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Current Fungal Infection Reports

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Open Access 01-12-2019 | Aspergillosis | Epidemiology of Fungal Infections (T Chiller and J Baddley, Section Editors)

Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

Authors: Katie Bechman, James B Galloway, Kevin L Winthrop

Published in: Current Fungal Infection Reports | Issue 4/2019

Abstract

Purpose of Review

This review discusses fungal infections associated with licenced small-molecule protein kinase inhibitors. For each major drug class, the mechanism of action and targeted pathways and the impact on host defence against fungi are described.

Recent Findings

Protein kinase inhibitors are successfully used in the treatment of malignancies and immune-mediated diseases, targeting signalling pathways for a broad spectrum of cytokines and growth-stimuli. These agents predispose to fungal infections by the suppression of integral components of the adaptive and innate immune response.

Summary

The greatest risk of fungal infections is seen with bruton tyrosine kinase inhibitors, e.g. ibrutinib. Infections are also reported with agents that target mTOR, Janus kinase and break point cluster (Bcr) gene–Abelson (Abl) tyrosine kinase (BCR-ABL). The type of fungal infection fits mechanistically with the specific pathway targeted. Infections are often disseminated and present soon after the initiation of therapy. The pharmacokinetic profile, possibility of off-target kinase inhibition, and underlying disease pathology contribute to infection risk.

Limper AH, Adenis A, Le T, Harrison TS. Fungal infections in HIV/AIDS. Lancet Infect Dis. 2017;17:e334–43. https://doi.org/10.1016/S1473-3099(17)30303-1.CrossRefPubMed

Wallis RS, Broder M, Wong J, Lee A, Hoq L. Reactivation of latent granulomatous infections by infliximab. Clin Infect Dis. 2005;41(Suppl 3):S194–8. https://doi.org/10.1086/429996.CrossRefPubMed

Hohl TM. Immune responses to invasive aspergillosis: new understanding and therapeutic opportunities. Curr Opin Infect Dis. 2017;30:364–71. https://doi.org/10.1097/QCO.0000000000000381.CrossRefPubMedPubMedCentral

Fidel P Jr. Immunity to Candida. Oral Dis. 2002;8:69–75. https://doi.org/10.1034/j.1601-0825.2002.00015.x.CrossRefPubMed

Mengesha BG, Conti HR. The role of IL-17 in protection against mucosal candida infections. J Fungi (Basel). 2017;3:52. https://doi.org/10.3390/jof3040052.CrossRef

Thompson A, Orr SJ. Emerging IL-12 family cytokines in the fight against fungal infections. Cytokine. 2018;111:398–407. https://doi.org/10.1016/j.cyto.2018.05.019.CrossRefPubMedPubMedCentral

Roskoski R. A historical overview of protein kinases and their targeted small molecule inhibitors. Pharmacol Res. 2015;100:1–23. https://doi.org/10.1016/j.phrs.2015.07.010.CrossRefPubMed

•• Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors. Pharmacol Res. 2019;144:19–50. https://doi.org/10.1016/j.phrs.2019.03.006This paper reviews the FDA approved 48 small molecule protein kinase inhibitors including protein kinase structure, mechanism of action and drug indication. CrossRefPubMed

Cohen P. Protein kinases — the major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002;1:309–15. https://doi.org/10.1038/nrd773.CrossRefPubMed

10.

Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhibitors: multi-targeted or single-targeted? World J Clin Oncol. 2011;2:80–93. https://doi.org/10.5306/wjco.v2.i2.80.CrossRefPubMedPubMedCentral

11.

Schamroth Pravda M, Schamroth Pravda N, Lishner M. The muddied waters of Ibrutinib therapy. Acta Haematol. 2019;141:209–13. https://doi.org/10.1159/000496555.CrossRefPubMed

12.

Ping L, et al. The Bruton's tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages. Oncotarget. 2017;8:39218–29. https://doi.org/10.18632/oncotarget.16836.CrossRefPubMedPubMedCentral

13.

Weber ANR, Bittner Z, Liu X, Dang TM, Radsak MP, Brunner C. Bruton's tyrosine kinase: an emerging key player in innate immunity. Front Immunol. 2017 Nov 8;8:1454. https://doi.org/10.3389/fimmu.2017.01454 ECollection 2017.

14.

