Invasive Fungal Disease in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation in China: A Multicenter Epidemiological Study (CAESAR 2.0)

Background: Thewidespread use of mold-active antifungal prophylaxis in recent years has altered the epidemiology of invasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, large-scale studies on IFD epidemiology with the use of mold-active prophylaxis are lacking. Therefore, an updated investigation into the epidemiology of IFD in China is necessary. This study (China Assessment of Antifungal Therapy in Hematological Diseases, CAESAR 2.0) aimed to provide updated epidemiological data on IFD in patients undergoing allo-HSCT. Methods: This multicenter, retrospective, observational study was conducted at 12 allo-HSCT centers in China. We retrospectively reviewed adult patients who underwent allo-HSCT between January 2021 and December 2021. Patients with a prior IFD before allo-HSCT or those who did not receive antifungal prophylaxis were excluded from the analysis. IFD was diagnosed according to the 2019 criteria of the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG). Follow-up was completed by December 31, 2022. All patients were monitored up for at least one year or until death before the last follow-up. Results: We revieweda total of 2015 patients, including 1301 (64.57%) haploidentical stem cell transplantations, 435 (21.59%) sibling donor transplantations, 157 (7.79%) unrelated donor transplantations, and 122 (6.05%) cord blood transplantations. The most common antifungal prophylaxis used was voriconazole (44.37%), followed by posaconazole (31.71%), echinocandins (15.78%), fluconazole (6.2%), itraconazole (1.59%), and amphotericin (0.35%). IFD was documented in 201 (11.0%) patients, including 24 (10.9%) proven cases, 99 (44.8%) probable cases, and 98 (44.3%) possible cases. The cumulative incidence of IFD (proven, probable, and possible) one year after allo-HSCT was 11%. The most common site of infection was the lungs (82.81%), followed by the bloodstream (11.76%). Pathogens were identified in 33.48% of IFD cases, mainly Candida (13.12%), Mucor (8.14%), Aspergillus (7.69%), and Pneumocystis jirovecii (3.62%). The IFD-attributable mortality rate was 50.59%, and the one-year overall survival rate for patients with IFD was 60.92%. Multivariate analysis identified the following factors associated with IFD: more than 2 comorbidities (hazard ratio [HR]=1.81; 95% confidence interval [CI]: 1 to 3.26 P=0.048), time of absolute neutrophil count (ANC) engraftment (HR=1.07; 95% CI: 1.03 to 1.12 P=0.002), acute graft-versus-host disease (aGVHD) grade 3-4 (HR=2.25; 95% CI: 1.58 to 3.2 P<0.001), chronic graft-versus-host disease [(cGVHD) moderate and severe] (HR=1.68; 95% CI: 1.15 to 2.45 P=0.008), Epstein-Barr virus (EBV) viremia (HR=1.69; 95% CI: 1.21 to 2.37 P=0.002) and cytomegalovirus (CMV) viremia (HR=1.42; 95% CI: 1.02 to 1.98 P=0.037). Conclusions: Despite the use of mold-active antifungal prophylaxis,the risk of IFD after allo-HSCT remains high. The most common pathogens are Candida, Mucor, Aspergillus, and Pneumocystis jirovecii.