Voriconazole therapeutic drug monitoring including analysis of CYP2C19 phenotype in immunocompromised pediatric patients with invasive fungal infections.

PURPOSE: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. METHODS: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR-RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. RESULTS: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. CONCLUSION: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.

Pre-Exposure Prophylaxis and Treatment with Tixagevimab/Cilgavimab for COVID-19 among Immunocompromised Pediatric Patients.

Background: Patients treated with hemato-oncological malignancies (HO) or undergoing cellular therapies such as hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T cells (CAR-T) were significantly affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the success of SARS-CoV-2 vaccination, immunocompromised patients remain at increased risk for severe coronavirus disease (COVID-19), rendering this group of population a high priority for additional prevention and treatment options. Tixagevimab and Cilgavimab (TIXA/CILGA, AZD7442, Evusheld®) is a combination of two fully human, long-acting monoclonal antibodies. TIXA/CILGA have been approved as pre-exposure prophylaxis and treatment in patients at risk of severe disease with impaired vaccine response. Our objective was to describe the efficacy and safety among immunocompromised pediatric patients. Methods: This was an observational multicenter cohort study of immunocompromised pediatric patients receiving TIXA/CILGA conducted at nine Polish centers of Pediatric Oncology, Hematology and Bone Marrow Transplantation. We analyzed patients in two groups; those treated with HO and those undergoing cellular therapies: HSCT or CAR-T cells. In addition, two other cohorts were identified: patients given TIXA/CILGA as pre-exposure prophylactic and therapeutic intervention. Results: A total of 78 patients were evaluated during the study period: 69 (88.5%) received TIXA/CILGA as pre-exposure prophylaxis and 9 (11.5%) as a treatment strategy. A total of 52 (66.6%) patients were treated with standard chemotherapy at HO departments; 21 (27%) underwent HSCT, and 5 (6.4%) received CAR-T cell therapy. All children with COVID-19 receiving TIXA/CILGA presented a mild degree of severity. The most common clinical manifestations were fever, cough and coryza. At least one adverse event (AE) was reported in two (3.8%) patients excluding standard injection site reactions. Reported AEs were mild or moderate in intensity. One child reported mild myalgia and one reported moderate bone pain and weakness. Conclusions: In our observational multicenter cohort study, we explored the use of TIXA/CILGA as pre-exposure prophylaxis and treatment for COVID-19 among immunocompromised pediatric patients. While our findings suggest a potential benefit in preventing and managing COVID-19 in this vulnerable population, it is important to note the study's non-comparative design. Our results highlight the need for well-designed clinical trials to confirm these observations and further assess the efficacy and safety of TIXA/CILGA in immunocompromised children.

Outcomes of allogeneic haematopoietic cell transplantation for myelofibrosis in children and adolescents: the retrospective study of the EBMT Paediatric Diseases WP.

This retrospective study evaluated 35 children (median age 5.2 years; range 0.4-18) with myelofibrosis (MF), including 33 with primary myelofibrosis and 2 with secondary myelofibrosis transplanted from matched sibling donor (MSD) (n = 17) or non-MSD (n = 18) between 2000 and 2022. Conditioning was usually chemotherapy-based (n = 33) and myeloablative (n = 32). Fifteen patients received bone marrow (BM), 14 haematopoietic cells (HC) from peripheral blood (PB), and 6 from cord blood (CB). Day +100 acute GvHD II-IV incidence was significantly lower after MSD-haematopoietic cell transplantation (MSD-HCT) than after non-MSD-HCT [18.8% (4.3-41.1) vs 58.8% (31-78.6); p = 0.01]. Six-year non-relapse mortality (NRM) was 18% (7.1-32.8), relapse incidence was 15.9% (5.6-30.9), progression-free survival (PFS) was 66.1% (47-79.7), GvHD-free relapse-free survival was 50% (30.6-66.7), and overall survival (OS) was 71.1% (51.4-84). Six-year PFS and OS were significantly higher after BM transplantation compared to HCT from other sources [85.1% (52.3-96.1) vs 50.8% (26.3-71), p = 0.03, and 90.9% (50.8-98.7) vs 54% (28.1-74.2), p = 0.01, respectively], whereas NRM was significantly lower [0% vs 32% (12.3-53.9); p = 0.02]. This first multicentre study on outcomes of allogeneic HCT in children with myelofibrosis proves feasibility and curative effect of transplantation in these children, suggests that bone marrow transplantation is associated with better outcomes, and indicates the need for further studies.

Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan.

Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.