Skip to main content

Advertisement

SpringerLink
Log in

A prospective feasibility study of primary prophylaxis against invasive fungal disease with voriconazole following umbilical cord blood transplantation with fludarabine-based conditioning

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

An Erratum to this article was published on 17 April 2014

Abstract

Despite the recent introduction of a new class of anti-Aspergillus agents, no standard regimen for the prevention of invasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation has been shown to be superior to fluconazole. The present prospective, single-arm study investigated the feasibility of voriconazole (VOR) administration as primary prophylaxis in 52 recipients of umbilical cord blood transplantation (CBT) with fludarabine-based conditioning, who had no previous IFD episodes. Proven or probable IFD was determined using 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) criteria were considered as breakthrough infections. VOR was administered as prophylaxis for a total of 6884 patient-days following CBT. The mean duration of VOR administration after transplantation was 132 days (range, 1–769); 44 patients (85 %) had advanced disease, 15 (29 %) had a history of allogeneic HSCT, and 29 (56 %) received systemic corticosteroid therapy for allogeneic immune-mediated complications. Under the prophylaxis with VOR, one patient developed probable invasive aspergillosis on day 71, and the cumulative incidence of IFD was 4.5 % at day 180. None of the patients developed breakthrough candida or zygomycetes infections. Under the extensive therapeutic dose monitoring, VOR was safely administered with a calcineurin inhibitor and was well tolerated. These results suggest that VOR represents a feasible primary prophylactic agent for IFD after CBT with fludarabine-based conditioning.

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
Fig. 2

Similar content being viewed by others

References

  1. Kurokawa 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.

    Article  Google Scholar 

  2. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34(7):909–17.

    Article  PubMed  Google Scholar 

  3. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100(13):4358–66.

    Article  CAS  PubMed  Google Scholar 

  4. Chamilos G, Luna M, Lewis RE, Bodey GP, Chemaly R, Tarrand JJ, et al. Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period (1989–2003). Haematologica. 2006;91(7):986–9.

    PubMed  Google Scholar 

  5. Marco F, Pfaller MA, Messer SA, Jones RN. Antifungal activity of a new triazole, voriconazole (UK-109,496), compared with three other antifungal agents tested against clinical isolates of filamentous fungi. Med Mycol. 1998;36(6):433–6.

    Article  CAS  PubMed  Google Scholar 

  6. Marco F, Pfaller MA, Messer S, Jones RN. In vitro activities of voriconazole (UK-109,496) and four other antifungal agents against 394 clinical isolates of Candida spp. Antimicrob Agents Chemother. 1998;42(1):161–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Wingard JR, Carter SL, Walsh TJ, Kurtzberg J, Small TN, Baden LR, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010;116(24):5111–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Martino R, Parody R, Fukuda T, Maertens J, Theunissen K, Ho A, et al. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the infectious diseases working party of the European group for blood and marrow transplantation. Blood. 2006;108(9):2928–36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Safdar A, Rodriguez GH, De Lima MJ, Petropoulos D, Chemaly RF, Worth LL, et al. Infections in 100 cord blood transplantations: spectrum of early and late posttransplant infections in adult and pediatric patients 1996–2005. Med (Baltimore). 2007;86(6):324–33.

    Article  Google Scholar 

  10. 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(12):1813–21.

    Article  PubMed Central  PubMed  Google Scholar 

  11. 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(6):730–51.

    Article  PubMed  Google Scholar 

  12. Kishi Y, Kami M, Miyakoshi S, Kanda Y, Murashige N, Teshima T, et al. Early immune reaction after reduced-intensity cord-blood transplantation for adult patients. Transplantation. 2005;80(1):34–40.

    Article  PubMed  Google Scholar 

  13. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 consensus conference on acute GVHD grading. Bone Marrow Transpl. 1995;15(6):825–8.

    CAS  Google Scholar 

  14. Sullivan KM, Agura E, Anasetti C, Appelbaum F, Badger C, Bearman S, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol. 1991;28(3):250–9.

    CAS  PubMed  Google Scholar 

  15. National Cancer Institute (2006) Serious adverse events definitions: National Cancer Institute online guidelines. available at: http://www.ctep.cancer.gov.

  16. Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18(6):695–706.

    Article  CAS  PubMed  Google Scholar 

  17. Miyakoshi S, Kusumi E, Matsumura T, Hori A, Murashige N, Hamaki T, et al. Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases. Biol Blood Marrow Transpl. 2007;13(7):771–7.

