Invasive Mold Infections in Patients with Chronic Lymphoproliferative Disorders
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).
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).
KeywordsMold 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
- 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
- 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
- 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.Varughese, T., et al., Serious infections in patients receiving Ibrutinib for treatment of lymphoid malignancies. Clin Infect Dis, 2018.Google Scholar
- 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
- 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
- 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
- 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.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
- 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
- 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
- 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.CrossRefGoogle Scholar
- 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.CrossRefGoogle Scholar