•• Chamilos G, Lionakis MS, Kontoyiannis DP. Call for action: invasive fungal infections associated with ibrutinib and other small molecule kinase inhibitors targeting immune signaling pathways. Clin Infect Dis. 2018;66:140–8. https://doi.org/10.1093/cid/cix687This paper identfied predisposing factors associated with an increased risk of fungal infectiosn in patients receiving small molecule kinase inhibitors. CrossRefPubMed

15.

Szymczak WA, Davis MJ, Lundy SK, Dufaud C, Olszewski M, Pirofski LA. X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans infection. MBio. 2013 Jul 2;4(4). pii: e00265–13 doi: https://doi.org/10.1128/mBio.00265-13.

16.

Lionakis MS, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31:833–843.e835. https://doi.org/10.1016/j.ccell.2017.04.012.CrossRefPubMedPubMedCentral

17.

Herbst S, et al. Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. EMBO Mol Med. 2015;7:240–58. https://doi.org/10.15252/emmm.201404556.CrossRefPubMedPubMedCentral

18.

•• Ghez D, et al. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018;131:1955–9 Large retrospective review of fungal infections with ibrutinib, indicating early-onset of fingal infections and an overrepresentation of invasive aspergillosis. CrossRef

19.

Swan CD, Gottlieb T. Cryptococcus neoformans empyema in a patient receiving ibrutinib for diffuse large B-cell lymphoma and a review of the literature. BMJ Case Rep. 2018;2018:1955–9. https://doi.org/10.1182/blood-2017-11-818286.CrossRef

20.

Messina JA, Maziarz EK, Spec A, Kontoyiannis DP, Perfect JR. Disseminated cryptococcosis with brain involvement in patients with chronic lymphoid malignancies on ibrutinib. Open Forum Infect Dis. 2017;4:ofw261. https://doi.org/10.1093/ofid/ofw261.CrossRefPubMedPubMedCentral

21.

Ruchlemer R, et al. Ibrutinib: a risk factor for invasive fungal infections? Blood. 2017;130:4323 http://www.bloodjournal.org/content/130/Suppl_1/4323.

22.

Baron M, et al. Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk Lymphoma. 58:2981–2. https://doi.org/10.1080/10428194.2017.1320710.CrossRef

23.

•• Rogers KA, et al. Incidence and type of opportunistic infections during ibrutinib treatment at a single academic center. Blood. 2017;130:830 Large retrospective review of fungal infections indicating independent risk factors for opportunisitc infection.

24.

Facchinelli D, Marchesini G, Nadali G, Pagano L. Invasive fungal infections in patients with chronic lymphoproliferative disorders in the era of target drugs. Mediterr J Hematol Infect Dis. 2018;10:e2018063–3. https://doi.org/10.4084/MJHID.2018.063.CrossRef

25.

Ahn IE, 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;128:1940–3. https://doi.org/10.1182/blood-2016-06-722991.CrossRefPubMedPubMedCentral

26.

Byrd JC, et al. Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in hematologic malignancies. Blood. 2017;130:4326–6 http://www.bloodjournal.org/content/130/Suppl_1/4326.

27.

Wilson PA, Melville K. Disseminated cryptococcal infection in a patient receiving acalabrutinib for chronic lymphocytic leukemia. Infect Dis Clin Pract. 2019;27:160–2. https://doi.org/10.1097/IPC.0000000000000722.CrossRef

28.

Xie J, Wang X, Proud CG. mTOR inhibitors in cancer therapy. F1000Res. 2016 Aug 25;5. pii: F1000 Faculty Rev-2078. doi: https://doi.org/10.12688/f1000research.9207.1. ECollection 2016.CrossRef

29.

Geissler EK. The influence of mTOR inhibitors on immunity and the relationship to post-transplant malignancy. Transp Res. 2013;2:S2–2. https://doi.org/10.1186/2047-1440-2-S1-S2.

30.

•• Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nature reviews. Immunology. 2009;9:324–37. https://doi.org/10.1038/nri2546A review of the mTOR signalling pathway and immunoregularoty functions. CrossRefPubMed

31.

Singh N, Heitman J. Antifungal attributes of immunosuppressive agents: new paradigms in management and elucidating the pathophysiologic basis of opportunistic mycoses in organ transplant recipients. Transplantation. 2004;77:795–800. https://doi.org/10.1097/01.tp.0000117252.75651.d6.CrossRefPubMed

32.

•• Neff RT, et al. Analysis of USRDS: incidence and risk factors for Pneumocystis jiroveci pneumonia. Transplantation. 2009;88:135–41. https://doi.org/10.1097/TP.0b013e3181aad256Retrospective cohort study of transplant recipients indicating Sirolimus (Rapamycin) associates with development of PCP. CrossRefPubMed

33.

Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation. 1999;68:1526–32. https://doi.org/10.1097/00007890-199911270-00016.CrossRefPubMed

34.

Kaymakcalan MD, Je Y, Sonpavde G, Galsky M, Nguyen PL, Heng DYC, et al. Risk of infections in renal cell carcinoma (RCC) and non-RCC patients treated with mammalian target of rapamycin inhibitors. Br J Cancer. 2013;108:2478–84. https://doi.org/10.1038/bjc.2013.278.CrossRefPubMedPubMedCentral

35.

Hu YN, Lee NY, Roan JN, Hsu CH, Luo CY. High-dose calcineurin inhibitor-free everolimus as a maintenance regimen for heart transplantation may be a risk factor for Pneumocystis pneumonia. Transpl Infect Dis. 2017;19. https://doi.org/10.1111/tid.12709.CrossRef

36.

•• Villarino AV, Kanno Y, O'Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol. 2017;18:374–84. https://doi.org/10.1038/ni.3691This paper reviews the JAK enzmye family and JAK-STAT pathway, focussing on recent advances in Jak–STAT biology, immune cell function and therapeutic intervention. CrossRefPubMed

37.

Scott L, Tofacitinib J. A review of its use in adult patients with rheumatoid arthritis. Drugs. 2013;73:857–74. https://doi.org/10.1007/s40265-013-0065-8.CrossRefPubMed

38.

Clark JD, Flanagan ME, Telliez JB. Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases. J Med Chem. 2014;57:5023–38. https://doi.org/10.1021/jm401490p.CrossRefPubMed

39.

Chen Y, Gong FY, Li ZJ, Gong Z, Zhou Z, Ma SY, et al. A study on the risk of fungal infection with tofacitinib (CP-690550), a novel oral agent for rheumatoid arthritis. Sci Rep. 2017;7:6779. https://doi.org/10.1038/s41598-017-07261-1.CrossRefPubMedPubMedCentral

40.

Hardison SE, Herrera G, Young ML, Hole CR, Wozniak KL, Wormley FL Jr. Protective immunity against pulmonary cryptococcosis is associated with STAT1-mediated classical macrophage activation. J Immunol. 2012;189:4060–8. https://doi.org/10.4049/jimmunol.1103455.CrossRefPubMedPubMedCentral

41.

Balish E, Wagner RD, Vazquez-Torres A, Pierson C, Warner T. Candidiasis in interferon-gamma knockout (IFN-gamma−/−) mice. J Infect Dis. 1998;178:478–87. https://doi.org/10.1086/515645.CrossRefPubMed

42.

Dioverti MV, Abu Saleh OM, Tande AJ. Infectious complications in patients on treatment with ruxolitinib: case report and review of the literature. Infect Dis Ther. 2018;50:381–7.CrossRef

43.

Prakash K, Richman D. A case report of disseminated histoplasmosis and concurrent cryptococcal meningitis in a patient treated with ruxolitinib. BMC Infect Dis. 2019;19:287–387. https://doi.org/10.1080/23744235.2017.1390248.CrossRefPubMedPubMedCentral

44.

•• Cohen S, et al. Worldwide, 3-year, post-marketing surveillance experience with tofacitinib in rheumatoid arthritis. Rheumatol Ther. 2018;5:283–91. https://doi.org/10.1007/s40744-018-0097-3Large safety analysis of infections with tofacitnib in the treatment of RA. CrossRefPubMedPubMedCentral

45.

•• Winthrop K, L. S, Harigai M, Bradley JD, Chen L, Hyslop DL, et al. Tuberculosis, potential opportunistic infections, and other infections of interest in patients with moderate to severe rheumatoid arthritis in the baricitinib program [abstract]. Arthritis Rheumatol. 2017, 2017;69(suppl 10) Large safety analysis of infections with baricitinib in the treatment of RA.

46.

•• Cilloni D, Saglio G. Molecular pathways: BCR-ABL. Clin Cancer Res. 2012;18:930–7. https://doi.org/10.1158/1078-0432.CCR-10-1613This paper reviews the deregulated tyrosine kinase activity of BCR-ABL, the molecular pathways involved and clinical translational advances. CrossRefPubMed

47.

Holyoake TL, Helgason GV. Do we need more drugs for chronic myeloid leukemia? Immunol Rev. 2015;263:106–23. https://doi.org/10.1111/imr.12234.CrossRefPubMed

48.

