isavuconazole and Hematologic-Neoplasms

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.

Topics: Administration, Intravenous; Administration, Oral; Adolescent; Antifungal Agents; Aspergillus; Child; Child, Preschool; Drug Administration Schedule; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Invasive Fungal Infections; Male; Microbial Sensitivity Tests; Mucor; Nitriles; Penicillium; Pyridines; Retrospective Studies; Transplantation, Homologous; Triazoles

Topics: Antifungal Agents; Hematologic Neoplasms; Humans; Nitriles; Triazoles

Isavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side-effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported.. In this single-center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs.. We evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21-91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%). Nineteen patients (17.9%) developed bIFIs-nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8-253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 μg/mL) were comparable to industry-sponsored clinical trials. All-cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co-infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups.. ISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side-effect and drug-interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Invasive Fungal Infections; Male; Middle Aged; Retrospective Studies; Young Adult

Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population.. Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages.. Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA.. ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.

Topics: Adolescent; Child; Child, Preschool; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Invasive Fungal Infections; Male; Nitriles; Pyridines; Retrospective Studies; Triazoles

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.. 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.. 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.. 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.

Topics: Adult; Antifungal Agents; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Nitriles; Pyridines; Retrospective Studies; Transplant Recipients; Triazoles

Prolonged courses of isavuconazole (ISA) are increasingly utilized in immunocompromised patients. Toxicities have been reported with long-term use of the other triazoles. We report the first real-life tolerability data in 50 patients with hematologic malignancy receiving ≥6 months of ISA. ISA was well tolerated in our ill patient population.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Female; Hematologic Neoplasms; Humans; Liver; Male; Middle Aged; Nitriles; Pyridines; Retrospective Studies; Skin; Triazoles; Young Adult