Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients

Abstract

Background Isavuconazole (ISA) is an attractive candidate for primary mold-active prophylaxis in high-risk patients with hematologic malignancies or hematopoietic cell transplant (HCT) recipients. However, data supporting the use of ISA for primary prophylaxis in these patients are lacking. Methods We conducted a retrospective review of breakthrough invasive fungal infections (bIFIs) among adult hematologic malignancy patients and HCT recipients who received ≥7 days of ISA primary prophylaxis between 1 September 2016 and 30 September 2018. The incidence of bIFIs in patients receiving ISA was compared to those receiving posaconazole (POS) and voriconazole (VOR) during the same time period. Results One hundred forty-five patients received 197 courses of ISA prophylaxis. Twelve bIFIs (Aspergillus fumigatus [5], Aspergillus species [2], Mucorales [2], Fusarium species [2], and Candida glabrata [1]) occurred, representing 8.3% of patients and 6.1% of courses, after a median duration of 14 days of ISA prophylaxis. All bIFIs occurred during periods of neutropenia. Seven patients (58.3%) died within 42 days of onset of bIFI. In addition, bIFIs complicated 10.2% of ISA, 4.1% of POS, and 1.1% of VOR courses among patients with de novo or relapsed/refractory acute myeloid leukemia during the study period, with invasive pulmonary aspergillosis (IPA) complicating 6.8% of ISA, 1.3% of POS, and zero VOR courses. Conclusions Although ISA has been approved for treatment of invasive Aspergillus and mucormycosis, we observed an increased rate of bIFI, notably IPA, using ISA for primary prophylaxis. These results support the need for further study to determine the role of ISA as primary prophylaxis.

Use of triazoles for the treatment of invasive aspergillosis: A three‐year cohort analysis

“…These results are consistent with previously published reports regarding the side effect profile and clinical efficacy of voriconazole . They further substantiate the findings of recent reports describing the progression of IA during isavuconazole treatment and the occurrence of breakthrough invasive fungal disease on isavuconazole prophylaxis, but also corroborate its excellent safety and tolerability profile …”

“…For these reasons, it is increasingly being used for treatment of IA in at‐risk patients, including those receiving Bruton's tyrosine kinase inhibitor therapy . However, breakthrough cases of IA and other invasive fungal infections have recently been reported in patients with haematological malignancies and SOT recipients on isavuconazole treatment . Motivated by similar observations in our hospital, we sought to systematically evaluate treatment responses and clinical outcomes among patients with haematological malignancies, allogeneic HCT and SOT recipients diagnosed with IA who received triazole antifungal therapy.…”

Defining breakthrough invasive fungal infection–Position paper of the mycoses study group education and research consortium and the European Confederation of Medical Mycology

“…Others used a clinical approach assigning breakthrough infection as the first day of patient symptoms consistent with fungal disease . Some refer to the day of the first positive mycological test or radiographic finding consistent with IFI as confirmatory for breakthrough infection, whilst others require the presence of all necessary diagnostic criteria (host, clinical and microbiological) for diagnosis (Figure ). Another area of substantial difficulty is the elapsed antifungal exposure time that separates pre‐existing (“baseline”) IFI from breakthrough IFI.…”

“…Some studies do not report on this aspect, while others refer to the beginning of chemotherapy . The majority of studies reviewed, used a very early time point, such as the day of randomisation, which frequently take place prior to the first antifungal dose, at the day of first dose, day 3 or at day 7 after initiation of prophylaxis. Some of this variability may reflect PK/PD considerations of the drugs studied, including the time necessary to reach pharmacologic steady state (Table 3).…”

Posaconazole versus Itraconazole as Prophylactic Antifungal Agents during Induction Chemotherapy for Acute Myeloid Leukemia: A Real-World Single Center Comparison

“…To prevent IFDs in AML patients, the use of prophylactic antifungal agents has become standard in that undergoing induction chemotherapy [2]. In recent years, studies have been conducted with various antifungal agents, such as fluconazole, itraconazole, posaconazole, voriconazole, isavuconazole, and micafungin [3][4][5][6][7][8][9]. Among these prophylactic fungal agents, the superiority of posaconazole was demonstrated by Cornely et al [3] in 2007.…”