Randomized Trial of Micafungin Versus Fluconazole in Prophylaxis Against Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients

Abstract

Introduction: Invasive fungal infections cause significant morbidity and mortality in hematopoietic stem cell transplantation (HSCT) recipients. Although fluconazole has been widely used as an antifungal prophylactic agent in these patients, it is not reliably effective against mold infection including invasive aspergillosis. Micafungin provides antifungal activity against Candida and Aspergillus species, and previous studies have demonstrated its efficacy when used as a prophylactic agent for fungal infection in neutropenic patients. Here, we evaluated and compared the incidence rate of proven or probable invasive fungal infections (IFIs) with antifungal prophylaxis using micafungin or fluconazole.Methods: This is a prospective, single center, phase II study involving adult patients who received allogeneic or autologous HSCT. Patients were randomly assigned to micafungin or fluconazole arms in the ratio of 2:1, and the treatment was initiated within 24 hour of hematopoietic stem cell infusion and maintained for up to 21 days. Primary objective was the incidence of proven or probable invasive fungal infections (IFIs) during the 100 days after HSCT. Secondary objectives involved the incidence of possible, proven or probable IFIs, need for change of anti-fungal agents before engraftment, IFI-related mortality and survival within 100 days after transplantation.Results: Between March 2010 and May 2015, a total of 257 patients were enrolled. Excluding 7 patients who did not receive at least one dose of study treatment, 250 patients (micafungin, n=165; fluconazole, n=85) were examined for clinical efficacy. The median age was 47 years (20-64) and allogeneic and autologous transplantation comprised 56.0% (n=140) and 44.0% (n=110) of the patients. Baseline characteristics were well balanced between the two groups. Overall, the incidence of proven and probable IFIs within 100 days of HSCT was 7.6% (n=19), and there was no significant difference in the proportion of patients who experienced proven or probable IFIs between the micafungin and the fluconazole groups (7.3% in micafungin group versus 8.2% in fluconazole group, p=0.786). Thirteen patients of micafungin arm (7.9%) and 8 patients of fluconazole arm (9.4%) had to have changed antifungals before engraftment (p=0.824). There was no significant difference in the mortality within 100 days after HSCT (9.1% in micafungin arm vs 12.9% in fluconazole arm, p=0.345).Conclusion: Micafungin is comparable to fluconazole in the prevention of IFIs in HSCT recipients.Table 1Clinical outcomes including invasive fungal infections within 100 days after transplantationCharacteristics (total n=250)Total patients(n=250)Fluconazole(n=85)Micafungin(n=165)p-valueProven IFIsAllCandidiasisAspergillosisMucormycosis5 (2.0%) 2 (0.8%) 1 (0.4%) 2 (0.8%)3 (3.5%) 1 (1.2%) 0 (0.0%) 2 (2.4%)2 (1.2%) 1 (0.6%) 1 (0.6%) 0 (0.0%)0.341 1.000 1.000 0.115Probable IFIs16 (6.4%)5 (5.9%)11 (6.7%)0.810Possible IFIs7 (2.8%)1 (1.2%)6 (3.6%)0.428Proven, probable IFIs19 (7.6%)7 (8.2%)12 (7.3%)0.786Proven, probable, possible IFIs26 (10.4%)8 (9.4%)18 (10.9%)0.713Invasive mold infections Proven, probable Proven, probable, possible18 (7.2%)25 (10.0%)6 (7.1%)7 (8.2%)12 (7.3%)18 (10.9%)0.9510.504Need for anti-fungal agents change before engraftment21 (8.4%)8 (9.4%)13 (7.9%)0.824Mortality within 100 days after HSCT26 (10.4%)11 (12.9%)15 (9.1%)0.345IFI related mortality within 100 daysafter HSCT5 (2.0%)3 (3.5%)2 (1.2%)0.34128 invasive fungal infections were observed in 26 patientsAbbreviations: IFI=invasive fungal infection, HSCT=Hematopoietic stem cell transplantation DisclosuresNo relevant conflicts of interest to declare.