Current Fungal Infection Reports

, Volume 12, Issue 4, pp 179–186 | Cite as

Invasive Mold Infections in Patients with Chronic Lymphoproliferative Disorders

  • Davide FacchinelliEmail author
  • Gessica Marchesini
  • Gianpaolo Nadali
  • Livio Pagano
Current Management of Fungal Infections (J Maertens, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Current Management of Fungal Infections


Purpose of the Review

This review summarizes data about epidemiology, treatment, and risk factors for invasive fungal infections (IFI) in patients affected by chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and indolent non Hodgkin lymphoma (iNHL).

Recent Findings

Despite advances in the prognosis and treatment of hematological malignancies in recent years, susceptibility to infection remains a significant challenge to patient care. A large amount of data regarding patients with acute leukemias have been published while little information is available on incidence of IFI in chronic lymphoproliferative disorders (CLD).


The overall incidence of IFI in CLL patients is reported from 1.3 to 7.8% and the main risk factors are related to disease status (high-risk in relapsed/refractory disease), number of previous chemotherapy regimens, and Ig levels.

In MM, most of the IFI occurred during refractory or progressive disease. The rate of IFI ranges from 0.5 to 12.3%. Neutropenia is the main risk factor in MM and risk seems to be related to its duration and severity. The overall incidence of IFI in iNHL ranges from 0.5 to 4% and the most important risk factors are disease status (high-risk in relapsed/refractory and advance stage disease) and type of treatment (high-risk for steroid administration, intensive chemotherapy with prolonged neutropenia, use of monoclonal antibodies and purine analogs).


Mold infection Epidemiology Chronic lymphoproliferative disease Risk factors 


Compliance with Ethical Standards

Conflict of Interest

Livio Pagano is a board member and speaker on behalf of Gilead, MSD, Pfizer, Basilea, and Janssen.