Seggewiss R, et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood. 2005;105:2473–9. https://doi.org/10.1182/blood-2004-07-2527.CrossRefPubMed

49.

•• Al-Ameri A, et al. Opportunistic infections are uncommon with dasatinib in patients with chronic myeloid leukemia in chronic phase (CML-CP). Blood. 2009;114:1120–0 A safety analysis eporting the frequency of opportunistic infections including fungal in clinical trials of dasatinib in CML. CrossRef

50.

Speletas M, Vyzantiadis TA, Kalala F, Plastiras D, Kokoviadou K, Antoniadis A, et al. Pneumonia caused by Candida krusei and Candida glabrata in a patient with chronic myeloid leukemia receiving imatinib mesylate treatment. Med Mycol. 2008;46:259–63. https://doi.org/10.1080/13693780701558969.CrossRefPubMed

51.

Sillaber C, Herrmann H, Bennett K, Rix U, Baumgartner C, Böhm A, et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Investig. 2009;39:1098–109. https://doi.org/10.1111/j.1365-2362.2009.02206.CrossRef

52.

Salih J, Hilpert J, Placke T, Grünebach F, Steinle A, Salih HR, et al. The BCR/ABL-inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity. Int J Cancer. 2010;127:2119–28. https://doi.org/10.1002/ijc.25233.CrossRefPubMed

53.

Appel S, Boehmler AM, Grünebach F, Müller MR, Rupf A, Weck MM, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34<sup>+</sup> peripheral blood progenitor cells. Blood. 2004;103:538–44. https://doi.org/10.1182/blood-2003-03-0975.CrossRefPubMed

54.

Knoll BM, Seiter K. Infections in patients on BCR-ABL tyrosine kinase inhibitor therapy: cases and review of the literature. Infection. 2018;46:409–18. https://doi.org/10.1007/s15010-017-1105-1.CrossRefPubMed

55.

Nasir T, Lee C, Lawrence AS, Brown JS. Invasive aspergillosis complicating treatment with tyrosine kinase inhibitors. BMJ Case Rep. 2019;12:e226121. https://doi.org/10.1136/bcr-2018-226121.CrossRefPubMed

56.

Lokeshwar N, Kumar L, Kumari M. Severe bone marrow aplasia following imatinib mesylate in a patient with chronic myelogenous leukemia. Leuk Lymphoma. 2005;46:781–4. https://doi.org/10.1080/10428190500046778.CrossRefPubMed

57.

Crisan AM, Ghiaur A, Stancioaca MC, Bardas A, Ghita C, Manea CM, et al. Mucormycosis during imatinib treatment: case report. J Med Life. 2015;8:365–70.PubMedPubMedCentral

58.

Chang H, Hung Y-S, Chou W-C. Pneumocystis jiroveci pneumonia in patients receiving dasatinib treatment. Int J Infect Dis. 2014;25:165–7. https://doi.org/10.1016/j.ijid.2014.04.030.CrossRefPubMed

59.

O'Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis. 2013;72(Suppl 2):ii111–5.CrossRef

60.

Cunha C, Aversa F, Bistoni G, Casagrande A, Rodrigues F, Romani L, et al. Immunogenetic profiling to predict risk of invasive fungal diseases: where are we now? Immunol Investig. 2011;40:723–34. https://doi.org/10.3109/08820139.2011.586395.CrossRef

61.

Vera-Badillo FE, et al. Bias in reporting of randomised clinical trials in oncology. Eur J Cancer (Oxford, England : 1990). 2016;61:29–35. https://doi.org/10.1016/j.ejca.2016.03.066.CrossRef

62.

Heine A, Brossart P, Wolf D. Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? Blood. 2013;122:3843–4. https://doi.org/10.1182/blood-2013-10-531103.CrossRefPubMed

63.

Varughese T, et al. Serious infections in patients receiving ibrutinib for treatment of lymphoid cancer. Clin Infect Dis. 2018;67:687–92. https://doi.org/10.1093/cid/ciy175.CrossRefPubMedPubMedCentral

64.

Zaytseva YY, Valentino JD, Gulhati P, Mark Evers B. mTOR inhibitors in cancer therapy. Cancer Lett. 2012;319:1–7. https://doi.org/10.1016/j.canlet.2012.01.005.CrossRefPubMed

65.

Hodge JA, et al. The mechanism of action of tofacitinib - an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34:318–28.PubMed

66.

