Invasive fungal infections (IFIs) are the leading cause of death in recipients of allogeneic haematopoietic stem cell transplants (allo-HSCTs), and patients are usually given broad-spectrum antifungal drugs alongside immune-transplantation drugs to prevent this condition and control possible infections. The 3rd European Conference on Leukemia Infections recommended posaconazole and voriconazole as the primary antifungal drugs for allo-HSCT, but subsequent studies have identified potential drug-to-drug interactions with these drugs that can lead to IFIs.

Isavuconazole (ISA) is a new-generation benzotriazole with broad-spectrum antifungal activity that has been used to treat Aspergillus and Trichoderma infections. Furthermore, ISA is equally effective as voriconazole in treating invasive fungal and lung infections caused by non-Aspergillus species. Retrospective studies have found ISA to have a favourable safety profile.

The retrospective study enrolled 377 allo-HSCT patients between 2017 and 2022. To prevent graft-versus-host disease, patients were first treated with rapamycin five days after surgery, with maintenance therapy continuing for 100 days before tapering off at 180 days after surgery. Blood levels of rapamycin were monitored twice weekly to maintain a target concentration of 5–14 ng/ml. Depending on the type of disease, other immunosuppressive drugs, including cyclophosphamide, mycophenolate and montelukast, were administered. To prevent viral infections, patients were given acyclovir, and those who were CMV seropositive were also given letermovir from 2019 onwards. Patients showing signs of fungal infection were given ISA, with blood levels monitored weekly to maintain a therapeutic level of 3–9 ng/ml depending on TDM.

All of the following information about the patient was accurately recorded: Demographic characteristics; underlying malignancy; disease status at the time of transplantation; pretreatment regimen; type of donor; prior antifungal medication use; presence of acute and chronic graft-versus-host disease (GvHD); prophylaxis with letermovir; indications for the use of immunosuppressant agents (ISAs), including reasons for switching to an ISA; duration of antifungal therapy; beta-lactam antifungals (b-IFIs); and steady-state concentrations of ISAs. ISA, duration of antifungal therapy, beta-lactam antifungal drugs (b-IFIs) and steady-state concentrations of ISA.

Of the 377 patients, 51 were treated with ISA for more than two weeks, with a median treatment period of 140 days (range 14 days to 40 months). A total of 22 patients experienced acute rejection, of whom nine eventually developed chronic rejection. Seventeen patients (4.5%) continued to take ISA due to a previous diagnosis of invasive fungal infection (IFI), and one patient switched from ISA to liposomal amphotericin B due to an unexplained fever, ultimately dying. Thirty-four patients were taking ISA following a postoperative diagnosis of IFI.

Sixteen of the 34 patients were treated with ISA for confirmed or suspected invasive fungal infection (IFI). Their median ISA trough-to-peak (TDM) ratio was 3.7 mg/L. Six of the 16 patients ultimately died of IFI, with a median ISA TDM of 2.7 mg/L. Five died of IFI and one died of disease progression. Eight patients had IFIs that were definitively cured with continued ISA therapy.

A total of 18 patients treated with ISA prophylaxis had a median ISA TDM of 4.1 mg/L. One patient died as a result of disease progression, two were switched due to worsening pneumonia and 15 patients achieved infection control. (See Figures 1 and 2.)

The clinical and radiological response rate (RR) was 68% across all 34 patients. The RR was higher in patients with low-probability IFN than in those with confirmed IFN: 15/18 versus 8/16, respectively.

No cases of overdose were observed with either ISA or rapamycin during the course of treatment. No toxic effects associated with either drug were observed, and therefore no patient had to discontinue treatment due to adverse reactions. However, it is important to note that treatment was always supplemented with targeted TDM. In a follow-up survey after 1 year, 22 out of 51 patients taking both ISA and rapamycin had died, eight of whom had died from IFI-related causes. Nevertheless, this 78% one-year survival rate is much higher than the 18% survival rate observed in ISA-naïve patients.