Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study

  • Ikuyo Tsutsumi
  • Susumu Kunisawa
  • Chikashi Yoshida
  • Masanori Seki
  • Takuya Komeno
  • Kiyohide Fushimi
  • Satoshi Morita
  • Yuichi ImanakaEmail author
Original Article



The prevention of invasive fungal infections is important in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) receiving cytoreductive chemotherapy. However, the role of oral voriconazole (VRCZ) in such patients has not been established. This study aimed to investigate the effectiveness of oral VRCZ compared to that of first-generation azoles prescribed within 7 days after the onset of chemotherapy in adult patients with AML/MDS using the Japanese administrative database.


This nationwide retrospective cohort study was conducted using the Diagnosis Procedure Combination/Per-Diem Payment System. The primary outcome was the proportion of patients who switched to intravenous antifungal agents. Analyses using the instrumental variable method were performed to address unmeasured confounding.


In total, data on 5517 inpatients from 142 hospitals were analyzed. An oral VRCZ prescription was significantly associated with a reduction in the proportion of patients switching to intravenous antifungal agents compared to first-generation azole prescription (21.0% (95% confidence interval [CI] − 33.4 to − 8.6)). The impact of oral VRCZ in reducing the proportion of patients switching to intravenous antifungal agents was stronger in patients aged < 65 years than in those aged ≥ 65 years (− 40.6%, 95% CI − 63.2 to − 17.9; − 21.9%, 95% CI − 35.8 to − 8.1, respectively) and in patients prescribed oral azole within 3 days from the onset of chemotherapy than in those prescribed the same later (− 32.9%, 95% CI − 46.7 to − 19.2; − 9.0%, 95% CI − 33.7 to 15.7, respectively).


Oral VRCZ administration may benefit adult patients with AML/MDS undergoing chemotherapy.


Invasive fungal infections Acute myeloid leukemia Myelodysplastic syndrome Cytoreductive chemotherapy Oral voriconazole 



The authors thank Editage by CACTUS (Tokyo, Japan) for proofreading our manuscript. This study was supported in part by a Grant-in-aid for Scientific Research from the Japan Society for the Promotion of Science (A) (16H02634). All the authors had full access to all the data in this study and take complete responsibility for the integrity of data and accuracy of the data analysis.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

10147_2019_1506_MOESM1_ESM.pdf (189 kb)
Supplementary file1 (PDF 188 kb)


