The Changing Epidemiology of Breakthrough Invasive Fungal Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients in the Era of Modified‐Release Posaconazole Prophylaxis

ABSTRACT Background Allogeneic hemopoietic stem cell transplant (aHSCT) recipients are at high‐risk for invasive fungal disease (IFD), even with mould‐active antifungal prophylaxis (AFP). Methods This was a retrospective, observational, single‐center cohort study involving 300 adult aHSCT recipients transplanted from January 2017–May 2020. Patient demographics, underlying hematological malignancy (HM), transplant characteristics and AFP were described. The primary objectives were rate and characteristics of breakthrough IFD (bIFD) within 1‐year post‐transplant. Results Of 300 aHSCT recipients, 195 (65%) were males; median age at transplantation was 54 years (IQR 43–62). Acute leukemia was the most common underlying HM (50%), and modified‐release posaconazole was the main primary AFP (88%). B‐IFD occurred in 26 patients (9%): 14 breakthrough invasive mould diseases (bIMD), which Aspergillus species predominated (56%), followed by Lomentospora prolificans (31%); and 12 breakthrough invasive yeast infections, with Nakaseomyces glabratus most frequently isolated. Neither Aspergillus fumigatus complex nor Candida albicans was cultured as breakthrough organisms. bIMD occurred late post aHSCT at median of 167 days, whereas breakthrough invasive yeast infection occurred at median of 21 days. Twelve patients (46%) had therapeutic‐drug‐monitoring at time of bIFD—all were within therapeutic range. All‐cause mortality at 12‐weeks from bIMD and breakthrough invasive yeast infection infections were 50% and 58%, respectively. Conclusion Although bIFD rate was consistent with other reports, mortality after bIFD remained significant. Use of mould‐active AFP likely explained the changing epidemiology of fungal isolates. Resistant breakthrough fungal organisms, especially L. prolificans , reflected local epidemiology. Ongoing surveillance of IFD including resistant organisms is warranted to optimize treatment and patient outcome.