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The impact of antifungal prophylaxis in patients diagnosed with acute leukemias undergoing induction chemotherapy: a systematic review and meta-analysis

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Abstract

Acute leukemias are complex diseases to treat and have a high mortality rate. The immunosuppression caused by chemotherapy also causes the patient to become susceptible to a variety of infections, including invasive fungal infections. Protocols established in many countries attempt to prevent these infections through the use of pharmacological antifungal prophylaxis. This systematic review and meta-analysis investigates the existing evidence for the use of antifungal prophylaxis in patients undergoing induction chemotherapy for acute leukemia, and how prophylaxis can affect treatment response and mortality. Through the use of a population-variable-outcome strategy, keywords were utilized to search online databases. The included studies were selected and the data was collected to develop descriptive results for all studies, and, for studies that met the criteria, a meta-analysis of the Relative Risk (RR) was analyzed for infection rates, in-hospital mortality, and complete remission. A total of 33 studies were included in this systematic review, with most studies presenting positive results (n = 28/33) from the use of antifungal prophylaxis. Using a random effects model, the pooled results of the meta-analysis presented lower invasive fungal infections in AML (RR: 0.527 (95% CI: 0.391; 0.709). p < 0.001). p < 0.001) and ALL (RR: 0.753 (95% CI: 0.574; 0.988). p = 0.041). when antifungal prophylaxis was used. No discernible difference was encountered in the rate of complete remission when using prophylaxis. Antifungal prophylaxis provides a lower risk of invasive fungal infections and in-hospital mortality in acute leukemia patients undergoing induction chemotherapy.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics. CA Cancer J Clin Wiley. 2022;72:7–33.

    Google Scholar 

  2. Roloff GW, Odenike O, Bajel A, et al. Contemporary approach to acute myeloid leukemia therapy in 2022. Am Soc Clin Oncol Educ Book. 2022;42:1–16.

    PubMed  Google Scholar 

  3. Elfaituri MK, Morsy S, Tawfik GM, et al. Incidence of Infection-related mortality in cancer patients: trend and survival analysis. Proc Am Soc Clin Oncol. 2019;37:e23095–e23095.

    Google Scholar 

  4. Zimmer AJ, Freifeld AG. Optimal management of neutropenic fever in patients with cancer. J Oncol Pract. 2019;15:19–24.

    PubMed  Google Scholar 

  5. Mendonça A, Santos H, Franco-Duarte R, et al. Fungal infections diagnosis—past, present and future. Res Microbiol. 2022;173:103915.

    PubMed  Google Scholar 

  6. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348:1546–54.

    PubMed  Google Scholar 

  7. Auberger J, Lass-Flörl C, Ulmer H, et al. Significant alterations in the epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. Int J Hematol Int J Hematol. 2008;88:508–15.

    PubMed  Google Scholar 

  8. Hammond SP, Marty FM, Bryar JM, et al. Invasive fungal disease in patients treated for newly diagnosed acute leukemia. Am J Hematol Am J Hematol. 2010;85:695–9.

    PubMed  Google Scholar 

  9. Pagano L, Mayor S. Invasive fungal infections in high-risk patients: report from TIMM-8 2017. Future Sci OA. Future Science Group; 2018;4.

  10. Maertens JA, Girmenia C, Brüggemann RJ, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European conference on infections in leukaemia. J Antimicrob Chemother. 2018;73:3221–30.

    CAS  PubMed  Google Scholar 

  11. Page MJ, McKenzie JE, Bossuyt PM, The PRISMA, et al. statement: an updated guideline for reporting systematic reviews. Br Med J. 2020;2021:372.

    Google Scholar 

  12. JBI Manual for Evidence Synthesis. JBI Manual for Evidence Synthesis. JBI; 2020.

  13. Board PATE. Adult Acute Lymphoblastic Leukemia Treatment (PDQ®). Bethesda, MD. National Cancer Institute (US); 2021.

  14. {Microsoft Corporation}. Microsoft excel. 2018.

  15. Owen RK, Bradbury N, Xin Y, et al. MetaInsight: an interactive web-based tool for analyzing, interrogating, and visualizing network meta-analyses using R-shiny and netmeta. Res Synth Methods. 2019;10(4):569–81.