  1. 1.
    Freifeld AG, Bow EJ, Sepkowitz KA et al (2011) 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 52:e56–e93. CrossRefGoogle Scholar
  2. 2.
    Committee for guidelines for deep mycoses (2014) Guidelines for diagnosis and treatment of deep mycoses 2014. Kyowa-kikaku, Tokyo, Japan. ISBN-13: 978-4877941611. Japanese Google Scholar
  3. 3.
    Cornely OA, Bohme A, Buchheidt D et al (2009) Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Haematologica 94:113–122. CrossRefGoogle Scholar
  4. 4.
    Marks DI, Pagliuca A, Kibbler CC et al (2011) Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation. Br J Haematol 155:318–327. CrossRefGoogle Scholar
  5. 5.
    Xu SX, Shen JL, Tang XF et al (2016) Newer antifungal agents micafungin and voriconazole for fungal infection prevention during hematopoietic cell transplantation: a meta-analysis. Euro Rev Med Pharmacol Sci 20:381–390Google Scholar
  6. 6.
    Pechlivanoglou P, Le HH, Daenen S et al (2014) Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrobial Chemother 69:1–11. CrossRefGoogle Scholar
  7. 7.
    Riedel A, Choe L, Inciardi J et al (2007) Antifungal prophylaxis in chemotherapy-associated neutropenia: a retrospective, observational study. BMC Infect Dis 7:70. CrossRefGoogle Scholar
  8. 8.
    Gergis U, Markey K, Greene J et al (2010) Voriconazole provides effective prophylaxis for invasive fungal infection in patients receiving glucocorticoid therapy for GVHD. Bone Marrow Transplant 45:662–667. CrossRefGoogle Scholar
  9. 9.
    Döring M, Blume O, Haufe S et al (2014) Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation. Eur J Clin Microbiol Infect Dis 33:629–638. CrossRefGoogle Scholar
  10. 10.
    Winston DJ, Chandrasekar PH, Lazarus HM et al (1993) Fluconazole prophylaxis of fungal infections in patients with acute leukemia. Results of a randomized placebo-controlled, double-blind, multicenter trial. Ann Intern Med 118:495–503CrossRefGoogle Scholar
  11. 11.
    Vehreschild JJ, Bohme A, Buchheidt D et al (2007) A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML). J Infect 55:445–449. CrossRefGoogle Scholar
  12. 12.
    Rotstein C, Bow EJ, Laverdiere M et al (1999) Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 28:331–340. CrossRefGoogle Scholar
  13. 13.
    Arndt CA, Walsh TJ, McCully CL et al (1988) Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. J Infect Dis 157:178–180CrossRefGoogle Scholar
  14. 14.
    Girmenia C (2009) New generation azole antifungals in clinical investigation. Expert Opin Investig Drugs 18:1279–1295. CrossRefGoogle Scholar
  15. 15.
    Kale P, Johnson LB (2005) Second-generation azole antifungal agents. Drugs Ttoday (Barc) 41:91–105. CrossRefGoogle Scholar
  16. 16.
    Jørgensen KJ, Gøtzsche PC, Dalbøge CS et al (2014) Voriconazole versus amphotericin B or fluconazole in cancer patients with neutropenia. Cochrane Database Syst Rev Issue 2:4707. Google Scholar
  17. 17.
    Ministry of Health, Labour and Welfare. Research on evaluation and impact of DPC introduction: aggregate results. Accessed 05 Mar 2019
  18. 18.
    Cameron AC, Trivedi PK (2010) Microeconometrics using stata: revised Edition, 2nd edn. Stata Press, College Station, TexasGoogle Scholar
  19. 19.
    Brookhart MA, Wang PS, Solomon DH et al (2006) Evaluating short-term drug effects using a physician-specific prescribing preference as an instrumental variable. Epidemiology (Camb) 17:268–275. CrossRefGoogle Scholar
  20. 20.
    Martens EP, Pestman WR, de Boer A et al (2006) Instrumental variables: application and limitations. Epidemiology 17(3):260–267. CrossRefGoogle Scholar
  21. 21.
    Fitzmaurice GM, Laird NM, Ware JH (2011) Applied longitudinal analysis, 2nd edn. Wiley, Hoboken, NJCrossRefGoogle Scholar
  22. 22.
    Maciejewski ML, Brookhart MA (2019) Using instrumental variables to address bias from unobserved confounders. JAMA 321(21):2124–2125. CrossRefGoogle Scholar
  23. 23.
    Baltagi BH (2013) Econometric analysis of panel data, 5th edn. Wiley, Chichester, West SussexGoogle Scholar
  24. 24.
    Davies NM, Gunnell D, Thomas KH et al (2013) Physicians' prescribing preferences were a potential instrument for patients' actual prescriptions of antidepressants. J Clin Epidemiol 66:1386–1396. CrossRefGoogle Scholar
  25. 25.
    Uddin MJ, Groenwold RHH, de Boer A et al (2016) Evaluating different physician's prescribing preference based instrumental variables in two primary care databases: a study of inhaled long-acting beta2-agonist use and the risk of myocardial infarction. Pharmacoepidemiol Drug Saf 25(Suppl 1):132–141. CrossRefGoogle Scholar
  26. 26.
    Shah A, Ganesan P, Radhakrishnan V et al (2016) Voriconazole is a safe and effective anti-fungal prophylactic agent during induction therapy of acute myeloid leukemia. Indian J Med Paediatr Oncol 37:53–58. CrossRefGoogle Scholar
  27. 27.
    Ping B, Zhu Y, Gao Y et al (2013) Second- versus first-generation azoles for antifungal prophylaxis in hematology patients: a systematic review and meta-analysis. Ann Hematol 92:831–839. CrossRefGoogle Scholar
  28. 28.
    Wingard JR, Carter SL, Walsh TJ et al (2010) Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 116:5111–5118. CrossRefGoogle Scholar
  29. 29.
    Ananda-Rajah MR, Grigg A, Downey MT et al (2012) Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica 97:459–463. CrossRefGoogle Scholar
  30. 30.
    Mattiuzzi GN, Cortes J, Alvarado G et al (2011) 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 19:19–26. CrossRefGoogle Scholar
  31. 31.
    Brookhart MA, Stürmer T, Glynn RJ et al (2010) Confounding control in healthcare database research: challenges and potential approaches. Med Care 48:S114–S120. CrossRefGoogle Scholar
  32. 32.
    Kimura S, Fujita H, Kato H et al (2017) Management of infection during chemotherapy for acute leukemia in Japan: a nationwide questionnaire-based survey by the Japan Adult Leukemia Study Group. Support Care Cancer 25:3515–3521. CrossRefGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  • Ikuyo Tsutsumi
    • 1
    • 2
  • Susumu Kunisawa
    • 1
  • Chikashi Yoshida
    • 2
  • Masanori Seki
    • 2
  • Takuya Komeno
    • 2
  • Kiyohide Fushimi
    • 3
  • Satoshi Morita
    • 4
  • Yuichi Imanaka
    • 1
    Email author
  1. 1.Department of Healthcare Economics and Quality Management, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of HematologyNational Hospital Organization Mito Medical CenterHigashiibarakigunJapan
  3. 3.Department of Health Policy and InformaticsTokyo Medical and Dental University Graduate School of MedicineTokyoJapan
  4. 4.Department of Biomedical Statistics and BioinformaticsKyoto University Graduate School of MedicineKyotoJapan

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