Isavuconazole as an alternative for antifungal prophylaxis in patients with hematological malignancies: Is the signal sufficient to support clinical practice?

The risks for invasive fungal infection (IFI) are enhanced by cytotoxic therapy-induced prolonged severe neutropenia, intestinal mucosal damage, and B- and T-cell immune suppression in patients receiving intensive therapy for acute myeloid leukemia (AML) or myelodysplasia (MDS) or hematopoietic stem cell transplantation (HSCT). Mortality rates have remained unacceptably high in the range of one in four to one in five or higher for invasive candidiasis and invasive mold infection. There are four strategic approaches to IFI management for consideration: universal chemoprophylaxis to prevent IFI, diagnostics-driven preemptive therapy for early recognition and treatment of IFI, empirical therapy for suspected IFI based upon persistent or recrudescent neutropenic fever syndromes, and directed or targeted therapy for probable or proven IFI. Universal chemoprophylaxis has the potential to lower the risk of life-threatening IFI through prevention. Three classes of agents have been studied for universal chemoprophylaxis, including topical, inhaled, and parenteral polyenes, parenteral echinocandins, and systemic triazoles. Of these, the triazoles have received the most attention because of the availability of oral and parenteral formulations, relative ease of administration, patient tolerance, safety, and efficacy. During the 1990s, a series of placebo- or no treatment-controlled randomized trials in acute leukemia and stem cell transplant patients demonstrated that fluconazole (FCZ) could reduce the risk of invasive yeast infection (IYI), but not invasive aspergillosis (IA) by about two-thirds from 12%–17% to 4%–7%, with an estimated number needed to treat of about 10.1, 2 These observations have, in part, served as a basis for the Infectious Disease Society of America and the American Society of Clinical Oncology recommendations for oral triazoles, such as FCZ, as primary antifungal prophylaxis against IYI among high-risk patients is expected to have prolonged severe neutropenia but a risk for IA of less than 6%.3 Changing anticancer treatment strategies have placed a greater number of patients at risk for IA; accordingly, interest in the use of mold-active triazole agents, such as itraconazole (ITR), posaconazole (PCZ), and voriconazole (VCZ), to prevent these infections has increased. Network meta-analyses of randomized studies of ITR compared to FCZ demonstrated reductions in the risk for IFI and IA by about 44% and 31%–47%, respectively, with numbers needed to treat of about 20–27 and 32–61, respectively, in patients with hematological malignancies.1, 4 Intolerance of the itraconazole formulations under study and toxicities have limited its wider acceptance for this indication. Trials in HSCT comparing PCZ or VCZ to FCZ have observed risk reductions for IFI and IA of about 65% and 69%, respectively, with numbers needed to treat of 13 and 22, respectively.4 The benefits of these agents for the prevention and treatment of IFI have been limited by tolerance, hepatocellular toxicities, CYP3A4-mediated drug–drug interactions, QTc prolongation, and the need to monitor drug levels to ensure efficacy and avoid toxicity. Isavuconazonium sulfate, a pro-drug of isavuconazole (ISA), is a newer antifungal triazole with oral and intravenous formulations, a predictable pharmacokinetic profile that may not require therapeutic drug monitoring, and safety profiles that make it a potentially useful therapeutic agent to prevent and treat IFI in high-risk patient populations.5 The antifungal activity includes common yeasts (Candida spp., Cryptococcus spp., and Trichosporon spp.), endemic fungi, and molds, including Aspergillus spp. and the order Mucorales. In randomized-comparative trials of first-line treatment for invasive aspergillosis, ISA and PCZ were non-inferior to VCZ.6, 7 Although ISA failed to demonstrate non-inferiority to caspofungin as first-line treatment of candidemia and invasive candidiasis,8 the results were consistent with previous reports comparing the efficacy of triazoles and echinocandins.9 Given these observations, what role could or should ISA play in universal chemoprophylaxis strategies in patients at high risk for invasive fungal infection? In this issue of Transplant Infectious Diseases, Scott and colleagues10 have reported a retrospective, single-center, matched cohort analysis of the relative prophylaxis efficacy among subjects with AML (n = 30) or HSCT (n = 96), who non-randomly received ISA (n = 42) or either PCZ (n = 81) or VCZ (n = 3) as “controls.” ISA recipients were matched in a 1:2 ratio, with subjects receiving PCZ or VCZ by age and by diagnosis (AML or HSCT). The primary outcome was the incidence of breakthrough possible, probable, or proven invasive fungal infection (bIFI). Secondary outcomes included triazole-related adverse events. The investigators observed a 28% non-statistically significant increase in the odds of bIFI rate among ISA recipients (7/42, 16.7% and 9/84, 10.7% among ISA and PCZ/VCZ recipients, respectively, p = .399); however, the rates for probable plus proven bIFI were very similar (3/42, 7.1% and 5/84, 6.0%, for ISA and PCZ/VCZ, respectively). ISA was administered as secondary chemoprophylaxis more often than PCZ/VCZ (69% vs. 26%, respectively). Hepatotoxicity was observed more often among PCZ/VCZ recipients (14/84, 16.7% compared to 2/42, 4.8%, p = .058). There were no instances of QTc prolongation in either group. Attributable mortality was similar (one patient in each group). Although the overall bIFI rates seemed somewhat higher among ISA recipients than for PCZ/VCZ recipients, the results may only reflect the bias of the imbalance in secondary prophylaxis. As a result, the clinician remains unsure about the role ISA should play compared to PCZ or VCZ. An ad hoc review of published studies examining probable and proven bIFI in hematological malignancy patients receiving ISA as primary or secondary prophylaxis suggested rates of 7.4% of 243 subjects in four single-center retrospective non-comparative cohort studies,11-14 4.4% of 160 subjects in two single-center prospective non-comparative cohort studies,15, 16 and 6.6% of 272 subjects in four single-center retrospective non-randomized comparative cohort studies,17-19 including the current experience reported by Scott and colleagues.10 Overall, these observations suggest modestly higher rates of bIFI among ISA recipients compared to 3.3% observed among 674 PCZ or VCZ recipients.17-19 Whether these observed efficacy differences are sufficient to offset the potential benefits for ISA related to reduced risks for drug–drug interactions, organ toxicities, and need for therapeutic drug monitoring has yet to be resolved in larger randomized comparative clinical trials in targeted high-risk patient populations as recommended by Scott et al.10 Notwithstanding, the American Society of Transplantation and Cellular Therapy has recommended ISA as an alternative to PCZ or VCZ for primary antifungal prophylaxis for high-risk patients in the setting of prolonged QTc, concomitant QTc prolonging medications, or to minimize CYP3A4-driven drug–drug interactions.20 It seems likely that such trials would confirm the relative efficacy and safety of ISA for universal chemoprophylaxis; however, clinicians would still be unclear regarding the relative value of a universal chemoprophylaxis strategy compared to diagnostics-driven preemptive or even refractory fever-driven empirical antifungal therapeutic strategies. To our knowledge, such trials have not been done. Accordingly, there remain many unanswered questions regarding the most appropriate IFI management strategy, the conditions under which each should be deployed, and the target patient groups who might glean the most benefit.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.