O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu Rev Med. 2015;66:311–28. https://doi.org/10.1146/annurev-med-051113-024537.CrossRefPubMedPubMedCentral

67.

Gambillara E, Laffitte E, Widmer N, Decosterd LA, Duchosal MA, Kovacsovics T, et al. Severe pustular eruption associated with imatinib and voriconazole in a patient with chronic myeloid leukemia. Dermatology. 2005;211:363–5. https://doi.org/10.1159/000088510.CrossRefPubMed

68.

Rodriguez GH, Ahmed SI, Al-akhrass F, Rallapalli V, Safdar A. Characteristics of, and risk factors for, infections in patients with cancer treated with dasatinib and a brief review of other complications. Leuk Lymphoma. 2012;53:1530–5. https://doi.org/10.3109/10428194.2012.656626.CrossRefPubMed

69.

Al-Ameri AM, Cortes JE, Kantarjian H, Burton E, Quintas Cardama A, Jabbour E, et al. Infectious events in patients with chronic myeloid leukemia treated with Nilotinib as a front line therapy and after Imatinib failure. Blood. 2010;116(21):1233. https://doi.org/10.1182/blood.V116.21.1233.1233.CrossRef

70.

Couturier M-A, et al. Blinatumomab + ponatinib for relapsed Ph1-positive acute lymphoblastic leukemia: the French experience. Blood. 2018;132:4014. https://doi.org/10.1182/blood-2018-99-111546.CrossRef

71.

Nadali G, et al. Infections in patients with lymphoproliferative diseases treated with target therapy. Italian Multicentric Retrospective Study Seifem 2017. Blood. 2018;132:4164. https://doi.org/10.1182/blood-2018-99-111518.CrossRef

72.

Duma N, et al. Invasive aspergillosis in chronic lymphocytic leukemia: therapy and outcomes. Blood. 2017;130:4327.

73.

Chaul Barbosa C, DeAngelis LM, Grommes C. Ibrutinib associated infections: a retrospective study. J Clin Oncol. 2017;35:e19020–0. https://doi.org/10.1200/JCO.2017.35.15_suppl.e19020.CrossRef

74.

Protin C, Paricaud K, Despas F, Martin-Blondel G, Ysebaert L. Risk factors and profile of infections on ibrutinib therapy outside clinical trials: a single center experience of 68 patients (conference abstract). EHA Library Protin C. Jun 9, 2016; 132624; E1075 Haematologica. Conference: 21st Congress of the European Hematology Association. Denmark. 101 (Supplement 1) (pp 443), 2016. Date of Publication: June 2016. (2016). https://library.ehaweb.org/eha/2016/21st/132624/caroline.protin.risk.factors.and.profile.of.infections.on.ibrutinib.therapy.html?f=m1

75.

Autore F, et al. Risk of infectious complications in patients with chronic lymphocytic leukemia in the era of BCR inhibitors: a retrospective single institution experience. Blood. 2018;132:5552. https://doi.org/10.1182/blood-2018-99-119654.CrossRef

76.

Tillman BF, Pauff JM, Satyanarayana G, Talbott M, Warner JL. Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies. Eur J Haematol. 2018;100:325–34. https://doi.org/10.1111/ejh.13020.CrossRefPubMed

77.

Beresford R, Dolot V, Foo H. Cranial aspergillosis in a patient receiving ibrutinib for chronic lymphocytic leukemia. Med Mycol Case Rep. 2019;24:27–9. https://doi.org/10.1016/j.mmcr.2019.02.005.CrossRefPubMedPubMedCentral

78.

Faisal MS, Shaikh H, Khattab A, Albrethsen M, Fazal S. Cerebral aspergillosis in a patient on ibrutinib therapy-a predisposition not to overlook. J Oncol Pharm Pract. 2019 Sep;25(6):1486–90. https://doi.org/10.1177/1078155218788717.CrossRef

79.

Park J. Pulmonary aspergillosis secondary to Ibrutinib use. Chest. 2015;148:104A. https://doi.org/10.1378/chest.2279372.CrossRef

80.

McCarter SJ, Vijayvargiya P, Sidana S, Nault AM, Lane CE, Lehman JS, et al. A case of ibrutinib-associated aspergillosis presenting with central nervous system, myocardial, pulmonary, intramuscular, and subcutaneous abscesses. Leuk Lymphoma. 2019;60:559–61. https://doi.org/10.1080/10428194.2018.1494271.CrossRefPubMed

81.