    Article  CAS  Google Scholar 

  18. Lewis RE. What is the “therapeutic range” for voriconazole? Clin Infect Dis. 2008;46(2):212–4.

    Article  CAS  PubMed  Google Scholar 

  19. Trifilio SM, Yarnold PR, Scheetz MH, Pi J, Pennick G, Mehta J. Serial plasma voriconazole concentrations after allogeneic hematopoietic stem cell transplantation. Antimicrob Agents Chemother. 2009;53(5):1793–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Capitano B, Potoski BA, Husain S, Zhang S, Paterson DL, Studer SM, et al. Intrapulmonary penetration of voriconazole in patients receiving an oral prophylactic regimen. Antimicrob Agents Chemother. 2006;50(5):1878–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction between voriconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transpl. 2009;44(6):371–4.

    Article  CAS  Google Scholar 

  22. Trifilio SM, Scheetz MH, Pi J, Mehta J. Tacrolimus use in adult allogeneic stem cell transplant recipients receiving voriconazole: preemptive dose modification and therapeutic drug monitoring. Bone Marrow Transpl. 2010;45(8):1352–6.

    Article  CAS  Google Scholar 

  23. Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, et al. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998;92(7):2303–14.

    CAS  PubMed  Google Scholar 

  24. Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, et al. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000;96(6):2062–8.

    CAS  PubMed  Google Scholar 

  25. Oshima K, Sato M, Terasako K, Kimura S, Okuda S, Kako S, et al. Target blood concentrations of CYA and tacrolimus in randomized controlled trials for the prevention of acute GVHD after hematopoietic SCT. Bone Marrow Transpl. 2010;45(4):781–2.

    Article  CAS  Google Scholar 

  26. Matsuno N, Wake A, Uchida N, Ishiwata K, Araoka H, Takagi S, et al. Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation. Blood. 2009;114(8):1689–95.

    Article  CAS  PubMed  Google Scholar 

  27. Takagi S, Masuoka K, Uchida N, Ishiwata K, Araoka H, Tsuji M, et al. High incidence of haemophagocytic syndrome following umbilical cord blood transplantation for adults. Br J Haematol. 2009;147(4):543–53.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Pfizer Japan Inc. for measuring VOR plasma concentrations. The authors also thank all physicians, nurses, pharmacists, transplantation coordinator (Ms. Madoka Narita), data managers (Ms. Naomi Yamada, Ms. Rumiko Tsuchihashi and Ms. Kaoru Kobayashi), and support personnel for their compassionate care of the patients involved in this study, which was supported in part by the Japanese Ministry of Health, Labor and Welfare (Research Grant for Allergic Disease and Immunology H20-015).

Conflict of interest

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Department of Hematology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan

    Shinsuke Takagi, Naoyuki Uchida, Daisuke Kaji, Hikari Ota, Kazuya Ishiwata, Masanori Tsuji, Hisashi Yamamoto, Go Yamamoto, Yuki Asano-Mori, Koji Izutsu & Shuichi Taniguchi

  2. Department of Infectious Diseases, Toranomon Hospital, Tokyo, Japan

    Hideki Araoka & Akiko Yoneyama

  3. Department of Pharmacy, Toranomon Hospital, Tokyo, Japan

    Yumiko Uchida, Tadaaki Ito & Masahiro Hayashi

  4. Department of Transfusion Medicine, Toranomon Hospital, Tokyo, Japan

    Hikari Ota & Shigeyoshi Makino

  5. Department of Hematology, Toranomon Hospital Kajigaya, Kanagawa, Japan

    Shinsuke Takagi, Aya Nishida, Naofumi Matsuno & Atsushi Wake

  6. Department of Hematology, Mishuku Hospital, Tokyo, Japan

    Kazuhiro Masuoka

  7. Okinaka Memorial Institute for Medical Research, Tokyo, Japan

    Shuichi Taniguchi

Authors
  1. Shinsuke Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideki Araoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naoyuki Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yumiko Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daisuke Kaji
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hikari Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aya Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuya Ishiwata
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masanori Tsuji
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hisashi Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tadaaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Naofumi Matsuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Go Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yuki Asano-Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Masahiro Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Koji Izutsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kazuhiro Masuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Atsushi Wake
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Shigeyoshi Makino
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Akiko Yoneyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Shuichi Taniguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shinsuke Takagi.

About this article

Cite this article

Takagi, S., Araoka, H., Uchida, N. 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 99, 652–658 (2014). https://doi.org/10.1007/s12185-014-1529-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-014-1529-7

Keywords

Search

Navigation