    PubMed  PubMed Central  Google Scholar 

  16. The Endnote Team. Endnote. Philadelphia, PA: Clarivate; 2013.

  17. Mattiuzzi GN, Estey E, Raad I, et al. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer. 2003;97:450–6.

    CAS  PubMed  Google Scholar 

  18. Mattiuzzi GN, Kantarjian H, O’Brien S, et al. Intravenous itraconazole for prophylaxis of systemic fungal infections in patients with acute myelogenous leukemia and high-risk myelodysplastic syndrome undergoing induction chemotherapy. Cancer. 2004;100:568–73.

    CAS  PubMed  Google Scholar 

  19. Mattiuzzi GN, Alvarado G, Giles FJ, et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother Antimicrob Agents Chemother. 2006;50:143–7.

    CAS  PubMed  Google Scholar 

  20. Wetzstein GA, George TJ, Sharifi M, et al. Comparable efficacy and safety with voriconazole or posaconazole as primary antifungal prophylaxis in acute myeloid leukemia (AML) patients receiving induction chemotherapy. Blood Am Soc Hematol. 2009;114:2059–2059.

    Google Scholar 

  21. Vehreschild JJ, Rüping MJGT, Wisplinghoff H, et al. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort. J Antimicrob Chemother J Antimicrob Chemother. 2010;65:1466–71.

    CAS  PubMed  Google Scholar 

  22. Girmenia C, Frustaci AM, Gentile G, et al. Posaconazole prophylaxis during front-line chemotherapy of acute myeloid leukemia: a single center real life experience. Haematologica. 2011;96:110.

    Google Scholar 

  23. Mattiuzzi GN, Cortes J, Alvarado G, et al. Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Support Care Cancer Support Care Cancer. 2011;19:19–26.

    PubMed  Google Scholar 

  24. Michallet M, Sobh M, Morisset S, et al. Risk factors for invasive aspergillosis in acute myeloid leukemia patients prophylactically treated with posaconazole. Med Mycol. 2011;49:681–7.

    PubMed  Google Scholar 

  25. Fisher BT, Kavcic M, Li Y, et al. Antifungal prophylaxis associated with decreased induction mortality rates and resources utilized in children with new-onset acute myeloid leukemia. Clin Infect Dis. 2014;58:502–8.

    CAS  PubMed  Google Scholar 

  26. Minetto P, Guolo F, Pastori G, et al. Posaconazole as primary prophylaxis reduces invasive fungal infections in AML patients: a single centre matched paired analysis. Haematologica. 2015;100:717–8.

    Google Scholar 

  27. Cho SY, Lee DG, Choi SM, et al. Posaconazole for primary antifungal prophylaxis in patients with acute myeloid leukaemia or myelodysplastic syndrome during remission induction chemotherapy: a single-centre retrospective study in Korea and clinical considerations. Mycoses. 2015;58:565–71.

    CAS  PubMed  Google Scholar 

  28. Devanlay C, Tavernier-Tardy E, Bourmaud A, et al. Impact of fluconazole versus posaconazole prophylaxis on the incidence of fungal infections in patients receiving induction chemotherapy for acute myeloid leukemia. Biomed J. 2015;38:235–43.

    PubMed  Google Scholar 

  29. Schrenk KG, Schnetzke U, Stegemann K, et al. Efficacy of antifungal prophylaxis with oral suspension posaconazole during induction chemotherapy of acute myeloid leukemia. J Cancer Res Clin Oncol. 2015;141:1661–8.

    CAS  PubMed  Google Scholar 

  30. Dahlén T, Kalin M, Cederlund K, et al. Decreased invasive fungal disease but no impact on overall survival by posaconazole compared to fluconazole prophylaxis: a retrospective cohort study in patients receiving induction therapy for acute myeloid leukaemia/myelodysplastic syndromes. Eur J Haematol Eur J Haematol. 2016;96:175–80.

    PubMed  Google Scholar 

  31. Venton G, Adam H, Colle J, et al. Micafungin as primary antifungal prophylaxis in patients presenting with acute myeloid leukemia. Med Mal Infect Med Mal Infect. 2016;46:226–9.

    CAS  PubMed  Google Scholar 

  32. Shah A, Ganesan P, Radhakrishnan V, et al. Voriconazole is a safe and effective anti-fungal prophylactic agent during induction therapy of acute myeloid leukemia. Indian J Med Paediatr Oncol. 2016;37:53.

