The use of micafungin in patients with hematological malignancies

The aim of this study was to evaluate indications, efficacy and rate of hepatic dysfunction in patients with hematological malignancies treated with micafungin.

Material and Methods. Micafungin was administered in dose of 100 mg intravenously once daily.

Results. Primary prophylaxis with micafungin was performed in 16 (46%) of 35 patients, all of them were recipients of allogeneic hematopoietic stem cells (allo-HSC), 81% – had graft-versus-host disease (GVHD) and  received prednisolone in dose of ≥ 1 mg/kg daily. Median duration of prophylaxis was of 27 (4–105) days, in 14 (88%) patients – 7 days and more, in 2 (12%) – less than 7 days. Invasive aspergillosis (“probable”) occurred in 1 (7%) of 14 allo-HSCT recipients under micafungin treatment for ≥ 7 days. Micafungin treatment was initiated in 19 (54%) of 35 patients with median duration of 13 (3–32) days. Indications for micafungin treatment were candidemia (n = 7), hepatosplenic candidiasis (n = 4), empirical therapy (n = 6) and preemptive therapy. Fatal outcome was in 2 of 7 patients with candidemia, other patients had favorable outcome. Prior to the beginning of the treatment with micafungin 21 (60%) of 35 patients had elevation in one or more liver function tests.  During micafungin treatment liver function parameters decreased in patients with initially elevated levels of these parameters and remained in reference ranges in patients with previously normal values.

Conclusion. The study demonstrated the efficacy of micafungin both for prophylaxis of invasive  mycoses in allo-HSCT recipients with GVHD and the treatment of proven and suspected invasive candidiasis.  We confirmed the safety of the micafungin use in patients with hematological malignancies.

1. Klyasova G.A., Okhmat V.A., Vasilyeva V.A., Popova M.O., Kaporskaya T.S., Sveshnikova U.V., et al. Invasive mycoses in patients with acute leukemia and hematopoietic stem cell transplant recipients. Results of prospective observational multicenter study in Russia (RIFI). Russian Journal of Hematology and Transfusiology. (Gematologiya i transfusiologiya). 2016; 61(1, Suppl. 1): 19. (in Russian)

2. Nucci M., Garnica M., Gloria A.B., Lehugeur D.S., Dias V.C., Palma L.C., et al. Invasive fungal diseases in haematopoietic cell transplant recipients and in patients with acute myeloid leukaemia or myelodysplasia in Brazil. Clin. Microbiol. Infect., 2013, 19(8): 745–51. doi: 10.1111/1469-0691.12002.

3. Klyasova G.A., Blokhina E.V., Gracheva A.N., Kravchenko S.K., Parovichnikova E.N., Okhmat V.A., et al. Factors influencing recovery in patients with hemoblastoses and candidemia. Therapeutic archive. Russian Journal (Terapevticheskiy arkhiv). 2015; 87(7): 77–87. (in Russian). doi: 10.17116/terarkh201587777-87.

4. ASTELLAS PHARMA US INC.: Mycamine® (micafungin sodium) for injection prescribing information. Tokyo: Astellas Pharma, US, Inc.; 2007.

5. Veselov A.V., Kozlov R.S. Invasive candidiasis: current aspects of epidemiology, diagnosis, therapy and prevention in different categories of patients (in questions and answers). Clinical Microbiology and Antimicrobial Chemotherapy. Russian Journal (Klinicheskaya microbiologiya i antimicrobnaya khimioterapiya). 2016; 18(S2): 1–104. (in Russian).

6. Wiederhold N., Lewis J. The echinocandin micafungin: A review of the pharmacology, spectrum of activity, clinical efficacy and safety. Expert Opin. Pharmacother. 2007; 8(8):1155–66. doi: 10.1517/14656566.8.8.1155.

7. Klyasova G.A. Antimicrobial therapy. In: Savchenko V.G., ed. Program treatment of blood system diseases. Moscow: Praktika; 2012: 829–53. (in Russian)

8. De Pauw B., Walsh T.J., Donnelly J.P., Stevens, D.A., Edwards J.E., 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. doi: 10.1086/588660.

9. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, June 14, 2010. US Department of Health and Human Services. National Institutes of Health National Cancer Institute. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (accessed 24 Nov 2017).

10. Maertens J., Marchetti O., Herbrecht R., Cornely O.A., Flückiger U., Frere P., et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3-2009 update. Bone Marrow Transplant. 2011; 46(5): 709–18. doi: 10.1038/bmt.2010.175.

11. Maertens J. Primary antifungal prophylaxis. Available at: https://www.ebmt.org/Contents/Resources/Library/ECIL/Documents/2014%20ECIL5/ECIL5antifungalprophylaxis%20%2020062014%20Final.pdf (accessed 24 Nov 2017).

12. van Burik J.A.H., Ratanatharathorn V., Stepan D.E., Miller C.B., Lipton J.H., Vesole D.H., et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin. Infect. Dis. 2004; 39(10): 1407–16. doi: 10.1086/422312.

13. Tissot F., Agrawal S., Pagano L., Petrikkos G., Groll A.H., Skiada A., et al. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica. 2017; 102(3): 433–44. doi: 10.3324/haematol.2016.152900.

14. Kuse E.R., Chetchotisakd P., da Cunha C.A., Ruhnke M., Barrios C., Raghunadharao D., et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidiasis: a phase III randomised double-blind trial. Lancet. 2007; 369(9572): 1519–27. doi: 10.1016/S0140-6736(07)60605-9. http://dx.doi.org/10.18821/0234-5730-2017-62-4-197-203

15. Pappas P.G., Rotstein C.M., Betts R.F., Nucci M., Talwar D., De Waele J.J., et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin. Infect. Dis. 2007; 45(7): 883–93. doi: 10.1086/520980.

16. Tamura K., Urabe A., Yoshida M., Kanamaru A., Kodera Y., Okamoto S., et al. Efficacy and safety of micafungin, an echinocandin antifungal agent, on invasive fungal infections in patients with hematological disorders. Leuk. Lymphoma. 2009; 50(1): 92–100. doi: 10.1080/10428190802635500.

17. Kubiak D.W., Bryar J.M., McDonnell M.A., Delgado-Flores J.O. Mui E., Baden L.R. Caspofungin vs micafungin for empirical therapy in adult neutropenic patients with persistent fever: a retrospective analysis. Proc. 48th Interscience Conference on Antimicrob. Agents Chemother. Washington, 25–28 Oct. 2008. Available at: http://www.abstractsonline.com/viewer/viewAbstract.asp?CKey={EF0CE20093C4-4625-8CDE-62E78BC17090}&MKey={26DFAE32-3D6D446F-9AE5-B759FE42C683}&AKey={B156596F-4F2B-4B7B-998853EF0A523ACC}&SKey={41A9FE49-0419-4B58-A874-6663711FCEBB} (accessed 24 Nov 2017)

18. Schneeweiss S., Carver P.L., Datta K., Galar A., Johnson M.D., Johnson M.G., et al. Short-term risk of liver and renal injury in hospitalized patients using micafungin: a multicentre cohort study. J. Antimicrob. Chemother. 2016; 71(10): 2938–44. doi:10.1093/jac/dkw225.

19. Huang X., Chen H., Han M., Zou P., Wu D., Lai Y., et al. Multicenter, randomized, open-label study comparing the efficacy and safety of micafungin versus itraconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplant. Biol. Blood Marrow Transplant. 2012; 18(10): 1509–16. doi:10.1016/j.bbmt.2012.03.014.

20. Shibata Y., Hagihara M., Kato H., Kawasumi N., Hirai J., Nishiyama N., et al. Caspofungin versus micafungin in the incidence of hepatotoxicity in patients with normal to moderate liver failure. J. Infect. Chemother. 2017; 23(6): 349– 53. doi: 10.1016/j.jiac.2017.02.008.

21. Luque S., Campillo N., Alvarez-Lerma F., Ferrandez O., Horcajada J.P., Grau S. Pharmacokinetics of micafungin in patients with pre-existing liver dysfunction: A safe option for treating invasive fungal infections. Enferm. Infecc. Mmicrobial. Clin. 2016; 34(10): 652–4. doi: 10.1016/j.eimc.2015.02.021.