Abid MB, Stromich J, Gundacker ND. Is ibrutinib associated with disseminated cryptococcosis with CNS involvement? Cancer Biol Ther. 2019;20(2):138–40. https://doi.org/10.1080/15384047.2018.1508622.CrossRef

82.

Okamoto K, Proia LA, Demarais PL. Disseminated cryptococcal disease in a patient with chronic lymphocytic leukemia on Ibrutinib. Case Rep Infect Dis. 2016;2016:4642831–3. https://doi.org/10.1155/2016/4642831.CrossRefPubMedPubMedCentral

83.

Stankowicz M, Banaszynski M, Crawford R. Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia. J Oncol Pharm Pract. 2019;25:710–4. https://doi.org/10.1177/1078155217752078.CrossRefPubMed

84.

Pouvaret A, Guery R, Montillet M, Molina TJ, Duréault A, Bougnoux ME, et al. Concurrent cerebral aspergillosis and abdominal mucormycosis during ibrutinib therapy for chronic lymphocytic leukaemia. Clin Microbiol Infect. 2019;25:771–3. https://doi.org/10.1016/j.cmi.2019.01.016.CrossRefPubMed

85.

Koehler AB, Vijayvargiya P, Ding W. Probable invasive pulmonary cryptococcosis and possible Cryptococcal empyema in CLL treated with frontline Ibrutinib. Mayo Clin Proc. 2019;94:915–7. https://doi.org/10.1016/j.mayocp.2019.02.002.CrossRefPubMed

86.

Kreiniz N, Bejar J, Polliack A, Tadmor T. Severe pneumonia associated with ibrutinib monotherapy for CLL and lymphoma. Hematol Oncol. 2018;36:349–54. https://doi.org/10.1002/hon.2387.CrossRefPubMed

87.

Marini G, Bertizzolo ML, Castelli G, Cattelan A, Girolami B, Zambello R, Zola E, Baggio G. Invasive candidiasis in B-cell chronic lymphocytic leukemia: an example of internal medicine complexity. Italian Journal of Medicine. Conference: 21st Congresso Nazionale della Societa Scientifica FADOI. Italy. 10 (Supplement 2) (pp 73), 2016. Date of Publication: 01 May 2016. [Conference Abstract] http://www.italjmed.org/index.php/ijm/article/view/itjm.2016.s2/858

88.

Serota DP, Mehta AK, Phadke VK. Invasive fungal sinusitis due to mucor species in a patient on Ibrutinib. Clin Infect Dis. 2018;66:1482–3. https://doi.org/10.1093/cid/cix1058.CrossRefPubMed

89.

Stein MK, et al. Cutaneous mucormycosis following a bullous pemphigoid flare in a chronic lymphocytic leukemia patient on ibrutinib. World J Oncol. 2018;9:62–5. https://doi.org/10.14740/wjon1099w.CrossRefPubMedPubMedCentral

90.

Figueroa Castro CE. Id: 54: cutaneous mucormycosis in a patient with chronic lymphocytic leukemia: a pharmacological dilemma. J Investig Med. 2016;64:956–95957. https://doi.org/10.1136/jim-2016-000120.93.CrossRef

91.

Sylvine P, Thomas S, Pirayeh E, The French network of regional pharmacovigilance, C. Infections associated with ruxolitinib: study in the French pharmacovigilance database. Ann Hematol. 2018;97:913–4. https://doi.org/10.1007/s00277-018-3242-8.CrossRefPubMed

92.

Polverelli N, Palumbo GA, Binotto G, Abruzzese E, Benevolo G, Bergamaschi M, et al. Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: a multicenter study on 446 patients. Hematol Oncol. 2018;36:561–9. https://doi.org/10.1002/hon.2509.CrossRef

93.

Torti L, Morelli A, Bacci F, Di Bartolomeo P. Infectious events in a cohort of patients with myelofibrosis under treatment comparing ruxolitinib with conventional therapy. A monocentric experience of 22 patients retrospectively analysed. Haematologica. Conference: 22th Congress of the European Hematology Association. Spain. 102 (Supplement 2) (pp 818–819), 2017. Date of Publication: June 2017. [Conference Abstract] https://doi.org/10.3324/haematol.2016.155390.CrossRef

94.

Chen C-C, Chen Y-Y, Huang C-E. Cryptococcal meningoencephalitis associated with the long-term use of ruxolitinib. Ann Hematol. 2016;95:361–2. https://doi.org/10.1007/s00277-015-2532-7.CrossRefPubMed

95.