Davide Facchinelli, Gessica Marchesini, and Gianpaolo Nadali declare that they have no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Nosari AM, Pioltelli ML, Riva M, Marbello L, Nichelatti M, Greco A, et al. Invasive fungal infections in lymphoproliferative disorders: a monocentric retrospective experience. Leuk Lymphoma. 2014;55(8):1844–8.CrossRefGoogle Scholar
  2. 2.
    •• Pagano L, et al. Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. Blood Rev. 2017;31(2):17–29 Important work that stratifies low, intermediate or high risk haematological patients for fungal infections. It also analyzes the possible correlated risk factors.CrossRefGoogle Scholar
  3. 3.
    Pagano L, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica. 2006;91(8):1068–75.PubMedGoogle Scholar
  4. 4.
    Safdar A, Armstrong D. Infections in patients with hematologic neoplasms and hematopoietic stem cell transplantation: neutropenia, humoral, and splenic defects. Clin Infect Dis. 2011;53(8):798–806.CrossRefGoogle Scholar
  5. 5.
    Stanzani M, Lewis RE, Fiacchini M, Ricci P, Tumietto F, Viale P, et al. A risk prediction score for invasive mold disease in patients with hematological malignancies. PLoS One. 2013;8(9):e75531.CrossRefGoogle Scholar
  6. 6.
    • Sun C, et al. Partial reconstitution of humoral immunity and fewer infections in patients with chronic lymphocytic leukemia treated with ibrutinib. Blood. 2015;126(19):2213–9 This paper, unlike most, suggests a decrease in fungal infections in CLL patients treated with Ibrutinib due to a partial immunological reconstitution, especially humoral.CrossRefGoogle Scholar
  7. 7.
    Teng JC, Slavin MA, Teh BW, Lingaratnam SM, Ananda-Rajah MR, Worth LJ, et al. Epidemiology of invasive fungal disease in lymphoproliferative disorders. Haematologica. 2015;100(11):e462–6.CrossRefGoogle Scholar
  8. 8.
    •• Tisi MC, et al. Invasive fungal infections in chronic lymphoproliferative disorders: a monocentric retrospective study. Haematologica. 2017;102(3):e108–11 This monocentric study evaluates the incidence of IFI (molds and yeasts) in patients with CLD also reporting clinical and treatment; there is also a good review of the literature.CrossRefGoogle Scholar
  9. 9.
    Varughese, T., et al., Serious infections in patients receiving Ibrutinib for treatment of lymphoid malignancies. Clin Infect Dis, 2018.Google Scholar
  10. 10.
    Visentin A, Gurrieri C, Imbergamo S, Lessi F, di Maggio SA, Frezzato F, et al. Epidemiology and risk factors of invasive fungal infections in a large cohort of patients with chronic lymphocytic leukemia. Hematol Oncol. 2017;35(4):925–8.CrossRefGoogle Scholar
  11. 11.
    • Williams AM, et al. Analysis of the risk of infection in patients with chronic lymphocytic leukemia in the era of novel therapies. Leuk Lymphoma. 2018;59(3):625–32 This study highlights how the recent treatments introduced for CLL have a high risk of serious infectious complications, not inferior to that of chemotherapy.CrossRefGoogle Scholar
  12. 12.
    Francis S, Karanth M, Pratt G, Starczynski J, Hooper L, Fegan C, et al. The effect of immunoglobulin VH gene mutation status and other prognostic factors on the incidence of major infections in patients with chronic lymphocytic leukemia. Cancer. 2006;107(5):1023–33.CrossRefGoogle Scholar
  13. 13.
    Sun Y, Huang H, Chen J, Li J, Ma J, Li J, et al. Invasive fungal infection in patients receiving chemotherapy for hematological malignancy: a multicenter, prospective, observational study in China. Tumour Biol. 2015;36(2):757–67.CrossRefGoogle Scholar
  14. 14.
    Forconi F, Moss P. Perturbation of the normal immune system in patients with CLL. Blood. 2015;126(5):573–81.CrossRefGoogle Scholar
  15. 15.
    Wadhwa PD, Morrison VA. Infectious complications of chronic lymphocytic leukemia. Semin Oncol. 2006;33(2):240–9.CrossRefGoogle Scholar
  16. 16.
    Ravandi F, O'Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother. 2006;55(2):197–209.CrossRefGoogle Scholar
  17. 17.
    Moreira J, Rabe KG, Cerhan JR, Kay NE, Wilson JW, Call TG, et al. Infectious complications among individuals with clinical monoclonal B-cell lymphocytosis (MBL): a cohort study of newly diagnosed cases compared to controls. Leukemia. 2013;27(1):136–41.CrossRefGoogle Scholar
  18. 18.
    Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, et al. Impact of therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: intergroup study cancer and leukemia group B 9011. J Clin Oncol. 2001;19(16):3611–21.CrossRefGoogle Scholar
