Real-Life Considerations on Antifungal Treatment Combinations for the Management of Invasive Mold Infections after Allogeneic Cell Transplantation

Background: Antifungal combination treatment is frequently administered for invasive mold infections (IMIs) after allogeneic hematopoietic cell transplantation (HCT). Here, we describe the indications, timing, and outcomes of combination antifungal therapy in post-HCT IMI. Methods: A single-center, 10-year, retrospective cohort study including all adult HCT recipients with proven/probable IMI between 1 January 2010 and 1 January 2020 was conducted. Results: During the study period, 515 patients underwent HCT, of whom 47 (9.1%) presented 48 IMI episodes (46 patients with one IMI episode and 1 patient with two separate IMI episodes): 33 invasive aspergillosis (IA) and 15 non-IA IMIs. Almost half (51%) of the patients received at least one course of an antifungal combination (median: 2/patient): 23 (49%), 20 (42%), and 4/47 (9%) patients received pure monotherapy, mixed monotherapy/combination, and pure combination treatment, respectively. Combination treatment was started at a median of 8 (IQR: 2, 19) days post-IMI diagnosis. Antifungal management was complex, with 163 treatment courses prescribed overall, 48/163 (29.4%) concerning antifungals in combination. The clinical reasons motivating the selection of initial combination antifungal therapy included severe IMI (18, 38%), lack of antifungal susceptibility data (14, 30%), lack of pathogen identification (5, 11%), and combination treatment until reaching a therapeutic azole serum level (6, 13%). The most common combination treatments were azole/liposomal amphotericin-B (28%) and liposomal amphotericin-B/echinocandin (21%). Combination treatment was administered cumulatively for a median duration of 28 days (IQR: 7, 47): 14 (IQR: 6, 50) days for IA and 28 (IQR: 21, 34) days for non-IA IMI (p = 0.18). Overall, 12-week mortality was 30%. Mortality was significantly higher among patients receiving ≥50% of treatment as combination (logrank = 0.04), especially those with non-IA IMI (logrank = 0.03). Conclusions: Combination antifungal treatment is frequently administered in allogeneic HCT recipients with IMI to improve clinical efficacy, albeit in an inconsistent and variable manner, suggesting a lack of relevant data and guidance, and an urgent need for new studies to improve therapeutic options.