Skip to main content

Advertisement

SpringerLink
Log in

A multicenter phase 2 study of empirical low-dose liposomal amphotericin B in patients with refractory febrile neutropenia

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Invasive fungal infection (IFI) is a major life-threatening problem encountered by patients with hematological malignancies receiving intensive chemotherapy. Empirical antifungal agents are therefore important. Despite the availability of antifungal agents for such situations, the optimal agents and administration methods remain unclear. We conducted a prospective phase 2 study of empirical 1 mg/kg/day liposomal amphotericin B (L-AMB) in 80 patients receiving intensive chemotherapy for hematological malignancies. All enrolled patients were high-risk and had recurrent prolonged febrile neutropenia despite having received broad-spectrum antibacterial therapy for at least 72 hours. Fifty-three patients (66.3 %) achieved the primary endpoint of successful treatment, thus exceeding the predefined threshold success rate. No patients developed IFI. The treatment completion rate was 73.8 %, and only two cases ceased treatment because of adverse events. The most frequent events were reversible electrolyte abnormalities. We consider low-dose L-AMB to provide comparable efficacy and improved safety and cost-effectiveness when compared with other empirical antifungal therapies. Additional large-scale randomized studies are needed to determine the clinical usefulness of L-AMB relative to other empirical antifungal therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Pagano L, Stamouli M, Tumbarello M, Verga L, Candoni A, Cattaneo C, et al. Risk of invasive fungal infection in patients affected by acute promyelocytic leukaemia. A report by the SEIFEM-D registry. Br J Haematol. 2015;170:434–9.

    Article  PubMed  Google Scholar 

  2. Chan TS, Gill H, Hwang YY, Sim J, Tse AC, Loong F, et al. Breakthrough invasive fungal diseases during echinocandin treatment in high-risk hospitalized hematologic patients. Ann Hematol. 2014;93:493–8.

    Article  CAS  PubMed  Google Scholar 

  3. 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;96:748–57.

    Article  PubMed  Google Scholar 

  4. Kume H, Yamazaki T, Abe M, Tanuma H, Okudaira M, Okayasu I. Epidemiology of visceral mycoses in patients with leukemia and MDS—analysis of the data in annual of pathological autopsy cases in Japan in 1989, 1993, 1997 and 2001. Nihon Ishinkin Gakkai Zasshi. 2006;47:15–24.

    Article  PubMed  Google Scholar 

  5. Lass-Flörl C. The changing face of epidemiology of invasive fungal disease in Europe. Mycoses. 2009;52:197–205.

    Article  PubMed  Google Scholar 

  6. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, Mullen CA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2011;52:e56–93.

    Article  PubMed  Google Scholar 

  7. Cordonnier C, Pautas C, Maury S, Vekhoff A, Farhat H, Suarez F, et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis. 2009;48:1042–51.

    Article  CAS  PubMed  Google Scholar 

  8. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013;73:919–34.

    Article  CAS  PubMed  Google Scholar 

  9. Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999;340:764–71.

    Article  CAS  PubMed  Google Scholar 

  10. Prentice HG, Hann IM, Herbrecht R, Aoun M, Kvaloy S, Catovsky D, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol. 1997;98:711–8.

    Article  CAS  PubMed  Google Scholar 

  11. Ellis M, Spence D, de Pauw B, Meunier F, Marinus A, Collette L, et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clin Infect Dis. 1998;27:1406–12.

    Article  CAS  PubMed  Google Scholar 

  12. Mizuno H, Sawa M, Yanada M, Shirahata M, Watanabe M, Kato T, et al. Micafungin for empirical antifungal therapy in patients with febrile neutropenia: multicenter phase 2 study. Int J Hematol. 2013;98:231–6.

    Article  CAS  PubMed  Google Scholar 

  13. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730–51.

    Article  PubMed  Google Scholar 

  14. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, Calandra T, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008;46:1813–21.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:225–34.

    Article  CAS  PubMed  Google Scholar 

  16. Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351:1391–402.

    Article  CAS  PubMed  Google Scholar 

  17. Ohta K, Nishiki Kosaka S, Nakao Y, Kumura T, Hagihara K, Sakamoto E, et al. Efficacy and safety of intravenous itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematological malignancies in Japan. Int J Hematol. 2009;89:649–55.

    Article  CAS  PubMed  Google Scholar 

  18. Ellis D. Amphotericin B: spectrum and resistance. J Antimicrob Chemother. 2002;49(Suppl 1):7–10.

    Article  CAS  PubMed  Google Scholar 

  19. Yamazaki S, Nakamura F, Yoshimi A, Ichikawa M, Nannya Y, Kurokawa M. Safety of high-dose micafungin for patients with hematological diseases. Leuk Lymphoma. 2014;55:2572–6.

    Article  CAS  PubMed  Google Scholar 

  20. Koh H, Hino M, Ohta K, Iino M, Urase F, Yamaguchi M, et al. Empirical voriconazole therapy for febrile neutropenic patients with hematological disorders: a prospective multicenter trial in Japan. J Infect Chemother. 2013;19:1126–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tacke D, Buchheidt D, Karthaus M, Krause SW, Maschmeyer G, Neumann S, et al. Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Ann Hematol. 2014;2014(93):1449–56.

