Infections in Chronic Lymphocytic Leukemia Patients Treated with Ibrutinib: Incidence and Predisposing Factors
Authors: Dmitrieva E.A. , Nikitin Evgenii Aleksandrovich , Markova E.E. , Dmitrieva N.Yu. , Ptushkin V.V. 
Published: October 2019

Background. Infections are a common complication of chronic lymphocytic leukemia (CLL). The lack of recommendations for infection prevention in CLL patients treated with ibrutinib can be attributed by an insufficiency of data in the literature. Aim. To assess the incidence and nature of infections in CLL patients treated with ibrutinib and to analyze predisposing factors. Materials & Methods. The paper provides data on bacterial, viral, and fungal infections in CLL patients treated with ibrutinib for 4.2 years (November 2014 to December 2018) in a single center. Severity grade was determined according to CTCAE criteria (version 4). Results. The trial included 240 CLL patients. Median age was 65 years (range 32-91), 86 (36 %) patients were female, and 117 (48 %) patients had Binet stage C. Ibrutinib as monotherapy was administered to 204 (85 %) patients, 36 (15 %) patients received it in combination with monoclonal anti-CD20 antibodies. Median follow-up was 14.8 months (range 1-54). Most patients (n = 224, 93 %) received ibrutinib for relapsed CLL. Median number of prior therapy lines was 3 (range 1-12). Neutropenia (specified as neutrophil level < 1000 cells/μL) before ibrutinib treatment was identified in 20 (8 %) patients. Glucocorticoid hormones (GCs) together with ibrutinib were administered to 20 patients. A total of 525 infectious episodes were registered in 183 patients. Out of them 381 (72.5 %) were bacterial/mixed, 115 (22 %) were viral, and 29 (5.5 %) were fungal infections. Among bacterial/mixed infections 121 (32 %) episodes were qualified as infection of grade 3 and 43 (11 %) episodes were qualified as grade 4. In 7 (1.8 %) patients infections were fatal. Within 12 months overall cumulative incidence of bacterial infections of grade 3/4 was 37 % (95% confidence interval [95% CI] 31-43 %), as for viral infections it was 28 % (95% CI 2234 %), and as for fungal infections it was 8 % (95% CI 4-12 %). Higher cumulative incidence of bacterial infections of grade 3/4 was identified in patients with > 3 lines of therapy before ibrutinib treatment (hazard ratio [HR] 2.0; 95% CI 1.36-2.97), with Binet stage C (HR 1.4; 95% CI 0.95-2.08), with ECOG status > 2 (HR 2.4; 95% CI 1.6-3.6), baseline neutropenia (HR 1.25; 95% CI 0.73-2.13), as well as in men (HR 1.8; 95% CI 1.16-2.8; p = 0.004). Multivariate analysis showed that male sex (HR 1.89; 95% CI 0.5-3.0; p = 0.006), ECOG status > 2 (HR 1.97; 95% CI 0.5-3.0), and baseline neutropenia (HR 1.76; 95% CI 0.99-3.1) were significant and independent risk factors. Cumulative incidence of any fungal infection was associated with simultaneous use of GCs (HR 6.0; 95% CI 5.85-14.7) and baseline neutropenia (HR 2.36; 95% CI 0.95-5.85). The only parameter significantly associated with viral infections was the number of prior therapy lines > 3 (HR 1.74; 95% CI 1.06-2.86; p = 0.029). Conclusion. Patients with baseline neutropenia and ECOG status > 2 face the highest risk of severe bacterial infections. We believe that antibacterial prophylaxis should be considered in such patients till ECOG status becomes < 2 and neutropenia resolves. Patients receiving GCs together with ibrutinib face the risk of fungal infections at any stage of treatment. In these patients the simultaneous antifungal prophylaxis should be considered.