  19. 19.
    Hensel M, Kornacker M, Yammeni S, Egerer G, Ho AD. Disease activity and pretreatment, rather than hypogammaglobulinaemia, are major risk factors for infectious complications in patients with chronic lymphocytic leukaemia. Br J Haematol. 2003;122(4):600–6.CrossRefGoogle Scholar
  20. 20.
    Steinbach WJ, et al. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry. J Inf Secur. 2012;65(5):453–64.Google Scholar
  21. 21.
    Anaissie EJ, et al. Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med. 1998;129(7):559–66.CrossRefGoogle Scholar
  22. 22.
    Wierda W, O’Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18):4070–8.CrossRefGoogle Scholar
  23. 23.
    Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18):4079–88.CrossRefGoogle Scholar
  24. 24.
    Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(26):4378–84.CrossRefGoogle Scholar
  25. 25.
    Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012;30(26):3209–16.CrossRefGoogle Scholar
  26. 26.
    Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, et al. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011;29(26):3559–66.CrossRefGoogle Scholar
  27. 27.
    Byrd JC, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from cancer and leukemia group B 9712 (CALGB 9712). Blood. 2003;101(1):6–14.CrossRefGoogle Scholar
  28. 28.
    Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–10.CrossRefGoogle Scholar
  29. 29.
    Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis. 2006;43(1):16–24.CrossRefGoogle Scholar
  30. 30.
    Elter T, Vehreschild JJ, Gribben J, Cornely OA, Engert A, Hallek M. Management of infections in patients with chronic lymphocytic leukemia treated with alemtuzumab. Ann Hematol. 2009;88(2):121–32.CrossRefGoogle Scholar
  31. 31.
    Sehn LH. Introduction to a review series: the paradox of indolent B-cell lymphoma. Blood. 2016;127(17):2045–6.CrossRefGoogle Scholar
  32. 32.
    Baden LR, Swaminathan S, Angarone M, Blouin G, Camins BC, Casper C, et al. Prevention and treatment of cancer-related infections, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2016;14(7):882–913.CrossRefGoogle Scholar
  33. 33.
    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(15):1940–3.CrossRefGoogle Scholar
  34. 34.
    •• 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(1):140–8 This comprehensive paper collects the cases described in the literature of IFI in patients treated with ibrutinib. The risk of IFI related to treatment with other target therapies as well as the potential risk factors predisposing to such complications in this patient setting is also described.CrossRefGoogle Scholar
  35. 35.
    Arthurs B, et al. Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia. Respir Med Case Rep. 2017;21:27–9.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Baron M, Zini JM, Challan Belval T, Vignon M, Denis B, Alanio A, et al. Fungal infections in patients treated with ibrutinib: two unusual cases of invasive aspergillosis and cryptococcal meningoencephalitis. Leuk Lymphoma. 2017;58(12):2981–2.CrossRefGoogle Scholar
  37. 37.
    Choquet S, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood. 2006;107(8):3053–7.CrossRefGoogle Scholar
  38. 38.
    Grommes C, DeAngelis LM. Primary CNS lymphoma. J Clin Oncol. 2017;35(21):2410–8.CrossRefGoogle Scholar
  39. 39.
    Teh BW, Teng JC, Urbancic K, Grigg A, Harrison SJ, Worth LJ, et al. Invasive fungal infections in patients with multiple myeloma: a multi-center study in the era of novel myeloma therapies. Haematologica. 2015;100(1):e28–31.CrossRefGoogle Scholar
  40. 40.
    Lortholary O, Ascioglu S, Moreau P, Herbrecht R, Marinus A, Casassus P, et al. Invasive aspergillosis as an opportunistic infection in nonallografted patients with multiple myeloma: a European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the Intergroupe Francais du Myelome. Clin Infect Dis. 2000;30(1):41–6.CrossRefGoogle Scholar
  41. 41.
    Kurosawa M, Yonezumi M, Hashino S, Tanaka J, Nishio M, Kaneda M, et al. Epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. Int J Hematol. 2012;96(6):748–57.CrossRefGoogle Scholar
  42. 42.
    Huang BH, et al. The clinical features and risk factors for invasive fungal infection in multiple myeloma. Zhonghua Nei Ke Za Zhi. 2009;48(12):1026–30.PubMedGoogle Scholar
  43. 43.
    Cornet M, Fleury L, Maslo C, Bernard JF, Brücker G. Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area. J Hosp Infect. 2002;51(4):288–96.CrossRefGoogle Scholar