Chakrabarti A, Sood N. Cryptococcal meningitis in an immunocompetent patient with primary myelofibrosis on long-term ruxolitinib: report of a rare case and review of literature Magazine of European Medical Oncology. 2018;11(4):348–50. https://doi.org/10.1007/s12254-018-0435-8.CrossRef

96.

Hirano A, et al. Pulmonary cryptococcosis in a ruxolitinib-treated patient with primary myelofibrosis. Respir Med Case Rep. 2017;22:87–90. https://doi.org/10.1016/j.rmcr.2017.06.015.CrossRefPubMedPubMedCentral

97.

Wysham NG, Sullivan DR, Allada G. An opportunistic infection associated with ruxolitinib, a novel Janus kinase 1,2 inhibitor. Chest. 2013;143:1478–9. https://doi.org/10.1378/chest.12-1604.CrossRefPubMedPubMedCentral

98.

Liu J, Mouhayar E, Tarrand JJ, Kontoyiannis DP. Fulminant Cryptococcus neoformans infection with fatal pericardial tamponade in a patient with chronic myelomonocytic leukaemia who was treated with ruxolitinib: case report and review of fungal pericarditis. Mycoses. 2018;61:245–55. https://doi.org/10.1111/myc.12735.CrossRefPubMed

99.

Chan JF, et al. Disseminated infections with Talaromyces marneffei in non-AIDS patients given monoclonal antibodies against CD20 and kinase inhibitors. Emerg Infect Dis. 2015;21:1101–6. https://doi.org/10.3201/eid2107.150138.CrossRefPubMedPubMedCentral

100.

Fleischmann R, Wollenhaupt J, Takiya L, Maniccia A, Kwok K, Wang L, et al. Safety and maintenance of response for tofacitinib monotherapy and combination therapy in rheumatoid arthritis: an analysis of pooled data from open-label long-term extension studies. RMD Open. 2017;3:e000491. https://doi.org/10.1136/rmdopen-2017-000491.CrossRefPubMedPubMedCentral

101.

Sarker S, et al. Su1874 - Histoplasmosis in the setting of biologic therapy: a tertiary care inflammatory bowel disease experience. Gastroenterology. 152:S579. https://doi.org/10.1016/S0016-5085(17)32090-5(2017).

102.

Saber LT, Ikeda MY, Almeida JM. Posttransplantation conversion to sirolimus-based immunosuppression: a single center experience. Transplant Proc. 2007;39:3098–100. https://doi.org/10.1016/j.transproceed.2007.04.021.CrossRefPubMed

103.

Leet AS, Bergin PJ, Richardson M, Taylor AJ, Esmore D, Kaye DM. Outcomes following de novo CNI-free immunosuppression after heart transplantation: a single-center experience. Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2009;9:140–8. https://doi.org/10.1111/j.1600-6143.2008.02456.x.CrossRef

104.

Schaffellner S, Wagner D, Jakoby E, Kniepeiss D, Iberer F. Efficacy and safetey of sirolimus after liver transplantation. Transplant international. Conference: 16th congress of the European Society for Organ Transplantation, ESOT. Vienna Austria. Conference Publication: (var.pagings). 26 (SUPPL. 2) (pp 200), 2013. Date of Publication: November 2013. [Conference Abstract] https://doi.org/10.1111/tri.12214.

105.

Dominguez J, Mahalati K, Kiberd B, McAlister VC, MacDonald AS. Conversion to rapamycin immunosuppression in renal transplant recipients: report of an initial experience. Transplantation. 2000;70:1244–7.CrossRef

106.

Saur SJ, Peter S, Sonnichsen K, Metzler G, Faul C, Schaller M, Bethge WA, Vogel W, Kanz L, Haen SP. Infections with Fusarium species in patients with hematological malignancies-immediate treatment required. j. Conference: Jahrestagung der Deutschen, Osterreichischen und Schweizerischen Gesellschaften fur Hamatologie und Medizinische Onkologie 2014. Hamburg Germany. Conference Publication: (var.pagings). 37 (SUPPL. 5) (pp 159), 2014. Date of Publication: October 2014. [Conference Abstract] https://doi.org/10.1159/000368945.

107.

Iijima Y, et al. Invasive pulmonary aspergillosis mimicking organizing pneumonia after mTOR inhibitor therapy: a case report. Int J Infect Dis. 2018;69:75–7. https://doi.org/10.1016/j.ijid.2018.01.033.CrossRefPubMed

108.

