Immunoglobulin replacement therapy not associated with reduced risk of serious infections in patients with CLL

In patients with chronic lymphocytic leukemia (CLL), regular treatment with immunoglobulin replacement therapy was not associated with a reduced risk of serious infections requiring hospitalization, according to a study published in Blood Advances.

This is the first large, real-world study to follow patients with CLL who are regularly receiving immunoglobulin replacement. Given its high cost and variable use in clinical practice, this is a critical issue from a policy, economic, and clinical perspective."

Sara Carrillo de Albornoz, lead study author, health economist and PhD candidate at Monash University, Australia

CLL, a common type of leukemia in adults, disrupts the body's production of antibodies (immunoglobulin molecules) that fight infections. As a result, patients with CLL are often susceptible to serious and potentially life-threatening infections. Treatment with immunoglobulin replacement therapy is often used to boost antibody levels in an effort to reduce infection risk.

"Many of the studies supporting the use of immunoglobulins to reduce infections in patients with blood cancers date back over thirty years, and the treatment for CLL has advanced significantly since then," said study author Erica Wood, AO, MD, professor at Monash University. "While immunoglobulins likely do benefit some patients, there remains a critical need to better understand the extent of that benefit, who is most likely to benefit, and how long these patients should be receiving treatment."

The research team used linked data from the Victorian Cancer Registry, Death Index, and Admitted Episodes Dataset, which included longitudinal hospital and death data for patients aged 18 years and older who had been diagnosed with CLL between January 1, 2008, and December 31, 2022, in Victoria, Australia. The total study cohort was 6,217 patients, with 5,464 (87.9%) not having received immunoglobulin replacement therapy and 753 (12.1%) having received at least one dose during their follow-up period, which averaged 6.9 years.

Over the entire 14-year follow-up period, among patients who remained alive, the proportion of those receiving immunoglobulin replacement therapy increased from 2% in the first year after diagnosis to 8.8% by year 14. During this time, 2,191 of the 6,217 (35.2%) patients died, with a median time to death from diagnosis of approximately ten years. Among the full study cohort, patients who had a serious infection were much more likely to begin receiving immunoglobulin replacement therapy in the 30 days following their infection, at a rate of 0.075 per person-month (a unit measuring incidence per each person observed for a month), compared to just 0.001 per person-month for those without a serious infection. Of the 753 patients who started immunoglobulin replacement therapy, 346 (45.9%) died during follow-up, with a median survival of approximately six years from first treatment. Consistent with the overall study cohort, recipients of immunoglobulin replacement therapy who had been hospitalized for a serious infection in the past month showed a higher 30-day mortality rate per person-month compared to those without infections (0.090 vs.0.008, respectively) – highlighting the significant impact of infections as a leading cause of death for patients with CLL.

Despite the increasing use of immunoglobulin replacement therapy over the study period, the rate of serious infections requiring hospitalization increased from 1.9% to 3.9%. The researchers also noted that, among patients receiving immunoglobulins regularly, there was a significantly higher incidence of infection while on immunoglobulin replacement therapy compared to off-treatment periods (0.056 vs. 0.038 infections per person-month, respectively). Among patients on regular immunoglobulins, 46.9% remained on treatment from one to five years, and 23.5% received immunoglobulins for more than five years, conditional on follow-up and survival.

"We not only saw no reduction in infection rates or hospitalizations among patients receiving immunoglobulins, we found that many were on this therapy for extended periods of time," said Dr. Wood. "It's essential that we evaluate how long these patients remain on treatment and why to avoid unnecessary, prolonged, and expensive therapy of a product in limited supply internationally."

Immunoglobulins are typically administered intravenously in a hospital setting, although at-home subcutaneous infusions are increasing in popularity. The therapy's high cost is largely driven by its complex manufacturing process and compounded by the frequency of treatment; for patients with CLL, intravenous immunoglobulins are generally administered on a monthly basis. In Australia, where this study took place, the cost of immunoglobulin is fully subsidized by the government, but in the United States and other countries, the financial burden can be significant.

"The cost of this therapy, its burden to patients, and the patterns of use and infection we observed are a clear call for better guidelines on the use of immunoglobulins," said Ms. Carrillo. "Although there are criteria for access to government-funded therapy in this population in Australia, clear clinical guidelines are lacking."

The study has some limitations given its retrospective nature, namely potential selection bias and incomplete data, particularly around clinical prognostic factors, disease severity, and cancer treatment. Additionally, there were significant differences at baseline between compared patient groups, specifically those who did and did not receive immunoglobulins and those who received it regularly versus intermittently.

The researchers currently have follow-up studies underway, including a clinical trial comparing immunoglobulins and antibiotics for infection prevention in patients with CLL, non-Hodgkin lymphoma, and multiple myeloma, and studies looking at the cost of immunoglobulins and serious infections for patients with blood cancers.