    Article  Google Scholar 

  22. Takagi S, Araoka H, Uchida N, Uchida Y, Kaji D, Ota H, et al. A prospective feasibility study of primary prophylaxis against invasive fungal disease with voriconazole following umbilical cord blood transplantation with fludarabine-based conditioning. Int J Hematol. 2014;99:652–8.

    Article  CAS  PubMed  Google Scholar 

  23. Rotstein C, Bow EJ, Laverdiere M, Ioannou S, Carr D, Moghaddam N. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. The Canadian Fluconazole Prophylaxis Study Group. Clin Infect Dis. 1999;28:331–40.

    Article  CAS  PubMed  Google Scholar 

  24. Morgenstern GR, Prentice AG, Prentice HG, Ropner JE, Schey SA, Warnock DW. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies. U.K. Multicentre Antifungal Prophylaxis Study Group. Br J Haematol. 1999;105:901–11.

    Article  CAS  PubMed  Google Scholar 

  25. Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348–59.

    Article  CAS  PubMed  Google Scholar 

  26. Weiler S, Bellmann R. Posaconazole prophylaxis in hematologic cancer. N Engl J Med. 2007;356:2214 (author reply 2215–18).

    Article  CAS  PubMed  Google Scholar 

  27. Vehreschild JJ, Böhme A, Buchheidt D, Arenz D, Harnischmacher U, Heussel CP, et al. A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML). J Infect. 2007;55:445–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank all of the physicians and staff at the cooperating centers for contributing patient data for this study. This study was supported by C-SHOT.

Author information

Authors and Affiliations

  1. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan

    Kotaro Miyao, Masashi Sawa, Reona Sakemura, Toshiyasu Sakai, Tomonori Kato, Satomi Sahashi, Natsuko Tsushita, Keisuke Watanabe & Yuichiro Inagaki

  2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Kotaro Miyao, Reona Sakemura & Keisuke Watanabe

  3. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Mio Kurata & Yoshiko Atsuta

  4. Center for Supporting Hematology-Oncology Trials, Nagoya, Japan

    Mio Kurata

  5. Department of HSCT Data Management and Biostatistics, Nagoya University, Nagoya, Japan

    Ritsuro Suzuki

  6. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  7. Department of Hematology, Fujita Health University, Toyoake, Japan

    Motohiro Tsuzuki & Nobuhiko Emi

  8. Department of Hematology and Oncology, Konan Kosei Hospital, Konan, Japan

    Akio Kohno

  9. Department of Hematology and Oncology, Chukyo Hospital, Nagoya, Japan

    Tatsuya Adachi

  10. Department of Hematology, Nishio Munishipal Hospital, Nishio, Japan

    Kaneyuki Ohbayashi

Authors
  1. Kotaro Miyao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masashi Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mio Kurata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ritsuro Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reona Sakemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshiyasu Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomonori Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Satomi Sahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Natsuko Tsushita
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yukiyasu Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Motohiro Tsuzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Akio Kohno
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tatsuya Adachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Keisuke Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kaneyuki Ohbayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Yuichiro Inagaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yoshiko Atsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Nobuhiko Emi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kotaro Miyao.

Ethics declarations

Conflict of interest

C-SHOT was partly supported by Chugai Pharmaceutical Co., Ltd, Novartis Pharmaceuticals Corporation, Astellas Pharma Inc., Nippon Shinyaku Co., Ltd., Nihon Schering K.K., SHIONOGI & CO., LTD., Bayer Yakuhin, Ltd., Zenyaku Kogyo Co., Ltd., Janssen Pharmaceutical K.K., Sumitomo Dainippon Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Meiji Seika Pharma Co., Ltd., Genzyme Japan K.K., Celgene K.K., Eisai Co., Ltd., Takeda Pharmaceutical Company Limited, Sanofi K.K., Otsuka Pharmaceutical Co., Ltd., ASAHI KASEI PHARMA CORPORATION, and Mitsubishi Tanabe Pharma Corporation. K. Miyao received an honorarium from Sumitomo Dainippon Pharma Co., Ltd. M. Sawa received honoraria from Sumitomo Dainippon Pharma Co., Ltd., MSD K.K, Astellas Pharma Inc., Janssen Pharmaceutical K.K., and Pfizer Japan Inc. R. Suzuki received honoraria from Sumitomo Dainippon Pharma Co., Ltd. and MSD K.K. N. Emi received honoraria from Sumitomo Dainippon Pharma Co., Ltd, MSD K.K and Astellas Pharma Inc. All remaining authors have nothing to disclose.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Miyao, K., Sawa, M., Kurata, M. et al. A multicenter phase 2 study of empirical low-dose liposomal amphotericin B in patients with refractory febrile neutropenia. Int J Hematol 105, 79–86 (2017). https://doi.org/10.1007/s12185-016-2095-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-016-2095-y

Keywords

Search

Navigation