Risk of Infectious Complications in Patients with Chronic Lymphocytic Leukemia in the Era of BCR Inhibitors: A Retrospective Single Institution Experience
Authors: Autore Francesco , Innocenti Idanna , Morelli Francesca , Sora Federica , Corbingi Andrea , Soldati Denise , Fianchi Luana , Criscuolo Marianna , Pagano Livio , Bacigalupo Andrea , Sica Simona , Laurenti Luca 
Published: October 2019

Abstract
Introduction. The development of novel therapeutic agents in the treatment of lymphoid malignancies seemed to decrease the rate of complications, including infections, in spite of standard immuno-chemotherapy regimens. Patients receiving Ibrutinib experienced serious infections and other recent studies found that these patients are at risk for serious or opportunistic infections.
Aim. The aim of our study was to evaluate incidence and type of infections in CLL patients treated with BCR inhibitors: Ibrutinib and Idelalisib plus Rituximab.
Results. Our retrospective study included 46 CLL patients treated at our Institution since 2015: 37 patients were treated with Ibrutinib and 9 patients were treated with Idelalisib plus Rituximab. The median number of prior treatment regimens was 2 (range 0-5); only 1 patient started Ibrutinib as first-line therapy because of TP53 mutation.
We recorded 32 episodes of infections, of which 23 occurred in 11 patients (out of 37, 30%) treated with Ibrutinib and 9 episodes in 5 patients (out of 9, 55%) treated with Idelalisib plus Rituximab. Daily Ibrutinib dose was 420 mg, Idelalisib was used at the dose of 150 mg twice a day. The median duration of treatment was 12 and 13 months in Ibrutinib and Idelalisib, respectively. We confirmed the higher prevalence of infections occurred during the first year of Ibrutinib treatment (84% in Varughese et al vs. 83% in our case series) and we found a high prevalence (78%) of infective episodes with Idelalisib plus Rituximab.
The rate of infections was 0.6 episodes/patient for Ibrutinib and 1.0 episodes/patient for Idelalisib; each patient with infection showed a median of 2.1 and 1.8 episodes for Ibrutinib and Idelalisib, respectively.
In the group of Ibrutinib the most common infections involved the upper respiratory tract (14 events, 61%), followed by urinary tract (6 events, 26%); in the Idelalisib group we found 6 infections (66%) of upper respiratory tract. Differences were found also in the pathogens implicated in the infections (Table I).
All the infections, except one bacterial sepsis, were grade I or II; the patients were treated with antibacterial, antiviral or antifungal drugs in 56% of the cases.
Only 3 patients treated with Ibrutinib required hospitalization and antibacterial or antifungal treatment as inpatients but no deaths were registered.
In 30% of the Ibrutinib cases and in 53% of the Idelalisib cases the treatment was temporarily stopped.
None of the patients received antifungal prophylaxis and nobody had invasive fungal infections. All patients received prophylaxis for Pneumocystis jirovecii and flu shot but no antiviral prophylaxis. Moreover, we detected 10 blood viral (EBV, CMV, HBV, BK) reactivations, without active disease, of which 60% with Idelalisib and 40% with Ibrutinib.
Discussion. In conclusion when we treat as second or following line CLL patients with Ibrutinib we should take in account that about 30% of patients will develop one or more episodes of infective complications; in more than 60% the type of infection is bacterial. When we use Idelalisib plus Rituximab the rate of infections will be higher, around 55%, only 1/3 will be bacterial, but viral complications will be common.

Disclosures
Pagano: Gilead: Speakers Bureau; Merck: Speakers Bureau; Pfizer: Speakers Bureau; Basilea: Speakers Bureau; Janssen: Speakers Bureau.