Tanaka Y, et al. Spontaneous resolution of Pneumocystis jirovecii pneumonia on high-resolution computed tomography in a patient with renal cell carcinoma. Am J Case Rep. 2014;15:496–500. https://doi.org/10.12659/AJCR.890947.CrossRefPubMedPubMedCentral

109.

M., O. F. B. Z. G. M. M. G. H. Experience with mTOR inhibitors in pediatric liver transplantation (Conference Abstract). Transplantation. Conference: 26th International Congress of the Transplantation Society, TTS 2016. Hong Kong. 100 (7 Supplement 1) (pp S354), 2016. Date of Publication: July 2016. (2016).

110.

King C, Clement S, Katugaha S, Brown AW Fungal thyroiditis in a lung transplant recipient Case Reports 2018;2018:bcr-2018-227033. https://doi.org/10.1136/bcr-2018-227033.

111.

Angermeier S, Leimer L, Aulitzky WE. Pneumocystis pneumonia associated with everolimus treatment. Onkologie. Conference: Jahrestagung der Deutschen, Osterreichischen und Schweizerischen Gesellschaften fur Hamatologie und Onkologie 2013. Wien Austria. Conference Publication: (var.pagings). 36 (SUPPL. 7) (pp 11), 2013. Date of Publication: October 2013. [Conference Abstract] https://www.karger.com/Article/Pdf/356365.

112.

Saito Y, Nagayama M, Miura Y, Ogushi S, Suzuki Y, Noro R, et al. A case of Pneumocystis pneumonia associated with everolimus therapy for renal cell carcinoma. Jpn J Clin Oncol. 2013;43:559–62. https://doi.org/10.1093/jjco/hyt019.CrossRefPubMed

113.

Carbonnaux M, Molin Y, Souquet PJ, Tantin A, Lombard-Bohas C, Walter T. Pneumocystis jirovecii pneumonia under everolimus in two patients with metastatic pancreatic neuroendocrine tumors. Investig New Drugs. 2014;32:1308–10. https://doi.org/10.1007/s10637-014-0150-1.CrossRef

114.

Chen KH, Weng MT, Chou YH, Lu YF, Hsieh CH. Epigastric distress caused by esophageal candidiasis in 2 patients who received sorafenib plus radiotherapy for hepatocellular carcinoma: case report. Medicine. 2016;95:e3133. https://doi.org/10.1097/md.0000000000003133.CrossRefPubMedPubMedCentral

115.

Visvardis EE, Gao F, Paes MN, Duprez O, Waxman J. Lung aspergillosis in renal cell carcinoma patient treated with sunitinib. QJM. 2012;105:689–92. https://doi.org/10.1093/qjmed/hcr091.CrossRefPubMed

116.

Kim YW, Lee HW, Cho J, Choi HS, Lee J, Park SS, et al. Conversion of aspergilloma to chronic necrotizing pulmonary aspergillosis following treatment with sunitinib: a case report. Oncol Lett. 2016;12:3472–4. https://doi.org/10.3892/ol.2016.5052.CrossRefPubMedPubMedCentral

117.

Park S, Park S, Choi H, Park JY, Lim HS, Park MJ, et al. Invasive pulmonary aspergillosis in a patient with metastatic non-small cell lung cancer after treatment with gefitinib. Korean J Intern Med. 2018;33:211–3. https://doi.org/10.3904/kjim.2015.276.CrossRefPubMed

118.

Deiana L, Grisanti S, Ferrari V, Tironi A, Brugnoli G, Ferrari L, et al. Aspergillosis superinfection as a cause of death of crizotinib-induced interstitial lung disease successfully treated with high-dose corticosteroid therapy. Case Rep Oncol. 2015;8:169–73. https://doi.org/10.1159/000381209.CrossRefPubMedPubMedCentral

Title: Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections
Authors: Katie Bechman
James B Galloway
Kevin L Winthrop
Publication date: 01-12-2019
Publisher: Springer US
Keywords: Aspergillosis
Cryptococcosis
Histoplasmosis
Cytokines
Ibrutinib
mTOR-Inhibitors
Published in: Current Fungal Infection Reports / Issue 4/2019
Print ISSN: 1936-3761
Electronic ISSN: 1936-377X
DOI: https://doi.org/10.1007/s12281-019-00350-w

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Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

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Abstract

Purpose of Review

Recent Findings

Summary

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