Infections in Patients with Lymphoproliferative Diseases Treated with Target Therapy. Italian Multicentric Retrospective Study Seifem 2017
Authors: Nadali Gianpaolo , Marchesini Gessica , Facchinelli Davide , Farina Francesca , Tisi Maria Chiara , Lessi Federica , Marchesi Francesco , Cattaneo Chiara , Candoni Anna , Fanci Rosa , Prezioso Lucia , Verga Luisa , Laurenti Luca , Trastulli Fabio , Picardi Marco , Del Principe Maria Ilaria , Silva Ronaldo , Busca Alessandro 
Published: October 2019

Abstract
Introduction: in the last 5 years new "target drugs" to treat lymphoproliferative disorders have been introduced in clinical practice, such as monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab), BTK inhibitors (ibrutinib) and PI3K inhibitors (idelalisib). Efficacy and safety of these drugs were assessed in registrative trials and data regarding infectious complications in the "real life" experience are currently unavailable. We aimed to assess the incidence of major infections in patients treated with the above mentioned drugs.
Methods: 555 patients were treated, for registered indications, with idelalisib, ibrutinib, brentuximab, ofatumumab and obinutuzumab (single agents or in combination as licensed) in 13 hematology centres in Italy, from time of their commercial availability to December 2016. The observation period was one year after study entry. Patients in clinical trials or treated within patient named programs were excluded as well as patients with active infections at beginning of treatment.
Results: in 132/555 patients (24%) infections occurred for a total number of 187 events, 56% of whom were of grade 3. The median age was 64 years (range 20-86), 46,2% (61/132) of patients were treated with 3 or more previous lines of therapy, 55/132 (42%) experienced 2 or more infective episodes. A bacterial cause of infection was reported in 35% of cases, viral in 22% and an invasive fungal infection (IFI) in 9% (17/187). In 2% of cases the infection was of mixed origin (bacterial/viral or bacterial/fungal) while in 32% of cases there was not microbiological documentation. The lower respiratory tract was the most frequent site of infection in 39% of cases (73/187) while the upper respiratory tract was involved in 30% of events (39/187). The urinary tract infections were 13% (24/187). Other sites involved were skin and soft tissue 7%, sepsis 7%, gastrointestinal site 5%, central nervous system 2% and fever of unknown origin 6%.
Patients treated with idelalisib were 106 (80% affected by chronic lymphocytic leukemia - CLL- and 20% follicular lymphoma) and 35 (33%) experienced one ore more infections for a total of 49 episodes. The incidence of bacterial infections was 37%, of viral infections 37% and of IFI 6%.
In 235 patients treated with ibrutinib, 70 (30%) had one ore more events for a total of 102 infective episodes. 60/70 (86%) patients had CLL and 10/70 (14%) had indolent or mantle cell lymphoma The incidence of bacterial infections was 50%, viral 20% and IFI 16%.
Focusing on IFI, 17 events were reported in 15 patients. According to the EORTC criteria, 11 cases (4 possible, 1 probable, 6 proven) were reported in patients treated with ibrutinib, 3 cases of possible IFI in patients treated with idelalisib and 3 cases of proven IFI in patients treated with brentuximab. The incidence of IFI in patients treated with ibrutinib (11/102 events) and idelalisib (3/49 events) was not different (11% vs. 6% respectively; p-value = 0.55) even considering proven/probable cases only (3% in ibrutinib vs. 0% in idelalisib p-value = 0.11). The incidence of bacterial infections in patients treated with ibrutinib (35/102) was not statistically different compared to patients treated with idelalisib (18/49) (34% vs. 37% respectively p-value =0.87). Noteworthy, the incidence of viral infections in patients treated with idelalisib (18/49) was significantly higher compared to patients treated with ibrutinib (14/102) (37% vs. 14% respectively; p-value =0.015).
Brentuximab was used in 175 patients, 70% of cases for Hodgkin Lymphoma and 30% for T cell lymphoma. The rate of infections was 11% for a total of 27 infection episodes. The incidence of bacterial, viral and fungal infections was 37%, 30% and 11% respectively. In 22% of cases the cause of infection could not be established.
Patients treated with ofatumumab or obinutuzumab were 39 and in 7/39 (18%) an infective episode was reported (four of bacterial origin, one viral and four undetermined). All patients were affected by CLL.
Conclusions: this "real life" experience confirm that the incidence of infections in patients treated with "target drugs" is not negligible. Ongoing analysis that take into account patient's clinical and demographical characteristics, may give insights on risk factors that will contribute to better characterizing patients at different risk levels.
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Disclosures
Cattaneo: GILEAD: Other: Advisory Board. Candoni:Pfizer: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau. Fanci:Gilead: Honoraria; Pfizer Pharmaceuticals: Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Del Principe:Gilead: Membership on an entity's Board of Directors or advisory committees. Busca:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merk: Honoraria, Speakers Bureau; Pfizer Pharmaceuticals: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Honoraria; Novartis: Speakers Bureau.