A Case Series and Literature Review of Isavuconazole Use in Pediatric Patients with Hemato-oncologic Diseases and Hematopoietic Stem Cell Transplantation

Abstract

We analyzed the use of isavuconazole (ISA) as treatment or prophylaxis for invasive fungal disease (IFD) in children with hemato-oncologic diseases. A multicentric retrospective analysis was performed among centers belonging to the Italian Association for Pediatric Hematology and Oncology (AIEOP). Pharmacokinetic (PK) monitoring was applied by a high-performance liquid chromatography-tandem mass spectrometry (HLPC-MS/MS) assay. Twenty-nine patients were studied: 10 during chemotherapy and 19 after allogeneic hematopoietic stem cell transplantation (HSCT). The patients consisted of 20 males and 9 females with a median age of 14.5 years (age range, 3 to 18 years) and a median body weight of 47 kg (body weight range, 15 to 80 kg). ISA was used as prophylaxis in 5 patients and as treatment in 24 cases (20 after therapeutic failure, 4 as first-line therapy). According to European Organization for Research and Treatment of Cancer (EORTC) criteria, we registered 5 patients with proven IFD, 9 patients with probable IFD, and 10 patients with possible IFD. Patients with a body weight of <30 kg received half the ISA dose; the others received ISA on the adult schedule (a 200-mg loading dose every 8 h on days 1 and 2 and a 200-mg/day maintenance dose); for all but 10 patients, the route of administration switched from the intravenous route to the oral route during treatment. ISA was administered for a median of 75.5 days (range, 6 to 523 days). The overall response rate was 70.8%; 12 patients with IFD achieved complete remission, 5 achieved partial remission, 5 achieved progression, and 3 achieved stable IFD. No breakthrough infections were registered. PK monitoring of 17 patients revealed a median ISA steady-state trough concentration of 4.91 mg/liter (range, 2.15 to 8.54 mg/liter) and a concentration/dose (in kilograms) ratio of 1.13 (range, 0.47 to 3.42). Determination of the 12-h PK profile was performed in 6 cases. The median area under the concentration-time curve from 0 to 12 h was 153.16 mg·h/liter (range, 86.31 to 169.45 mg·h/liter). Common Terminology Criteria for Adverse Events grade 1 to 3 toxicity (increased transaminase and/or creatinine levels) was observed in 6 patients, with no drug-drug interactions being seen in patients receiving immunosuppressants. Isavuconazole may be useful and safe in children with hemato-oncologic diseases, even in the HSCT setting. Prospective studies are warranted.

Therapeutic Drug Monitoring of Isavuconazole: Serum Concentration Variability and Success Rates for Reaching Target in Comparison with Voriconazole

“…The clinical phase III trial SECURE found the majority of s-ISZ measurements were within the range of 1–7 mg/L [ 23 ]. The median value in the present study was 4.3 mg/L and well within that range, the same as in other studies [ 7 , 8 , 9 , 12 , 17 , 24 , 25 , 26 ]. In the present study, the majority of the s-ISZ measurements were also within the recommended range, but for VRZ a third of TDM measurements were outside the recommended range, which is also in accordance with the literature [ 27 ].…”

“…Adverse events to ISZ in the present study were mostly gastroenteric and hepatic, reported by the treating physician and also reported by others [ 12 , 14 , 25 , 29 , 30 , 31 ]. Adverse events were not closely related to high median TDMs.…”

“…Limitations to this study are the retrospective design and the limited number of patients. Since many studies, including ours, are retrospective [ 12 , 17 , 24 , 26 ], there is no certainty that the included samples were trough samples. One prospective trial did however manage to include trough levels only and found a median s-ISZ of 2.35 mg/L [ 25 ].…”

“…In addition to treatment, ISZ was found to be safe as prophylaxis in a clinical trial with acute myeloid leukemia and myelodysplastic syndrome patients of which almost half received targeted treatments such as venetoclax and FLT3 inhibitors [7]. Isavuconazole as prophylaxis has also been reported in other studies [8][9][10][11] as well as the use of ISZ in children [12] and patients with chronic pulmonary aspergillosis (CPA) [13,14]. Although ISZ has been used as prophylaxis, this is a non-approved and off-label intervention.…”

Central Nervous System Mold Infections in Children with Hematological Malignancies: Advances in Diagnosis and Treatment

“…and mucorales) reported on an excellent overall survival of 80.6% on day 42 [76]. Although a retrospective study including 29 immunocompromised children receiving isavuconazole off-label suggested the usefulness of the compound in the pediatric setting, data of isavuconazole in children are very limited [77]. As there is a lack of pediatric data regarding the treatment of rare molds, such as Fusarium spp.…”