Hypogammaglobulinemia in CLL: Analysis of clinical and laboratory correlates

Abstract Background: Hypogammaglobulinemia is commonly noted in chronic lymphocytic leukemia (CLL) patients, predisposing patients to infections, sepsis and increased morbidity. Prior studies have reported associations between hypogammaglobulinemia and risk factors such as the presence of high-risk cytogenetic abnormalities and longer disease duration. We conducted a retrospective study to evaluate clinical and laboratory risk factors associated with the presence of hypogammaglobulinemia in CLL patients which may help guide risk stratification for infectious complications and subsequent management. Methods: We assessed 44 CLL patients for serum immunoglobulin levels (IgG, IgA, IgM) along with clinical and laboratory parameters, including absolute lymphocyte count (ALC), Rai and Binet staging, age, sex, treatment history, comorbidities, and infection history. Hypogammaglobulinemia was defined as low IgG, IgA or IgM based on established laboratory thresholds. Statistical analysis included both multivariate and univariate comparisons using STATA. Fisher's exact tests were used for small cell counts. Odds ratios were calculated to identify risk factors associated with increased risk of hypogammaglobulinemia. Results: The mean age of the patients was 70 years with 16 females (36.4%). The mean time since diagnosis for the cohort was 6.8 years. Thirty-two out of the 44 patients (72.7%) had not yet started treatment for CLL. Hypogammaglobulinemia was observed in 33 (75%) patients. IgG, IgA and IgM deficiencies were present in 39%, 27% and 68% of patients, respectively. Twenty-one patients (47.7%) had been diagnosed with CLL for less than 5 years. ALC > 15 × 10⁹/L was found in 19/44 (43.2%) patients. Sixteen patients (36.4%) had a history of infections either requiring hospitalization or treatment with outpatient antibiotics in the previous 12 months. In multivariate logistic regression, we included ALC > 15 x 10^9/ L, age, sex, treatment history, infection history, time since diagnosis and Rai staging > 0. ALC greater than 15 x 10^9/ L was the only variable that showed statistical significance in the multivariate analysis with higher odds of having hypogammaglobulinemia (OR estimate = 2.71, p = 0.02). A subsequent univariate Fisher exact test showed an odds ratio of 11.42 (95% CI 1.35-547.37) with p = 0.01. Univariate analysis suggested a statistically non-significant trend toward higher odds of hypogammaglobulinemia in patients with older age, male sex, and greater than 5 years since diagnosis. Conclusions: Elevated absolute lymphocyte count is a strong predictor of hypogammaglobulinemia in CLL, likely reflecting disease burden and immune dysregulation. CLL patients with increasing ALC should have their Ig levels routinely evaluated as this may facilitate early identification of patients with hypogammaglobulinemia who are at increased risk of infectious complications. These patients may benefit most from strategies for risk mitigation against infectious complications, such as prophylactic antibiotics or Ig replacement therapy. Further studies are warranted to confirm additional risk factors that could help refine stratification of patients at high risk of hypogammaglobulinemia.