Among a total of 123 patients undergoing an allo-HSCT enrolled in the study, 93 (75.6%) patients received posaconazole as PAP and 30 (24.4%) had a past history of IFD received posaconazole as SAP. The patients had a median age of 39 years (range 14-72 years), with 70 (56.9%) males and 53 (43.1%) females. The underlying diseases were mainly AML (n = 41), acute lymphoid leukemia (n = 33), MDS (n = 22), and aplastic anemia (n = 19), and chronic myeloid leukemia (n = 4), lymphoblastic lymphoma (n = 3) as well as myelofibrosis (n = 1) were also included. Thirteen patients had diabetes as a complication. A hundred and three patients achieved CR and 20 patients were in non-CR at the time of transplantation. 37 patients received MSD transplantation and 86 received HID transplantation. Of the 30 patients who had a history of IFD pre-transplantation, 23 patients had stable IFD and 7 patients had active IFD at the time of transplantation. Among those 30 patients, 5 proven IFD patients was found, along with 13 probable IFD and 12 possible IFD patients. Out of all patients, 21 cases (17.1%) developed aGVHD (grade III-IV) while 32 (26.0%) developed extensive cGVHD. Based on the patient and transplant characteristics of PAP and SAP groups in Table 1, the similar demographic and transplantation characteristics could be seen.
Antifungal prophylaxis and efficacy
A documented reason for prophylaxis failure was identified in 43.1% (54/123) cases. There were no significant differences in the incidence of IFD, gastrointestinal intolerance, persistent fever, drug-drug interaction and death between the groups with and without a past history of IFD, respectively (data shown in Table 2). The median duration of antifungal prophylaxis with posaconazole was 90 days (range, 9-365 days) in PAP group and 180 days (range, 15-365 days) in SAP group. The 1-year cumulative incidence of prophylaxis failure was 50.0% (95% CI, 28.5-65.0%) in group with a past history of IFD and 44.1% (95% CI, 32.7-53.6%) in the group without a past history of IFD (p = 0.470) (Figure 1). The primary reason for prophylaxis failure of posaconazole intervention was GI, accounting for 46.3% (25/54) of failures. It is followed by the suspected IFD, accounting for 35.2% (19/54) of failures. Five (9.2%) patients had to discontinue posaconazole due to persistent fever. Three (5.6%) patients resulted in prophylaxis failure due to drug-drug interaction that developed hepatic toxicity, but two were later attributed to histologically proven GVHD. The two (3.7%) deaths were caused by relapse and hematencephalon, respectively.
IFD occurence post-transplantation
The 1-year cumulative incidence of IFD was 15.4% (95% CI, 7.0%-23.0%) in the patients without a history of IFD and 25.9% (95% CI, 7.4%-40.7%) in the group with a past history of IFD (p = 0.148, Figure 2). Among the 93 patients who used posaconazole as PAP, twelve (12.9%) cases developed IFD, including 8 during prophylaxis period and 4 after the period. The IFD occurred at a median time of day +107 after transplantation (range, day +8 to +262). Seven (23.3%) of the 30 patients with a history of IFD pre-transplantation after allo-HSCT developed breakthrough IFD, including six during the prophylaxis and one after the SAP. In these SAP patients, the IFD occurred at a median time of day +27 after transplantation (range, day +15 to +235). Among these proven IFD, the pathogens after the end of PAP were aspergillosis (2 cases), followed by Candida spp (1 case) and pneumocystis carnii (1 case) while the pathogen after the end of SAP were pneumocystis carnii (1 case).
Treatment and outcome of post-transplantation IFD
Nineteen patients who developed post-transplantation IFD received salvage therapy. Of these, eight (42.1%) patients were treated with voriconazole, the rest included 4 (21.1%) patients with caspofungin, 5 (26.3%) patients with combination therapy, 1 (5.3%) patient with L-AmB and 1 (5.3%) patient dose adjustment on posaconazole. After salvage therapy, besides 3 (15.8%) died of IFD, 12 (63.2%) patients achieved CR and 4 (21.0%) achieved PR. Among those 19 patients, twelve patients belonged to PAP group and 7 belongs to SAP group. One (8.3%) death happened in PAP group while 2 (28.5%) happened in the SAP group.
Risk factors for IFD
The potential risk factors for post-transplantation IFD are presented in Table 3. Two risk factors were found post-transplantation IFD from both univariate and multivariate analysis, Having cytomegalovirus (CMV) disease post-transplantation (HR, 14.369, 95% CI 2.302 to 89.699, p = 0.004) was identified as a serious risk factor, while steroid treatment longer than 90 days (HR, 6.059, 95% CI 1.854-19.803, p = 0.003) was the other risk factor.
With a median follow-up of 685 days (range 8-2005 days) post-transplantation, there were 26 deaths, the causes of which included relapse (10 cases), infections (6 cases including 3 fungal and 1 bacterial infection, 1 caused by CMV encephalitis and 1 by adenovirus encephalitis), GVHD (5 cases), thrombotic microangiopathy (4 cases) and hematencephalon (1 case). The 2-year OS after allo-HSCT was 74.9% ± 4.0%. No significant differences of 2-year OS were seen between PAP group and SAP group (76.9% ± 4.5% versus 68.1% ± 8.9%, p = 0.559, Figure 3). In the multivariable analysis, aGVHD III-IV [hazard ratio (HR), 5.817, 95% CI, 2.644 to 12.801, p = 0.001] and relapse of underlying primary diseases (HR, 4.068, 95% CI, 1.854 to 8.928, P = 0.001) were risk factors associated with worse OS (Table 4).