40 Years of Preventing Fungal Infections in Hematological Malignancies - Lessons Learned from Clinical Trials with 20,753 Patients
Authors: Karthaus Meinolf , Kiehl Michael G. , Reinhold Ilana , Cornely Oliver A. , Stemler Jannik 
Published: December 2024

Background
Invasive fungal infections (IFI) represent a severe cause of morbidity and mortality in patients (pts) with neutropenia such as those with acute leukemia (AL) and myelodysplastic syndrome (MDS) receiving intensive chemotherapy (CTx) with a high IFI-related mortality of up to 50%. Antifungal prophylaxis (AFP) reduces occurrence of IFI and mortality and has been studied with azoles, polyenes and echinocandins within the last 40 years, without new drugs approved for AFP for more than 15 years.
Material and Methods
A literature search was done for AFP in AL/MDS in medical databases (PubMed, Medline, EMBASE, Cochrane Library). To provide a best-practice overview for clinicians, a meta-analysis of prospective and/or randomized trials (RT) for AFP as well as studies in pts receiving AFP during novel treatments for AL/MDS was performed.
Results
A total of 20,753 AFP pts episodes (eps) were included since 1984 from 95 studies during CTx and 17,482 pts received AFP within a clinical trial for AFP from 1992 to 2022. Out of these, 7,586 received fluconazole (FLU), 4,080 were included in trials with posaconazole (POS) or voriconazole (VOR), 1,717 received itraconazole (ITRA), 1,895 echinocandins and 1,594 amphotericin B (AmB)(AmB deoxycholate, liposomal AmB or inhalational AmB), respectively. In pts receiving novel targeted therapies (e.g. hypomethylating agents (HMA), FLT3-inhibitors, bcl2-inhibitor) AFP is usually recommended, while no prospective RTs with an endpoint of IFI or OM rates are available. 10 retrospective studies in pts with HMA monotherapy (n=1,185), 10 with HMA/venetoclax (n=956) and 4 with FLT3-inhibitors (n=273) were reviewed. Incidence rate of proven and probable IFI was up to 27% of pts in these trials. Six double-blind placebo-controlled RTs with 1,382 pts studied FLU in the 1990s. While there was a reduction of proven IFI rates in 5 out of 6 RT, improved mortality (OM) rate was observed in only one. 17 trials used POS or VOR. Superiority of POS versus FLU was demonstrated in 2 trials, with a reduction in OM in 1 trial, while there was no reduction of OM in VOR AFP trials. ITRA AFP with capsules or solution had no advantage in OM. Echinocandin AFP was compared with azoles in 5 RTs. Incidence varied from 1.7% to 20% (proven/probable IFI) and a reduction of IFI was shown in 1 RT, but no reduction of OM was observed. Inhalational AmB was studied in 2 large RTs with 653 pts with a reduction of proven IFI in 1 trial, but no reduction in OM. No prospective studies for AFP with isavuconazole and new antifungal agents like rezafungin or olorofim are available.
In pts receiving HMA as monotherapy, incidence of IFI ranged between 1.6 and 10.3% while AFP was usually not given. In those receiving venetoclax/HMA, AFP practices were heterogeneous and IFI incidence ranged from 5% to 16.1% (overall probable/proven IFI: n=102 (10.6%), possible IFI not reported in all studies). In pts treated with midostaurin, 2 studies (n= 218 pts) reported 29 probable/proven IFI (13.3%). In pts treated with gilteritinib, 2 studies reported 55 pts with an IFI rate of 27.2% (including possible IFI).
Conclusion
AFP remains a challenge after 40 years due to changing patient populations, higher pts age, other immunomodulating Tx, changing fungal epidemiology and emerging azole resistance. Despite numerous trials for prevention of IFI, only posaconazole and fluconazole proved reduction in OM rates. There is a need for prospective clinical trials addressing risk-adjusted prophylaxis in AL and MDS in particular due to high observed IFI rates during treatment with novel targeted therapies.