  44. 44.
    Lortholary O, Gangneux JP, Sitbon K, Lebeau B, de Monbrison F, le Strat Y, et al. Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005-2007). Clin Microbiol Infect. 2011;17(12):1882–9.CrossRefGoogle Scholar
  45. 45.
    Liu J, Huang H, Li Y, Liu L, Li J, Liu Z, et al. Epidemiology and treatment of invasive fungal diseases in patients with multiple myeloma: findings from a multicenter prospective study from China. Tumour Biol. 2016;37(6):7893–900.CrossRefGoogle Scholar
  46. 46.
    Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis. 2009;49(8):1211–25.CrossRefGoogle Scholar
  47. 47.
    Nosari AM, Caira M, Pioltelli ML, Fanci R, Bonini A, Cattaneo C, et al. Hema e-chart registry of invasive fungal infections in haematological patients: improved outcome in recent years in mould infections. Clin Microbiol Infect. 2013;19(8):757–62.CrossRefGoogle Scholar
  48. 48.
    Takaoka K, Nannya Y, Shinohara A, Arai S, Nakamura F, Kurokawa M. A novel scoring system to predict the incidence of invasive fungal disease in salvage chemotherapies for malignant lymphoma. Ann Hematol. 2014;93(10):1637–44.CrossRefGoogle Scholar
  49. 49.
    Jantunen E, Salonen J, Juvonen E, Koivunen E, Siitonen T, Lehtinen T, et al. Invasive fungal infections in autologous stem cell transplant recipients: a nation-wide study of 1188 transplanted patients. Eur J Haematol. 2004;73(3):174–8.CrossRefGoogle Scholar
  50. 50.
    Herbrecht R, Bories P, Moulin JC, Ledoux MP, Letscher-Bru V. Risk stratification for invasive aspergillosis in immunocompromised patients. Ann N Y Acad Sci. 2012;1272:23–30.CrossRefGoogle Scholar
  51. 51.
    Montagna MT, Giglio OD, Napoli C, Lovero G, Caggiano G, Delia M, et al. Invasive fungal infections in patients with hematologic malignancies (aurora project): lights and shadows during 18-months surveillance. Int J Mol Sci. 2012;13(1):774–87.CrossRefGoogle Scholar
  52. 52.
    Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, et al. Ibrutinib for patients with rituximab-refractory Waldenstrom's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18(2):241–50.CrossRefGoogle Scholar
  53. 53.
    Klingspor L, Saaedi B, Ljungman P, Szakos A. Epidemiology and outcomes of patients with invasive mould infections: a retrospective observational study from a single centre (2005-2009). Mycoses. 2015;58(8):470–7.CrossRefGoogle Scholar
  54. 54.
    Pagano L, Caira M, Candoni A, Offidani M, Martino B, Specchia G, et al. Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study. Haematologica. 2010;95(4):644–50.CrossRefGoogle Scholar
  55. 55.
    Fleming S, Yannakou CK, Haeusler GM, Clark J, Grigg A, Heath CH, et al. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J. 2014;44(12b):1283–97.CrossRefGoogle Scholar
  56. 56.
    Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N. Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother. 2011;66(Suppl 1):i5–14.CrossRefGoogle Scholar
  57. 57.
    Gil L, Kozlowska-Skrzypczak M, Mol A, Poplawski D, Styczynski J, Komarnicki M. Increased risk for invasive aspergillosis in patients with lymphoproliferative diseases after autologous hematopoietic SCT. Bone Marrow Transplant. 2009;43(2):121–6.CrossRefGoogle Scholar
  58. 58.
    Vazquez L, et al. Delphi-based study and analysis of key risk factors for invasive fungal infection in haematological patients. Rev Esp Quimioter. 2017;30(2):103–17.PubMedGoogle Scholar
  59. 59.
    van Hal SJ, et al. Survey of antifungal prophylaxis and fungal diagnostic tests employed in malignant haematology and haemopoietic stem cell transplantation (HSCT) in Australia and New Zealand. Intern Med J. 2014;44(12b):1277–82.CrossRefGoogle Scholar
  60. 60.
    Mellinghoff SC, Panse J, Alakel N, et al. Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Haematol. 2018;97(2):197–207.Google Scholar
  61. 61.
    Reinwald M, Silva JT, Mueller NJ, et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors). Clin Microbiol Infect. 2018;2:S53–S70.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Davide Facchinelli
    • 1
    Email author
  • Gessica Marchesini
    • 1
  • Gianpaolo Nadali
    • 1
  • Livio Pagano
    • 2
  1. 1.Hematology UnitAzienda Ospedaliera Universitaria Integrata di VeronaVeronaItaly
  2. 2.Institute of Haematology, Fondazione Policlinico A. Gemelli–IRCCSUniversità Cattolica S. CuoreRomeItaly

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