Safety & Efficacy of Liposomal Amphotericin B Followed By Micafungin to Prevent Invasive Fungal Infection in Pediatric Allogeneic Stem Cell Transplantation Recipients

Introduction: Invasive fungal infections (IFI) and invasive mold infections (IMI) are a leading cause of mortality post allogeneic stem cell transplantation (AlloSCT) (Satwani/Cairo et al., BBMT, 2009). This risk of infectious complications, especially from invasive Candida and Aspergillus species, is greatest during the first 100 days post AlloSCT (Fukuda et al., Blood, 2003; Satwani/Cairo et al., BBMT, 2009). Although fluconazole has been the standard for anti-fungal prophylaxis in AlloSCT recipients, other anti-fungal agents with activity against molds are now under investigation, especially with increasing numbers of HLA disparate transplantations (van Burik et al., Clin Infec Dis 2004; Science et al., PBC, 2014). We have previously demonstrated the effectiveness of prophylactic liposomal amphotericin B (L-AmB) at a dose of 3 mg/kg/day for 100 days in preventing IFI and IMI (Roman/Cairo et al., PBC, 2008). Methods: The aim of this study was to determine the tolerability and efficacy of sequential L-AmB (3 or 1.5 mg/kg/day, day 0-44) followed by micafungin (1.5 or 1 mg/kg/day in children <8 or ≥ 8 years respectively, up to 50 mg, day 45-100) prophylaxis in the first 100 days post AlloSCT in pediatric and young adult AlloSCT recipients. We also compared the effectiveness of L-Amb at 3 mg/kg/day with a reduced dose of L-Amb at 1.5 mg/kg/day for day 0-44 post AlloSCT in patients with < grade II acute graft versus host disease (AGVHD). IFI and IMI were defined as we have previously described (Satwani/Cairo et al., BBMT, 2009). AGVHD prophylaxis included tacrolimus and mycophenolate mofetil as we have previously described (Osunkwo/Cairo et al., 2004 BBMT; Bhatia/Cairo et al., BBMT, 2010). Results: Ninety-six patients, (.1-23 years); M/F = 67/29; received 40 related and 56 unrelated AlloSCT. Intravenous (IV) L-AmB at a dose of 1.5-3 mg/kg/day was administered on day 0 until day +44, followed by IV micafungin from day 45 through day 100 post AlloSCT in patients with < grade II AGVHD or L-AmB from day 45 through day100 post AlloSCT with ≥ grade II AGVHD. No serious adverse events from micafungin were observed. Incidence of grade II renal toxicity in patients secondary to L-AmB was 18.75%, although multiple medications also contributed to the development of renal toxicity. Probability of grade II-IV acute and chronic GVHD was 24 and 19%, respectively. Probability of IFI and IMI by day 100 was 7.3 and 3.1%, respectively (Figure 1A,B). There was no increase in number of resistant IFI cases. Probability of 3-year overall survival was 77.08% (Figure 2).Figure 2Three Year Overall Survival Post-AlloSCT.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusion: L-AmB followed by micafungin appears to be tolerable and effective in preventing IFI/IMI in the first 100 days in pediatric and young adult AlloSCT recipients. The reduction in L–Amb dose from 3 mg/kg/day to 1.5 mg/kg/day for days 0-44 also appears to be safe and effective in prevention of IFI/IMI in the first 100 days post AlloSCT.