Despite advancements in diagnosis and therapy of infectious complications over the last decades, invasive fungal infections (IFIs) continue to be a major cause of morbidity and mortality among immunocompromised patients, particularly in oncohematologic patients.5,9 Since the introduction of isavuconazole as part of the effective anti-mold drugs in the transplant setting,8 a number of studies that include real-world experience with isavuconazol as therapy, and also as prophylaxis, have been reported. In a single-center retrospective study, 30 patients with acute myeloid leukemia (AML) and/or allogeneic hematopoietic stem cell transplant (HSCT) recipients received isavuconazole as prophylaxis (33.3%) or treatment (66.6%) (Table 1).6 The most frequent indications for isavuconazole administration were adverse events associated with prior antifungal treatment, safety profile and clinical efficacy. Notably, patients with abnormal baseline liver function showed a rapid decline of transaminases within the first two weeks after starting isavuconazole treatment. There was no breakthrough fungal infection observed and none of the patients included died due to an IFI. A single academic center reported the use of isavuconazole in 91 adult patients for treatment or prophylaxis, that included allogeneic-HSCT recipients (n=15) and patients with acute leukemia (n=58).4 Seven percent received primary prophylaxis, 11% received treatment followed by secondary prophylaxis, and 82% received treatment alone. Overall, treatment response was 62%. Six-week mortality rate was 24%. Sixty-three percent of 32 patients treated with isavuconazole following prophylaxis with another antifungal agent exhibited a treatment response. Among 49 patients in whom isavuconazole was prescribed in replace of a previous antifungal treatment, 53% had a clinical response. Thirty-four patients received isavuconazole empirically, and 65% responded to the treatment. Individuals given isavuconazole prophylaxis did not develop any invasive fungal infection. In another single-center, retrospective study, 54 patients with IFI received isavuconazole as prophylaxis or treatment. Almost half of the patients were HSCT recipients (48.1%) and 35.2% had an underlying hematological malignancy. Isavuconazole was indicated as either primary prophylaxis (34.4% of patients), secondary prophylaxis (8.2%), or treatment of an IFI (57.4%). Four cases of breakthrough invasive fungal disease were reported, leading to a breakthrough rate of 7.8% for isavuconazole courses. Two breakthrough invasive fungal diseases occurred in patients receiving primary prophylaxis and two occurred while on treatment.12 In another retrospective study, 200 patients with high-risk hematologic malignancies (n=148) or allogeneic HSCT recipients (n=52) were treated with isavuconazole for IFIs that were classified as definite (11), probable (63) and possible (126). Aspergillus was the most commonly isolated pathogen. The majority of patients (59%) received prophylaxis with anti-mold therapy and isavuconazole was used as a primary therapy in 43% of the patients, and as salvage therapy in 58%. The switch to isavuconazole was driven by the failure of the primary therapy in 66% of the cases, and by adverse effects in 29%. Adverse events possibly related to isavuconazole were reported in eight patients (4%), leading to drug discontinuation. A favorable response was reported in 40% of the patients after 6 weeks, and in 60% after 12 weeks.3 Multicentric studies also analyzed the experience with the real-world use of isavuconazole in high-risk hematological patients. Possible/probable/proven IFIs treated with isavuconazole in 122 patients with hematological malignances from 17 Italian centers were retrospectively analyzed.2 Patients were diagnosed with acute leukemia (69%) and lymphoma (21%), and received treatment during induction (22%), consolidation (17%), relapse (28%) or allo-HSCT (33%). Isavuconazole was employed as first line therapy in 43 (35%) patients and as a subsequent therapy in 79 (65%). The response rate was 67%, with no differences whether it was used in first or second line. The 1-year overall survival was 49.9%. In multivariate analysis, the response to isavuconazole was favorably associated to overall survival, while IFI refractoriness to previous antifungals was identified as a negative factor. Adverse events were reported in 12.3% of the cases, with 4% of the patients experiencing events of grade 3–4 that led to isavuconazole discontinuation.