    PubMed  PubMed Central  Google Scholar 

  33. Bansal D, Seth T, Kumar R, et al. Efficacy of posaconazole prophylaxis in patients with acute myeloid leukemia undergoing induction chemotherapy: an observational study in resource limited settings. Indian J Hematol Blood Transfus. 2018;34:460.

    PubMed  PubMed Central  Google Scholar 

  34. Chen T-C, Wang RC, Lin Y-H, et al. Posaconazole for the prophylaxis of invasive aspergillosis in acute myeloid leukemia: Is it still useful outside the clinical trial setting? Ther Adv Hematol. 2020;11:2040620720965846–2040620720965846.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hsu A, Matera R, Reagan JL, et al. Survival benefits from antifungal prophylaxis and a dedicated inpatient malignant hematology service during induction chemotherapy for acute myeloid leukemia. Blood. 2019;134:3436.

    Google Scholar 

  36. Hsu A, Matera R, Vieira K, et al. Antifungal prophylaxis during 7 + 3 induction chemotherapy for acute myeloid leukemia is associated with improved survival, in a setting with low incidence of invasive mold infections. Support Care Cancer. 2020;29:707–12.

    PubMed  Google Scholar 

  37. Mishra P, Agrawal N, Bhurani D, et al. Invasive fungal infections in patients with acute myeloid leukemia undergoing intensive chemotherapy. Indian J Hematol Blood Transfus. 2020;36:64–70.

    PubMed  Google Scholar 

  38. Signorelli J, Lei M, Lam J, et al. Incidence of invasive fungal infections in acute myeloid leukemia without antifungal prophylaxis. Clin Lymphoma Myeloma Leuk. 2020;20:e883–9.

    PubMed  Google Scholar 

  39. Bekadja MA, Michallet M, Benzineb B, et al. Evaluation of posaconazole for primary prophylaxis of IFI in acute myeloid leukemia under intensive induction chemotherapy comparative real life study with fluconazole in two hematological centers in Algeri. Asian Pac J Cancer Biol. 2021;6:249–54.

    CAS  Google Scholar 

  40. Bose P, McCue D, Wurster S, et al. Isavuconazole as primary antifungal prophylaxis in patients with acute myeloid leukemia or myelodysplastic syndrome: an open-label, prospective, phase 2 study. Clin Infect Dis Clin Infect Dis. 2021;72:1755–63.

    CAS  PubMed  Google Scholar 

  41. Yang E, Choi EJ, Park HS, et al. Comparison of invasive fungal diseases between patients with acute myeloid leukemia receiving posaconazole prophylaxis and those not receiving prophylaxis: a single-center, observational, case-control study in South {Korea}. Medicine (Baltimore). 2021;100:e25448.

    CAS  PubMed  Google Scholar 

  42. Cornely O, Leguay T, Maertens J, et al. A double-blind, multicentre, randomised, placebo-controlled study to assess the efficacy, safety and tolerability of prophylactic liposomal amphotericin B (AmBisome®) for the prevention of invasive fungal infections in subjects receiving remission-induction chemotherapy for acute lymphoblastic leukaemia (AmBiGuard trial). Blood Am Soc Hematol. 2014;124:3646–3646.

    Google Scholar 

  43. Cornely OA, Leguay T, Maertens J, et al. Randomized comparison of liposomal amphotericin B versus placebo to prevent invasive mycoses in acute lymphoblastic leukaemia. J Antimicrob Chemother J Antimicrob Chemother. 2017;72:2359–67.

    CAS  PubMed  Google Scholar 

  44. Zhang T, Bai J, Huang M, et al. Posaconazole and fluconazole prophylaxis during induction therapy for pediatric acute lymphoblastic leukemia. J Microbiol Immunol Infect. 2021;54:1139–46.

    CAS  PubMed  Google Scholar 

  45. Chabrol A, Cuzin L, Huguet F, et al. Prophylaxis of invasive aspergillosis with voriconazole or caspofungin during building work in patients with acute leukemia. Haematologica. 2010;95:996–1003.

