Progress and current challenges in the management of invasive fungal infections in hematologic malignancy patients and allogeneic hematopoietic cell transplant recipients

Invasive aspergillosis (IA) is a common complication in allogeneic hematopoietic cell transplant (HCT) recipients, associated with high mortality and morbidity rates. Significant improvement in overall survival in patients with IA has been demonstrated in the post-voriconazole era. However, voriconazole may be discontinued in up to 40-45% of allogeneic HCT recipients, who receive this agent as primary antifungal prophylaxis. This is due to a number of limitations, associated with voriconazole, including hepatotoxicity, neurotoxicity, co-administration with cyclodextrin for the intravenously administered voriconazole formulation, and important drug-drug interactions. Additional options exist, with isavuconazole and posaconazole representing effective and safe treatments for IA. Isavuconazole was found non-inferior and better tolerated than voriconazole, in a prospective, randomized, non-inferiority international clinical trial. Similarly, posaconazole was recently shown to be non-inferior to voriconazole for the treatment of IA, also with a more favorable side effect profile. However, posaconazole use may be hindered by the large variability of blood concentrations observed and the important drug-drug interactions, as a result of its complex metabolism. Considering the above, it is evident that none of the available treatments for IA has an optimal toxicity and drug-drug interaction profile. Moreover, existing data suggest that all-cause 6- and 12-week mortality in patients with IA have remained in the range of 20% and 35%, respectively, since the early 2000s. Hence, despite the progress attained in the fields of infectious diseases and hematology / HCT, clinical outcomes in patients with IA have stagnated during the last two decades due to a variety of reasons. Whether the existing gap of 20-30% in all-cause mortality may be further decreased remains to be discussed. No new antifungal agent classes have been introduced in clinical practices since echinocandins in the early 2000s. However, for the first time after many decades, new classes of antifungals are under consideration and clinical investigation. Some of those new agents / classes appear to have excellent activity against most Aspergillus species and favorable pharmacokinetic and toxicity profiles. In addition to the available treatment options, genetic factors may eventually prove to be important players in the fight against IA. A number of genetic polymorphisms have been associated with susceptibility to different infections, including IA. The effect of genetic factors as such on clinical outcomes has not been, as yet, further studied. However, the realization that underlying genetic factors may impact clinical outcomes may open new opportunities in the field of invasive fungal infections. To conclude, significant progress has been attained in the management of IA in allogeneic HCT recipients, with the new generation azoles having dominated the field during the last two decades, offering viable, effective and safe treatment options. Having achieved a plateau in overall survival since the early 2000s, it is time to explore additional options, including new antifungal treatments and personalized medicine approaches, in order to further improve clinical outcomes and survival in allogeneic HCT recipients with a severe infection due to Aspergillus spp. and other molds