PI-05. Real-life large cohort single-center study on epidemiology of breakthrough invasive aspergillosis in the context of antifungal prophylaxis after allogeneic hematopoietic stem cell transplantation
Vladislav V. Markelov1, Yulia A. Rogacheva1, Marina O. Popova1, Alisa G. Volkova1, Ilya Yu. Nikolaev1, Olga N. Pinegina1, Nikita P. Volkov1, Svetlana M. Ignatieva2, Tatyana S. Bogomolova2, Sergey N. Bondarenko1, Nikolay N. Klimko1,2, Alexander D. Kulagin1
1 RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia
2 I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia, St. Petersburg, Russia
Vladislav V. Markelov, e-mail: email@example.com
Invasive aspergillosis (IA) is dominant among invasive fungal disease (IFD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Current European guidelines for primary antifungal prophylaxis in adult allo-HSCT recipients propose phase-specific recommendations where primary antifungal prophylaxis is required for three groups of patients . Group 1 is low pre-engraftment risk of mold infections with the only one quality of evidence and strength of recommendations AI – fluconazole, group 2 is high pre-engraftment risk of mold infections with absence of any antifungal agent recommendations AI, and group 3 is high risk post-engraftment period (GVHD) with AI recommendation – posaconazole oral solution or tablet. The limitation of these guidelines include non-comprehensive list of risk groups, evidence based medications, and forms of agents administration. The aim was to study the real-life practice implementation of European guidelines for antifungal prophylaxis in large cohort adult allo-HSCT recipients and estimate the incidence of breakthrough IA.
Patients and methods
We analyzed 672 adult patients underwent allo-HSCT from 2017 to 2020 years in CIC 725. Patients were divided in into 3 groups according to the antifungal prophylaxis in the first 100 days of the post-transplant period: Group 1 – primary antifungal prophylaxis with fluconazole (low-risk of mold infections, n=434); Group 2 – primary antifungal prophylaxis with anti-mold active agents (high-risk of mold infections, including cases with non-prophylactic use, n=212) and Group 3 – secondary antifungal prophylaxis in patients with pre-existing IA, n=26. The characteristic of antifungal agents used the first 100 days of the post-transplant period are outline in Table 1. During the 1-year observation period, 2 proven and 41 probable cases of breakthrough IA, according to EORTC/MSG criteria, were diagnosed. We conducted a comparative analysis of the main patients and HSCT characteristics in order to identify the reasons for choosing the type of primary antifungal prophylaxis, calculated the cumulative incidence (CI) of breakthrough IA and identified the risk factors. The median follow-up time for all patients was 12 (0-51) months.
The comparative analysis of real-life practice showed the main characteristics of high-risk group of patients where the anti-mold active agents mainly as primary antifungal prophylaxis have been used (Table 2): absence of complete remission of underlying disease (p=0.002), subsequent allo-HSCT (p<0.001), haploidentical donor (p<0.001), CMV-reactivation (<0.001), aGVHD grade 3-4 (p<0.001), severe chGVHD (p=0.010) and reduced intensity conditioning regimen (p=0.001). The low-risk group had the following characteristics: matched related (p=0.002) and unrelated donors (p=0.009), myeloablative conditioning regimen (p<0.001). One-year CI of breakthrough IA after allo-HSCT in low-risk of mold infections group with the first and subsequent allo-HSCT was 3.7% and 8.6%, respectively, in high-risk of mold infections group – 10% and 26%, in patients with pre-existing IA – 5% and 14%. The median time of development of breakthrough IA was 66 (2-282) days. Breakthrough IA more common diagnosed in patients with acute leukemia – 30% and lymphomas – 30%. The main sites of infection were lungs 93%, sinuses – 2%, disseminated lesions – 5%. The breakthrough IA was diagnosed by bronchoalveolar (BAL) or sinuses liquid culture in 41% cases, and the etiology were Aspergillus niger – 8 (42%), Aspergillus fumigatus – 7 (36%), Aspergillus flavus – 2 (11%), Aspergillus terreus – 1 (5%), Aspergillus spp. – 1 (5%). Overall survival at 12 weeks in patients with breakthrough IA was 73%. Multivariate analysis showed, that significant risk factors, associated with incidence of breakthrough IA after allo-HSCT, in low-risk of mold infections group was diagnosis of Ph (-) MPNs (p=0.025), in high-risk of mold infections group – diagnosis of NHL (p=0.007). In patients with pre-existing IA, due to the few number of cases of IA (n=2), the analysis was not performed.
The real-life data in large cohort adult allo-HSCT recipients showed that absence of complete remission, subsequent allo-HSCT, haploidentical donor, CMV-reactivation, aGVHD grade 3-4, severe chGVHD and reduced intensity conditioning regimen are characteristics of high-risk of mold infections group. CI of breakthrough IA demonstrated extra-high risk group – subsequent allo-HSCT. The most common etiological agent of breakthrough IA was Aspergillus niger. Diagnosis of Ph (-) MPNs was associated with higher risk of IA in post-transplant period in patients, received fluconazole prophylaxis, and diagnosis of NHL – in patients, received primary anti-mold prophylaxis.
1. Maertens JA, Girmenia C, Brüggemann RJ, Duarte RF, Kibbler CC, Ljungman P, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother. 2018; 73(12):3221-3230. doi: 10.1093/jac/dky286.
Stem cell transplantation, Aspergillus, invasive aspergillosis, antifungal prophylaxis.
Table 1. The characteristic of antifungal agents used in the first 100 days of the post-transplant period
Table 2. Patients characteristics and comparative analysis