Abstract
Background: Antifungal combination treatment is frequently administered for invasive mold infections (IMIs) after allogeneic hematopoietic cell transplantation (HCT). Here, we describe the indications, timing, and outcomes of combination antifungal therapy in post-HCT IMI. Methods: A single-center, 10-year, retrospective cohort study including all adult HCT recipients with proven/probable IMI between 1 January 2010 and 1 January 2020 was conducted. Results: During the study period, 515 patients underwent HCT, of whom 47 (9.1%) presented 48 IMI episodes (46 patients with one IMI episode and 1 patient with two separate IMI episodes): 33 invasive aspergillosis (IA) and 15 non-IA IMIs. Almost half (51%) of the patients received at least one course of an antifungal combination (median: 2/patient): 23 (49%), 20 (42%), and 4/47 (9%) patients received pure monotherapy, mixed monotherapy/combination, and pure combination treatment, respectively. Combination treatment was started at a median of 8 (IQR: 2, 19) days post-IMI diagnosis. Antifungal management was complex, with 163 treatment courses prescribed overall, 48/163 (29.4%) concerning antifungals in combination. The clinical reasons motivating the selection of initial combination antifungal therapy included severe IMI (18, 38%), lack of antifungal susceptibility data (14, 30%), lack of pathogen identification (5, 11%), and combination treatment until reaching a therapeutic azole serum level (6, 13%). The most common combination treatments were azole/liposomal amphotericin-B (28%) and liposomal amphotericin-B/echinocandin (21%). Combination treatment was administered cumulatively for a median duration of 28 days (IQR: 7, 47): 14 (IQR: 6, 50) days for IA and 28 (IQR: 21, 34) days for non-IA IMI (p = 0.18). Overall, 12-week mortality was 30%. Mortality was significantly higher among patients receiving ≥50% of treatment as combination (logrank = 0.04), especially those with non-IA IMI (logrank = 0.03). Conclusions: Combination antifungal treatment is frequently administered in allogeneic HCT recipients with IMI to improve clinical efficacy, albeit in an inconsistent and variable manner, suggesting a lack of relevant data and guidance, and an urgent need for new studies to improve therapeutic options.
Highlights
Invasive mold infections (IMI) constitute a serious threat for the long-term outcomes of allogeneic hematopoietic cell transplant (HCT) recipients, especially those under continuous immunosuppression due to graft-versus-host disease (GvHD) [1,2,3,4,5]
Despite in vitro and retrospective observational clinical data suggesting a potential benefit, the only prospective, placebo-controlled randomized clinical trial conducted in hematologic patients failed to clearly show a definitive benefit of an azole/echinocandin combination compared to azole monotherapy for the treatment of invasive aspergillosis (IA) [8,9,14]
There were no significant differences in baseline attributes between IA and non-IA IMI cases, there was a trend towards an increased frequency of leukemia as a baseline condition in non-IA IMI patients compared to IA (82% vs. 49%, p = 0.06)
Summary
Invasive mold infections (IMI) constitute a serious threat for the long-term outcomes of allogeneic hematopoietic cell transplant (HCT) recipients, especially those under continuous immunosuppression due to graft-versus-host disease (GvHD) [1,2,3,4,5]. Invasive aspergillosis (IA) is the most frequent among these infections, followed by non-Aspergillus species (non-IA) IMI, with mucormycosis being the predominant infection among the latter in terms of frequency and severity [3,4,5,6,7]. Despite in vitro and retrospective observational clinical data suggesting a potential benefit, the only prospective, placebo-controlled randomized clinical trial conducted in hematologic patients (including HCT recipients) failed to clearly show a definitive benefit of an azole/echinocandin combination compared to azole monotherapy for the treatment of IA [8,9,14]. In the case of mucormycosis, patients frequently receive multiple antifungals in combination, based on conflicting observational retrospective data, while robust evidence of superiority over polyene monotherapy is lacking both in the first line and salvage context [10,12,13,15,16]. Data on combinations of antifungal drugs for the treatment of other rarer non-IA, non-Mucorales IMI are sparse, with combination regimens proposed for some of them mainly based on expert opinion [17]
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