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

Overview

Journal Clin Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2017 Oct 14

PMID 29029010

Citations 124

Authors

Georgios Chamilos

Michail S Lionakis

Dimitrios P Kontoyiannis

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Invasive Fungal Disease After Chimeric Antigen Receptor-T Immunotherapy in Adult and Pediatric Patients.

Evangelidis P, Tragiannidis K, Vyzantiadis A, Evangelidis N, Kalmoukos P, Vyzantiadis T Pathogens. 2025; 14(2).

PMID: 40005545 PMC: 11858289. DOI: 10.3390/pathogens14020170.

Epidemiology of Coronavirus Disease 2019-Associated Fungal Infections in the Intensive Care Unit: A Single-Center Retrospective Study.

Little J, McGwin G, Tushla L, Benedict K, Lyman M, Toda M Mycopathologia. 2025; 190(1):16.

PMID: 39838211 DOI: 10.1007/s11046-025-00928-8.

Severe atypical skin disease in two patients with CLL/SLL after BTKi treatment - a case report and literature review.

Zhou J, Ma W, Hu N, Ma Y, Zhu H, Gao L Front Oncol. 2024; 14:1467891.

PMID: 39720567 PMC: 11666501. DOI: 10.3389/fonc.2024.1467891.

Dematiaceous Molds.

Li L, Yoon H Infect Dis Clin North Am. 2024; 39(1):75-92.

PMID: 39701900 PMC: 11786988. DOI: 10.1016/j.idc.2024.11.006.

Sequelae of B-Cell Depleting Therapy: An Immunologist's Perspective.

Kacar M, Al-Hakim A, Savic S BioDrugs. 2024; 39(1):103-130.

PMID: 39680306 DOI: 10.1007/s40259-024-00696-9.

References

Bodey G . Managing infections in the immunocompromised patient. Clin Infect Dis. 2005; 40 Suppl 4:S239. DOI: 10.1086/427328. View

Wilson W, Young R, Schmitz R, Yang Y, Pittaluga S, Wright G . Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015; 21(8):922-6. PMC: 8372245. DOI: 10.1038/nm.3884. View

Szymczak W, Davis M, Lundy S, Dufaud C, Olszewski M, Pirofski L . X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans Infection. mBio. 2013; 4(4). PMC: 3705448. DOI: 10.1128/mBio.00265-13. View

Arthurs B, Wunderle K, Hsu M, Kim S . Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia. Respir Med Case Rep. 2017; 21:27-29. PMC: 5369366. DOI: 10.1016/j.rmcr.2017.03.011. View

Levade M, David E, Garcia C, Laurent P, Cadot S, Michallet A . Ibrutinib treatment affects collagen and von Willebrand factor-dependent platelet functions. Blood. 2014; 124(26):3991-5. DOI: 10.1182/blood-2014-06-583294. View

Hutchinson C, Dyer M . Breaking good: the inexorable rise of BTK inhibitors in the treatment of chronic lymphocytic leukaemia. Br J Haematol. 2014; 166(1):12-22. DOI: 10.1111/bjh.12895. View

OBrien S, Jones J, Coutre S, Mato A, Hillmen P, Tam C . Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016; 17(10):1409-1418. DOI: 10.1016/S1470-2045(16)30212-1. View

Obar J, Hohl T, Cramer R . New advances in invasive aspergillosis immunobiology leading the way towards personalized therapeutic approaches. Cytokine. 2016; 84:63-73. PMC: 4904826. DOI: 10.1016/j.cyto.2016.05.015. View

Grabinski N, Ewald F . Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells. Invest New Drugs. 2014; 32(6):1096-104. DOI: 10.1007/s10637-014-0141-2. View

10.

Wang M, Blum K, Martin P, Goy A, Auer R, Kahl B . Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015; 126(6):739-45. PMC: 4528064. DOI: 10.1182/blood-2015-03-635326. View

11.

Lionakis M, Dunleavy K, Roschewski M, Widemann B, Butman J, Schmitz R . Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma. Cancer Cell. 2017; 31(6):833-843.e5. PMC: 5571650. DOI: 10.1016/j.ccell.2017.04.012. View

12.

Lougaris V, Baronio M, Vitali M, Tampella G, Cattalini M, Tassone L . Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation. J Allergy Clin Immunol. 2014; 133(6):1644-50.e4. DOI: 10.1016/j.jaci.2013.12.1085. View

13.

Rieber N, Gazendam R, Freeman A, Hsu A, Collar A, Sugui J . Extrapulmonary infection in patients with CARD9 deficiency. JCI Insight. 2016; 1(17):e89890. PMC: 5070961. DOI: 10.1172/jci.insight.89890. View

14.

Fiedler K, Sindrilaru A, Terszowski G, Kokai E, Feyerabend T, Bullinger L . Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X-linked agammaglobulinemia. Blood. 2010; 117(4):1329-39. DOI: 10.1182/blood-2010-04-281170. View

15.

Baron M, Zini J, Challan Belval T, Vignon M, Denis B, Alanio A . Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk Lymphoma. 2017; 58(12):2981-2982. DOI: 10.1080/10428194.2017.1320710. View

16.

Byrd J, Furman R, Coutre S, Flinn I, Burger J, Blum K . Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013; 369(1):32-42. PMC: 3772525. DOI: 10.1056/NEJMoa1215637. View

17.

Perkhofer S, Kehrel B, Dierich M, Donnelly J, Nussbaumer W, Hofmann J . Human platelets attenuate Aspergillus species via granule-dependent mechanisms. J Infect Dis. 2008; 198(8):1243-6. PMC: 2980866. DOI: 10.1086/591458. View

18.

Ahn I, Jerussi T, Farooqui M, Tian X, Wiestner A, Gea-Banacloche J . Atypical Pneumocystis jirovecii pneumonia in previously untreated patients with CLL on single-agent ibrutinib. Blood. 2016; 128(15):1940-1943. PMC: 5064717. DOI: 10.1182/blood-2016-06-722991. View

19.

Futatani T, Miyawaki T, Tsukada S, Hashimoto S, Kunikata T, Arai S . Deficient expression of Bruton's tyrosine kinase in monocytes from X-linked agammaglobulinemia as evaluated by a flow cytometric analysis and its clinical application to carrier detection. Blood. 1998; 91(2):595-602. View

20.

Wu P, Nielsen T, Clausen M . Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov Today. 2015; 21(1):5-10. DOI: 10.1016/j.drudis.2015.07.008. View