Results of a retrospective study revealed an incidence of invasive fungal infection of 2.5% in a large cohort of “real-life” patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib. These findings were reported in Leukemia and Lymphoma.

Although the reported incidence of invasive fungal infections was low in clinical trials of the Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, in patients with CLL, a number of case studies showing such infections, particularly in atypical locations, have recently been reported for patients receiving this agent for the treatment of CLL.

Furthermore, evidence of ibrutinib-mediated impairment of the immune response through macrophage inhibition has also been reported, leading to the hypothesis that such a mechanism may underlie the development of invasive fungal infections in patients with CLL receiving this drug. Nevertheless, clinical risk factors for such infections in ibrutinib-treated patients with CLL have not yet been identified.

This case-control study included 841 adult patients with CLL treated with ibrutinib at MD Anderson Cancer Center in Houston, Texas, who did not receive primary antifungal prophylaxis. Twenty-one of these patients (2.5%) had been diagnosed with 1 or more proven or probable invasive fungal infections and were classified as cases, with the remaining patients placed in the control group.


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Characteristics of case patients included a median age of 65 years, male sex (81%), and receipt of ibrutinib in the frontline setting (38%) or following at least 3 prior treatments for CLL (29%). The median duration of ibrutinb therapy prior to diagnosis of an invasive fungal infection was 4 months.

Of the invasive fungal infections identified in the study, Aspergillis was the most common (62%), followed by Cryptococcus (24%), and Candida (10%). The most common sites for these infections were the lung (95%), blood (14%), and CNS (10%), with multiple sites of infection occurring in 4 patients, and 3 patients experienced coinfection with more than 1 fungal organism.

At a median follow-up of 36.79 months, 10 patients in the case group had died, with death attributed to an invasive fungal infection in 5 patients. In the latter group, 4 deaths occurred within 2 weeks of diagnosis of an invasive fungal infection. 

A risk factor analysis showed that receipt of at least 3 prior lines of CLL therapy (odds ratio [OR], 5.36; 95% CI, 1.25-23.03), and the presence of monocytopenia (OR, 6.00; 95% CI, 1.41-25.45) were significantly associated with the occurrence of invasive fungal infection.

“It is possible that ibrutinib’s immunosuppressive effects were additive to monocytopenia, a described risk factor for [invasive fungal infection],” the study authors noted.

A significant association between the presence of hypoalbuminemia and invasive fungal infection was also observed (OR, 17.70; 3.84–81.46), although the study authors stated that this finding was more likely to be attributable to the presence of active infection. No association between invasive fungal infection and glucocorticoid use, neutropenia, or hypogammaglobulinemia was observed.

In their concluding remarks, the study authors noted that these results “support active surveillance of [invasive fungal infections] in CLL patients on ibrutinib treatment with [at least] 3 prior lines of therapy or monocytopenia. Additional studies are required to confirm risk factors for [invasive fungal infections] and develop recommendations for appropriate antifungal prophylaxis in this patient population.”

Editor’s note: This article was updated on 8/11/20.

Reference

Frei M, Aitken SL, Jain N, et al. Incidence and characterization of fungal infections in chronic lymphocytic leukemia patients receiving ibrutinib [published online June 12, 2020]. Leuk Lymphoma.  doi: 10.1080/10428194.2020.1775215