LOUIS — Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections due to impaired immunity, from both complications of disease and treatments.

A presentation at the 61st American Society of Hematology Annual Meeting and Exposition in Orlando, FL,  described how specific therapies, such as fludarabine or rituximab,  are incorporated in chemotherapy regimens for CLL and cause lymphocyte depletion and impaired humoral immunity, which can result in increased risk of fungal infections.1

A study team led by St. Louis VAMC researchers sought to explore the incidence rates of fungal infections in patients before and after treatment for CLL. To do that, they identified VHA patients diagnosed with CLL using ICD9 code 204.1X between 1999 and 2013, before the availability of novel agents for CLL. A cohort of 20,023 patients were identified with CLL and followed for a mean of 5.33 years for a total surveillance of 106,772 person-years.

The study team used pharmacy records to document use of both CLL treatment – including alemtuzumab, bendamustine, chlorambucil, fludarabine, ofatumumab, pentostatin, and rituximab – and anti-fungal agents – including amphotericin, caspofungin, fluconazole, flucytosine, itraconazole, ketoconazole, micafungin, posaconazole, and voriconazole.

Researchers employed two approaches to identify fungal infections — using ICD9 codes alone (candida 112.X; pneumocystis 136.3; coccidiomycosis 114.x; histoplasmosis 115.X; blastomycosis 116.X; aspergillus 117.3; cryptococcus 117.5; opportunistic mycoses 118.X), as well as using ICD9 codes combined with evidence of treatment with an anti-fungal. They then categorized the number of infections and incidence rates as occurring in patients prior to first treatment or after first treatment (post-treat), or in patients who had never received treatment within the VHA.

The team calculated the incidence rate ratio between pre- and post-treatment period to quantify the magnitude of risk increase in patients who received CLL treatment.

Of the participants, (18.6%) received treatment for CLL within the VHA. Using ICD9 codes alone, researchers identified 970 fungal infections and combining ICD9 with anti-fungal treatment, they calculated 415 patients had an infection.

Candida, with 765 infections, was the most common determined by ICD9 codes, according to the study, followed by aspergillus with 58 and pneumocystis with 39 infections.

Researchers also determined that rates of infections based on ICD9 were highest in the post-treat group with 2.98 infections per 100 person-years, followed by 1.08 infections per 100 person-years in the pre-treatment group and 0.58 infections per 100 person-years in the no-treatment group.

Rituximab alone was the most common first treatment, used in 35.9% of patients, followed by chlorambucil in 31.9%, fludarabine in 20.4%, and bendamustine in 9.9%.

“In comparison to pre-treat patients, post-treat patients had 2.91 times increased risk of fungal infection (95% confidence interval (CI) 2.24-3.81) determined by ICD9 code and 4.74 times increased risk (95% CI 3.09-7.57) determined by ICD9+antifungal,” the authors pointed out. “The rate of candida infection increased 2.9 fold (95% CI 2.24-3.81) with ICD9 and 4.7 fold (95% CI 3.09-7.57) with ICD9+antifungal while aspergillus infections increased 8.7 fold (95% CI 3.01-35.4) with ICD9 and 10.2 fold (95% CI 2.88-63.1) with ICD9+antifungal between post-treat and pre-treat groups.”

Researchers concluded that, in their retrospective analysis, treatment for CLL significantly increased the rate of fungal infections, primarily candida and aspergillus. They called for further study to better understand the effect of modern treatments on fungal infections in CLL.

  1. Schoen MW, Georgantopoulos P, Yalavarthi NS, Bennett C. Fungal Infections in Chronic Lymphocytic Leukemia before and after Treatment. Presented at the 61st American Society of Hematology Annual Meeting and Exposition; December 2019; Orlando, FL