Low Dose Liposomal Amphotericin B Followed by Micafungin Prophylaxis of Invasive Fungal Infections (IFI) in Pediatric Allogeneic Stem Cell Transplantation Recipients

Background :

We have previously demonstrated the safety/efficacy of prophylactic liposomal amphotericin B (L-AMB) in preventing IFI for 100 days in pediatric allogenic stem cell transplant (AlloSCT) recipients (Roman/Cairo et al PBC, 2008). Prophylaxis with L-AMB 3 mg/kg/day (Day 0 to +44) and micafungin (Day +45 to +100) has been shown by our group to be both safe and effective in preventing IFI (Small/Cairo et al ASBMT, 2011).

Methods:

Pediatric AlloSCT recipients received low dose L-AMB at 1.5 mg/kg IV daily (Day 0 to +44), followed by micafungin 1.5 mg/kg (max 50 mg) (Day +45 to +100). All patients received Tacrolimus and MMF for acute GVHD prophylaxis as we previously described Bhatia / Cairo, BBMT, 2010. Plasma galactomannan and beta-glucan assays were monitored BIW. Treatment success was defined as prevention of IFI by day 100.

Results:

23 patients (8 ALL, 2 AML, 3 TNHL, 1 HL, 1 DLBCL, 2 SAA, 1 FA, 1 SCD, 2 CGD, 1 SCID, 1 HLH) Median age: 11.7 yrs (1mo-23.5 yr) Sex: 3F,  20M Conditioning: 12 myeloablative, 11 reduced toxicity; 7 CB donors (6 -unrelated, 1-related), 2 related PBSC, 6 RBM , 7 URBM, and 1 RBM+CB. Median time to myeloid and platelet engraftment was 17 and 32.5 days, respectively. Chimerism = 98-100% day +100. Absolute CD4 count day +100 was (29-439 cells/µL). Probability of Grade II-IV aGVHD was 17% and cGVHD 4%. Probability of 1-yr OS was 87% (95% CI: 64.8-95.6). One patient, history of CGD, had IFI Aspergillus spp on lung biopsy Day +49. Probability of IFI by day 100 was 4% (95% CI 0-64.3). Grade 3-4 toxicities: renal insufficiency with concomitant other nephrotoxins occurred in 14 pts (60.8%), low K+ in 12 (52.1%), and low Mg++ in 5 (21.7%). L-AMB dosing was changed due to renal toxicity in 10 patients (decreased dose in 1, decreased frequency in 4, changed to micafungin in 2, and held doses in 3). False positive beta-glucan was observed in 8 and galactomannan in 3 pts.

Conclusions:

Low dose (1.5 mg/kg/day) L-AMB followed by micafungin is as effective in preventing IFI as prior studied higher doses (3 mg/kg/day). Future studies should focus on reducing toxicity but maintaining efficacy. Beta-glucan and galactomannan assays may be associated with a high incidence of false positive results in pediatric AlloSCT recipients and should not be used alone in clinical decision making.