Page 244 - 2020_02-Haematologica-web

Complications in Hematology
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):478-489
Ibrutinib induces multiple functional defects in the neutrophil response against Aspergillus fumigatus
Damien Blez,1,* Marion Blaize,1,* Carole Soussain,2 Alexandre Boissonnas,1 Aïda Meghraoui-Kheddar,1 Natacha Menezes,3 Anaïs Portalier,4 Christophe Combadière,1 Véronique Leblond,1,4 David Ghez5,♭ and Arnaud Fekkar1,3,♭
1Sorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris; 2Hématologie, Institut Curie - Site de Saint-Cloud, Saint- Cloud; 3Service de Parasitologie Mycologie, Assistance Publique – Hôpitaux de Paris (AP- HP), Groupe Hospitalier Pitié-Salpêtrière, Paris; 4Service d’Hématologie, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris and 5Département d’Hématologie, Gustave Roussy, Villejuif, France
*DB and MB contributed equally to the work. ♭DG and AF share senior co-authorship.
ABSTRACT
The Bruton tyrosine kinase inhibitor ibrutinib has become a leading therapy against chronic lymphoid leukemia. Recently, ibrutinib has been associated with the occurrence of invasive fungal infec- tions, in particular invasive aspergillosis. The mechanisms underlying the increased susceptibility to fungal infections associated with exposure to ibrutinib are currently unknown. Innate immunity, in particular polymor- phonuclear neutrophils, represents the cornerstone of anti-Aspergillus immunity; however, the potential impact of ibrutinib on neutrophils has been little studied. Our study investigated the response to Aspergillus fumigatus and neutrophil function in patients with chronic lymphoid leukemia or lymphoma, who were undergoing ibrutinib therapy. We studied the consequences of ibrutinib exposure on the functions and anti-Aspergillus responses of neutrophils obtained from healthy donors and 63 blood samples collected at different time points from 32 patients receiving ibrutinib for lymphoid malignancies. We used both flow cytometry and video-microscopy approaches to analyze neutrophils’ cell surface molecule expression, cytokine production, oxidative burst, chemotaxis and killing activity against Aspergillus. Ibrutinib is associated, both in vitro and in patients under treatment, with multiple functional defects in neutrophils, including decreased production of reactive oxygen species, impairment of their capacity to engulf Aspergillus and inability to efficiently kill germinating conidia. Our results demonstrate that ibruti- nib-exposed neutrophils develop significant functional defects that impair their response against Aspergillus fumigatus, providing a plausible explanation for the emergence of invasive aspergillosis in ibrutinib-treat- ed patients.
Introduction
Bruton tyrosine kinase (BTK), a member of the TEC kinase family, plays a key role in the signaling pathway of the B-cell receptor, which controls B-cell devel- opment, activation and proliferation. In humans, inactivating BTK mutations are responsible for a maturation block in early B-cell development at the pro-B-cell stage which results in a nearly complete absence of B cells and agammaglobuline- mia, a disease known as X-linked agammaglobulinemia (XLA).1 Ibrutinib, a small covalent BTK inhibitor, has ushered a new era in the therapeutic strategy for chronic lymphocytic leukemia and displays interesting clinical efficacy in other types of lymphoid malignancies.2 Recently, ibrutinib has been linked to the occur-
Correspondence:
ARNAUD FEKKAR
arnaud.fekkar@aphp.fr
Received: February 15, 2019. Accepted: June 6, 2019. Pre-published: June 6, 2019.
doi:10.3324/haematol.2019.219220
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/478
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
478
haematologica | 2020; 105(2)
ARTICLE