Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib

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Abstract

Ibrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

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Most cited references 11

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Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry.

William J. Steinbach, Kieren A. Marr, Elias Anaissie … (2012)

The study investigated the epidemiology and outcome of invasive aspergillosis (IA), an important cause of morbidity and mortality in immunocompromised patients. Cases of proven/probable IA from the Prospective Antifungal Therapy Alliance (PATH Alliance(®)) registry - a prospective surveillance network comprising 25 centers in the United States and Canada that collected data on invasive fungal infections from 2004 to 2008 - were analyzed with respect to clinical outcome. Nine hundred and sixty patients with IA were enrolled, the most frequent underlying disease being hematologic malignancy (n=464 [48.3%]). Two hundred and eighty patients (29.2%) received solid organ transplant; 268 patients (27.9%) underwent hematopoietic stem cell transplantation. Identified isolates included Aspergillus fumigatus (72.6%), Aspergillus flavus (9.9%), Aspergillus niger (8.7%) and Aspergillus terreus (4.3%). The lung was most frequently affected. Following diagnosis, 47% patients received monotherapy - voriconazole (70%), an amphotericin B formulation (13.8%), or an echinocandin (10.5%) - while 279 patients (29%) received combination therapy. Twelve-week overall survival was 64.4%. In this series of patients with IA, the lung was the predominant focus of infection, A. fumigatus was the major species isolated, and overall survival appeared slightly improved compared with previous reports. Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

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Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007).

J-P Gangneux, Katherine Y. Le, F Dromer … (2011)

A prospective (2005-2007) hospital-based multicentre surveillance of EORTC/MSG-proven or probable invasive aspergillosis (IA) cases whatever the underlying diseases was implemented in 12 French academic hospitals. Admissions per hospital and transplantation procedures were obtained. Cox regression models were used to determine risk factors associated with the 12-week overall mortality. With 424 case-patients included, the median incidence/hospital was 0.271/10(3) admissions (range 0.072-0.910) without significant alteration of incidence and seasonality over time. Among the 393 adults (62% men, 56 years (16-84 years)), 15% had proven IA, 78% haematological conditions, and 92.9% had lung involvement. Acute leukaemia (34.6%) and allogeneic stem cell transplantation (21.4%) were major host factors, together with chronic lymphoproliferative disorders (21.6%), which emerged as a new high-risk group. The other risk host factors consisted of solid organ transplantation (8.7%), solid tumours (4.3%), systemic inflammatory diseases (4.6%) and chronic respiratory diseases (2.3%). Serum galactomannan tests were more often positive (≥69%) for acute leukaemia and allogeneic stem cell transplantation than for the others (<42%; p <10(-3)). When positive (n = 245), cultures mainly yielded Aspergillus fumigatus (79.7%). First-line antifungal therapy consisted of voriconazole, caspofungin, lipid formulations of amphotericin, or any combination therapy (52%, 14%, 8% and 19.9%, respectively). Twelve-week overall mortality was 44.8% (95% CI, 39.8-50.0); it was 41% when first-line therapy included voriconazole and 60% otherwise (p <0.001). Independent factors for 12-week mortality were older age, positivity for both culture and galactomannan and central nervous system or pleural involvement, while any strategy containing voriconazole was protective. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

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Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways.

Georgios Chamilos, Michail Lionakis, Dimitrios Kontoyiannis (2018)

Opportunistic infections caused by Pneumocystis jirovecii, Cryptococcus neoformans, and ubiquitous airborne filamentous fungi have been recently reported in patients with hematological cancers historically considered at low risk for invasive fungal infections (IFIs), after receipt of the Bruton tyrosine kinase inhibitor ibrutinib. The spectrum and severity of IFIs often observed in these patients implies the presence of a complex immunodeficiency that may not be solely attributed to mere inhibition of Bruton tyrosine kinase. In view of the surge in development of small molecule kinase inhibitors for treatment of malignant and autoimmune diseases, it is possible that there would be an emergence of IFIs associated with the effects of these molecules on the immune system. Preclinical assessment of the immunosuppressive effects of kinase inhibitors and human studies aimed at improving patient risk stratification for development of IFIs could lead to prevention, earlier diagnosis, and better outcomes in affected patients.