    CAS  PubMed  Google Scholar 

  46. Cattaneo C, Monte S, Algarotti A, et al. A randomized comparison of caspofungin versus antifungal prophylaxis according to investigator policy in acute leukaemia patients undergoing induction chemotherapy ({PROFIL}-{C} study). J Antimicrob Chemother. 2011;66:2140–5.

    CAS  PubMed  Google Scholar 

  47. Mandhaniya S, Swaroop C, Thulkar S, et al. Oral voriconazole versus intravenous low dose amphotericin B for primary antifungal prophylaxis in pediatric acute leukemia induction: a prospective, randomized, clinical study. J Pediatr Hematol Oncol. 2011;33(8):e333–41.

    CAS  PubMed  Google Scholar 

  48. Epstein DJ, Seo SK, Huang YT, et al. Micafungin versus posaconazole prophylaxis in acute leukemia or myelodysplastic syndrome: a randomized study. J Infect J Infect. 2018;77:227–34.

    PubMed  Google Scholar 

  49. Park H, Youk J, Shin DY, et al. Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy. BMC Cancer. 2019;19:358.

    PubMed  PubMed Central  Google Scholar 

  50. Teh BW, Yeoh DK, Haeusler GM, et al. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation. Intern Med J. 2021;51(7):67–88.

    CAS  PubMed  Google Scholar 

  51. Young AY, Leiva Juarez MM, Evans SE. Fungal pneumonia in patients with hematologic malignancy and hematopoietic stem cell transplantation. Clin Chest Med Clin Chest Med. 2017;38:479–91.

    PubMed  Google Scholar 

  52. Stemler J, Cornely OA. Antifungal prophylaxis in acute myeloid leukemia: new drugs new challenges? Hemasphere. Ovid Technol. 2022;6:e742.

    Google Scholar 

  53. Busca A, Lessi F, Verga L, et al. SEIFEM 2010-{E}: economic evaluation of posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia receiving induction chemotherapy. Leuk Lymphoma. 2017;58:2859–64.

    CAS  PubMed  Google Scholar 

  54. Schonfeld W, Wang Cheng J, Tong KB, et al. Cost-effectiveness analysis of antifungal prophylaxis in patients undergoing hematopoietic stem cell transplantation. Clin Ther. 2008;30:964–73.

    CAS  PubMed  Google Scholar 

  55. Özen M, Yılmaz G, Coşkun B, et al. A quasi-experimental study analyzing the effectiveness of portable high-efficiency particulate absorption filters in preventing infections in hematology patients during construction. Turk J Hematol. 2016;33:41.

    Google Scholar 

  56. Spernovasilis N, Kofteridis DP. Pre-existing liver disease and toxicity of antifungals. J Fungi. 2018;4(4):133.

    CAS  Google Scholar 

  57. Michallet M, Sobh M, Morisset S, et al. Validation of positive effect of posaconazole prophylaxis during induction chemotherapy in AML: study of invasive aspergillosis incidence and of risk factors on short and long-term survival. Blood. 2009;114:4124.

    Google Scholar 

  58. Maciej S, Becker FG, Cleary M, et al. Management of acute leukemias. In: Balint G, Antala B, Carty C, Mabieme JMA, Amar IB, Kaplanova A, editors., et al., Uniwersytet śląski. UK: Wolters Kluwer Health Pharma Solutions Europe Ltd; 2018. p. 1743–63.

    Google Scholar 

  59. Fisher MC, Alastruey-Izquierdo A, et al. Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol. 2022;20(9):557–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Pagano L, Busca A, Candoni A, et al. Risk stratification for invasive fungal infections in patients with hematological malignancies: SEIFEM recommendations. Blood Rev Blood Rev. 2017;31:17–29.

    PubMed  Google Scholar 

  61. Ostrosky-Zeichner L, Marr KA, Rex JH, et al. Amphotericin B: time for a new “gold standard.” Clin Infect Dis Clin Infect Dis. 2003;37:415–25.

    CAS  PubMed  Google Scholar 

  62. Cronin S, Chandrasekar PH. Safety of triazole antifungal drugs in patients with cancer. J Antimicrob Chemother J Antimicrob Chemother. 2010;65:410–6.

    CAS  PubMed  Google Scholar 

  63. Vazquez L. Antifungal prophylaxis in immunocompromised patients. Mediterr J Hematol Infect Dis Catholic University in Rome. 2016;8:2016040.

