Real-World Insights into the Demographics, Infection Burden, and Use of Immunoglobulin Replacement in Patients with Chronic Lymphocytic Leukemia and Secondary Immune Deficiency

Background: Patients (pts) with chronic lymphocytic leukemia (CLL) experience an increased risk of severe, frequent, and fatal infections due to hypogammaglobulinemia, a type of secondary immune deficiency (SID). Treatment of hypogammaglobulinemia-related SID (referred to as SID) includes infection prevention measures, including prophylactic antimicrobial therapies and immunoglobulin replacement therapy (IgRT); however, the use of IgRT and these measures is not well characterized in the US.

Aims: To investigate real-world infection management and clinical outcomes in pts with CLL and SID, and how these are managed, in the US.

Methods: Using the US Optum Market Clarity database (data cut: 10/2015–6/2022), this retrospective study assessed infection-related outcomes in pts with CLL and SID (CLL/SID pts), and in pts with CLL but without SID (CLL non-SID pts). The index date for CLL/SID pts was defined as the first of initial SID diagnosis (Dx) date or the first date when serum immunoglobulin G (IgG) levels were ≤4 g/L. The index date for CLL non-SID pts was matched to CLL/SID pts on calendar date. Key eligibility criteria for both cohorts were: age ≥18 years, CLL Dx, no history of other diseases indicated for IgRT, no IV prophylactic antimicrobial use, and ≥365 days observable pre-index data, and for the CLL/SID pts: Dx of SID following CLL Dx. The follow-up (FU) period began 1 day post-index and lasted for ≤365 days. Risk categories for the CLL/SID cohort were developed based on serum IgG level and infection history. IgRT use was defined as initiation at any point during FU. In this retrospective analysis, only descriptive statistics were performed.

Results: Overall, there were 30,667 CLL non-SID pts and 2,898 CLL/SID pts during the FU period. Of the 2,898 pts, 213 had a high-risk infection history and IgG ≤4 g/L (highest risk category). Rate of severe infections per Patient Year (PY; 95% confidence interval [CI]) was 0.17 (0.16, 0.17) for CLL non-SID pts, 0.29 (0.26, 0.33) for CLL/SID pts, and 0.79 (0.62, 1.02) for high-risk CLL/SID pts. Infection-related hospitalization rate per PY was 0.10 (0.10, 0.11), 0.18 (0.16, 0.21), and 0.52 (0.40, 0.67), respectively. All-cause mortality rate per PY was 0.05 (0.05, 0.05), 0.08 (0.07, 0.10), and 0.28 (0.21, 0.38), respectively.

Thirty percent (n=64) of pts in the high-risk SID group received IgRT in FU, compared with 20.2% (n=586) of the overall CLL/SID population. In the high-risk SID pts, mean (SD) duration of IVIG treatment (time in days from IVIG initiation until the last observed IVIG receipt for the first episode [a continuous period of treatment, allowing up to 45-day gaps between records]) for the 50 pts confirmed on IVIG was 46.8 days (78.9), for the overall CLL/SID pts this was 53.0 days (89.8). Antibiotic use was far more prevalent than IgRT use: antibiotics were received by 84.5% (n=180) of the high-risk pts and 63.6% (n=1,843) of the overall CLL/SID pts.

In a multivariate regression model assessing demographics contributing to IgRT use, pts who were most likely to receive IgRT were those who were also more likely to receive prophylactic antimicrobials (odds ratio [95% CI]: 1.85 [1.53, 2.24]); prophylactic antimicrobials were independently associated with IgRT receipt in FU. Other factors that were associated with IgRT use included high-risk infection history at baseline (2.12 [1.72, 2.63]), being treated for CLL (1.76 [1.46, 2.12]), having a history of sinusitis (1.60 [1.23, 2.09]), and other non-heme malignancy (1.39 [1.09, 1.77]). Age, sex, seasonality, and other pt comorbidities were not independently associated with IgRT receipt.

Conclusion: These real-world data reveal a high infection burden in CLL/SID pts. Pts with high-risk SID, those with high infection history, and IgG ≤4 g/L are at greatest risk of morbidity/mortality from infection. Guidelines recommend use of IgRT for high-risk patients in order to reduce morbidity/mortality from infections. Despite meeting guideline thresholds, high-risk SID pts are often undertreated with only 1 in 3 receiving IgRT and many receiving a shorter than recommended IgRT course. Findings from this study suggest clinical practice patterns and physician treatment choices, or other patient barriers are a major contributor to patients not receiving IgRT as standard of care. Improved pt and physician education about the risk of infection and infection prevention best practice is needed.