Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole

Abstract

Background Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high‐risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted. Methods This retrospective, matched cohort, single‐center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. Results A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. 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 = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole. Conclusion Patients who received isavuconazole prophylaxis during AML induction therapy or post‐HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

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

“…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][18][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 feverdriven empirical antifungal therapeutic strategies.…”

“…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][12][13][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][18][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][18][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.…”

“…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 …”

“…In this issue of Transplant Infectious Diseases , Scott and colleagues 10 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).…”

“…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 .…”