    Google Scholar 

  64. Rabaan AA, Alfaraj AH, Alshengeti A, et al. Antibodies to combat fungal infections: development strategies and progress. Microorganisms 2023, Vol 11, Page 671 [Internet]. Multidisciplinary Digital Publishing Institute; 2023 [cited 2023 Mar 21];11:671. Available from: https://www.mdpi.com/2076-2607/11/3/671/htm

  65. Xin H, Rosario-Colon JA, Eberle K. Novel Intravenous Immunoglobulin Therapy for the Prevention and Treatment of Candida auris and Candida albicans Disseminated Candidiasis. mSphere [Internet]. mSphere; 2023 [cited 2023 Mar 21];8. Available from: https://pubmed.ncbi.nlm.nih.gov/36688668/

  66. Vacca A, Melaccio A, Sportelli A, et al. Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial. Clin Immunol [Internet]. Clin Immunol; 2018 [cited 2023 Mar 21];191:110–5. Available from: https://pubmed.ncbi.nlm.nih.gov/29191714/

  67. Kaya Z, Gursel T, Kocak U, et al. Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatr Blood Cancer Pediatr Blood Cancer. 2009;52:470–5.

    PubMed  Google Scholar 

  68. Pagano L, Caira M, Nosari A, et al. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study—sorveglianza epidemiologica infezioni fungine nelle emopatie maligne. Clin Infect Dis. 2007;45:1161–70.

    CAS  PubMed  Google Scholar 

  69. Koeffler HP, Leong G. Preleukemia: one name, many meanings. Leukemia 2017 31:3 [Internet]. Nature Publishing Group; 2016 [cited 2023 Mar 22];31:534–42. Available from: https://www.nature.com/articles/leu2016364

  70. Minetto P, Guolo F, Mikulska M, et al. Posaconazole for primary antifungal Prophylaxis in AML patients: a real life single center experience and a comparison with the Historical cohort. Blood [Internet]. Am J Hematol. 2014;124:5255. Available from: https://ashpublications.org/blood/article/124/21/5255/92439/Posaconazole-for-Primary-Antifungal-Prophylaxis-in.

  71. Michallet M, Sobh M, Morisset S, et al. Antifungal Prophylaxis in AML patients receiving intensive induction chemotherapy: a prospective observational study from the acute leukaemia french association (ALFA) group. Clin Lymphoma Myeloma Leuk [Internet]. Clin Lymphoma Myeloma Leuk. 2022;22:311–8. Available from: https://pubmed.ncbi.nlm.nih.gov/34895843/.

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Acknowledgements

To the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and the Graduate Program in Immunology and Applied Parasitology at the Federal University of Uberlândia, Brazil.

Funding

A scholarship was provided by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES Foundation).

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Authors and Affiliations

  1. Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Minas Gerais, Brazil

    Luiz Ricardo Soldi, Yasmin Nascimento Bernardes Coelho, Luiz Renato Paranhos & Marcelo José Barbosa Silva

  2. Tumor Biomarkers and Osteoimmunology Laboratory, Av. Pará - 1720 - Block 6T, Room 07 - District Umuarama, Uberlândia, Minas Gerais, Brazil

    Luiz Ricardo Soldi & Marcelo José Barbosa Silva

  3. Student of the Graduate Program in Applied Immunology and Parasitology, Universidade Federal de Uberlândia, Uberlândia, Brazil

    Luiz Ricardo Soldi & Yasmin Nascimento Bernardes Coelho

  4. Professor responsible for the area of Immunology at the Institute of Biomedical Sciences, Universidade Federal de Uberlândia, Uberlândia, Brazil

    Marcelo José Barbosa Silva

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All authors contributed to the study's conception and design. Data collection was performed by Luiz RS, YNBC, and MJBS. Data analyses were performed by LRS. The first draft of the manuscript was written by LRS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Soldi, L.R., Coelho, Y.N.B., Paranhos, L.R. et al. The impact of antifungal prophylaxis in patients diagnosed with acute leukemias undergoing induction chemotherapy: a systematic review and meta-analysis. Clin Exp Med 23, 3231–3249 (2023). https://doi.org/10.1007/s10238-023-01062-9

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