The largest series of allogeneic HSCT adult recipients in real-world included 166 patients who received isavuconazole in Spanish centers for both treatment and prophylaxis. Eighty-one (49%) received isavuconazole for treating IFI, and 85 (51%) as prophylaxis. Median duration of isavuconazole administration in IFI treatment was 57 days, and 86 days for prophylaxis. Invasive aspergillosis (78%) was the most frequent infection, followed by mucormycosis (6%). The main reasons for choosing isavuconazole were a more favorable toxicity profile and the need of switching to another antifungal agent (second-line treatment) due to toxicity with prior antifungals. Fifty-four percent of patients with ongoing liver toxicity (including liver graft-versus-host-disease and veno-occlusive disease) were in those situations. The antifungal spectrum or prior therapy failure were the reasons in 23% of the cases, and a more favorable pharmacologic interaction profile was the reasoning behind in 17% of the patients. Therapeutic success (45%) was the most frequent reason for isavuconazole withdrawal. With a median follow-up of 420 days, overall survival after 1 year of isavuconazole was 49%, with no difference between patients receiving isavuconazole as first-line therapy and those receiving it as second-line therapy. In the prophylaxis group, 72 patients (85%) had received a different prior prophylactic antifungal, most frequently posaconazole (33%). The resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough invasive fungal infections were reported. Pharmacologic interactions were described in the majority of patients (80%). Twenty-one patients (13%) reported adverse events related to isavuconazole, mainly liver biochemistry abnormalities, which led to withdrawal in 7 patients (4%).7

In most of these studies the need for safer, better tolerated antifungal treatment was one of the main reasons to choose isavuconazole; there were adverse events or drug–drug interactions associated with previously administered antifungal treatments. The allogeneic HSCT setting represents one of the most challenging scenarios in IFI prevention and management due to the frequently complex, fragile and poly-medicated population. A propensity score-matched cohort analysis of 210 allogeneic HSCT recipients compared the use of voriconazole (n=210) and isavuconazole (n=95) as primary antifungal prophylaxis.1 Median duration of prophylaxis was longer in the isavuconazole cohort (94 days; voriconazole, 76 days) with a more frequent premature discontinuation in the voriconazole cohort. The most common reason for premature discontinuation was biochemical hepatotoxicity. Transaminases values between baseline and end-of-treatment significantly increased in the voriconazole group but remained unchanged in the isavuconazole cohort. The incidence of IFI at day +180 was not significantly different between both groups (2.9% vs. 3.2%, p=0.881), as well as all-cause mortality at day +180 (2.4% vs. 6.3%, p=0.089).

The introduction in recent years of several new drugs for treating hematological malignancies, especially in the acute myeloid leukemia setting, has expanded the therapeutic possibilities of these patients. Targeted therapies and the combination of different classes of therapeutic agents to overcome treatment resistance, further expanded the treatment options and improved survival. In this new setting, management and prevention of IFIs become challenging considering toxicity profiles and the potential drug-to-drug interactions. A retrospective, single-center cohort study that encompassed 241 patients with acute myeloid leukemia reported their experience with azole as prophylaxis. Twelve (5%) patients received isavuconazole and 229 (95%) received posaconazole. IFIs were reported in 14.5% and 0% of participants in the posaconazole and isavuconazole groups, respectively.13 In another retrospective study including 60 patients receiving venetoclax for AML, 33 patients (55%) received antifungal prophylaxis. Twenty-three patients (38%) were treatment-naïve AML, and 37 (62%) had relapsed/refractory AML. Venetoclax dosage was reduced to 50 or 100 mg daily in case of concomitant strong CYP3A4 inhibitors (e.g. posaconazole), or to 200 mg daily in case of moderate CYP3A4 inhibitors (e.g. isavuconazole). The duration of neutropenia and thrombocytopenia was lower, and less infections grade 3–4 were reported in patients who received concomitant CYP3A4 inhibitors in comparison with those who did not. Azole prophylaxis did not affect treatment response and was associated with a significant lower rate of invasive fungal infections (6% vs. 26%, p=0.0659).10

Finally, a retrospective, matched cohort, single-center study, included patients with AML, high-risk myelodysplastic syndrome, or HSCT recipients. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. Forty-two, 81, and 3 received isavuconazole, posaconazole and voriconazole, respectively. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI – 0.9–1.4; p=0.67), suggesting no difference in antifungal prophylactic efficacy. Hepatotoxicity occurred in 14 (17.3%) patients receiving posaconazole and 2 (4.8%) receiving isavuconazole.11

In conclusion, the cumulative experience with the use of isavuconazole in the real-world setting as treatment of IFIs in oncohematological patients is increasingly reported. Results in terms of efficacy and safety are comparable to those reported in the pivotal trial. Furthermore, in clinical practice reports show a considerable off-label use of isavuconazole as prophylaxis due to its favorable toxicity profile compared to other azoles in patients with acute leukemia at the first phases of chemotherapy treatment and in further phases during allogeneic HSCT, among others. Although careful follow-up should be considered in the absence of randomized trials in the prophylaxis setting, especially regarding breakthrough infections, real-world data suggest that isavuconazole provides a safe alternative for patients that present high-risk of IFI, and organ toxicity or potential drug-to-drug interactions.