries, the authors explain, and its pathophysiology is closely tied to immune dysfunction. IgE, an immunoglobulin class traditionally associated with allergic responses, has drawn growing interest for its potential role in hematologic malignancies. Prior studies suggested an inverse relationship between serum IgE levels and CLL risk, but those investigations were constrained by small sample sizes and inadequate adjustment for immunoglobulin deficiencies that may precede CLL onset.

The present study researchers conducted a retrospective quantitative observational study drawing on data from Clalit Health Services, a large Israeli health maintenance organization serving more than 4.8 million patients. The analysis included 118,740 adults aged 40 to 80 years who had at least 1 serum IgE measurement on record, and the index date for each patient was defined as the date of each patient’s first IgE measurement. Patients had to be diagnosed between January 1, 2004, and December 31, 2024.

The primary exposure was a baseline IgE level below 25 IU/mL, and the primary outcome of interest was time to CLL diagnosis over a 7-year follow-up period. Kaplan-Meier curves and a multivariable Cox proportional hazards model were used to assess the association between low IgE and CLL diagnosis. Covariates included age, sex, obesity, smoking, alcoholic cirrhosis, asthma, atopic dermatitis, allergic rhinitis, urticaria, hypogammaglobulinemia, immunoglobulin A deficiency, and immunoglobulin M deficiency. Hypogammaglobulinemia was defined as serum IgG below 700 mg/dL.

Key Study Findings

Out of the entire study population, 36,429 patients (30.7%) had IgE levels below 25 IU/mL, and 82,311 (69.3%) had IgE levels at or above that threshold. Over the 7-year follow-up, 224 CLL cases were identified: 105 in the low-IgE group and 119 in the higher-IgE group.

In the multivariable model, a serum IgE level below 25 IU/mL was associated with a significantly increased chances of developing CLL (HR, 1.94; 97.5% CI, 1.47-2.56), and this association remained statistically significant when the analysis was restricted to the period 2 to 7 years before diagnosis (HR, 1.83; 97.5% CI, 1.28-2.62) and when follow-up was extended to 10 years (HR, 1.93; 97.5% CI, 1.53-2.44). Established risk factors were also confirmed. Each year of older age (HR, 1.07; 97.5% CI, 1.05-1.08) and male sex (HR, 1.82; 97.5% CI, 1.38-2.40) were both independently associated with CLL risk.

Hypogammaglobulinemia in a patient—a condition in which low levels of immunoglobulins can increase the risk of infection and other illnesses²—at the index date was strongly associated with CLL in the primary model (HR, 4.09; 95% CI, 1.93-8.65), but this association did not hold when the index date was restricted to 2 to 7 years before diagnosis, a finding the authors interpreted as consistent with hypogammaglobulinemia being a later-stage consequence of CLL rather than a predisposing risk factor. By contrast, low IgE remained significantly associated with CLL risk across both timeframes.

At 3 years of follow-up, the risk ratio between the low-IgE and high-IgE groups was 0.398, reflecting a 60.2% relative risk reduction in the higher-IgE group. By 7 years, the risk ratio was 0.493, corresponding to a 50.7% relative risk reduction, a pattern the authors described as a sustained but attenuating protective association over time.

Real-World Implications

The authors situate their findings within the emerging field of “AllergoOncology,” which examines how immune processes traditionally linked to allergy may confer protection against certain cancers, and they highlight how their findings “provide supporting evidence regarding the role of serum IgE in the development of CLL.” Proposed mechanisms include IgE’s capacity to engage effector cells, such as monocytes, macrophages, and dendritic cells, through FcεRI receptors to mediate antibody-dependent cellular cytotoxicity and pro-inflammatory responses within the tumor microenvironment.

The authors acknowledge several limitations of the study, including its retrospective design, the absence of systematic IgE screening, and the potential for selection bias given that IgE measurements were clinically indicated rather than on a population-wide basis. Monoclonal B-cell lymphocytosis data were also unavailable.

They note that the 25 IU/mL threshold requires external validation before clinical application, and they call for prospective studies with broader IgE stratification to better define threshold effects and explore whether a shared genetic or epigenetic pathway may link reduced IgE production and CLL susceptibility.

“This work contributes to our understanding of the complex relationship between immune function and hematological malignancy,” the authors concluded. “They support the need for further study on the role of IgE in oncology, for example, to explore a potential causal link between IgE deficiency and CLL.”

References

1. Cohen R, Elbirt D, Nemet S, et al. Low serum IgE is associated with an increased risk of chronic lymphocytic leukemia: a large retrospective cohort study. Front Immunol. 2026:17:1772840. doi:10.3389/fimmu.2026.1772840
2. Hypogammaglobulinemia. Cleveland Clinic. Updated August 14, 2023. Accessed March 31, 2026. https://my.clevelandclinic.org/health/diseases/25195-hypogammaglobulinemia