Long term use of eltrombopag in children with chronic immune thrombocytopenia: extended real life retrospective multicenter experience of the Italian Association of Pediatric Hematology and Oncology.

Background: The present multicenter retrospective study on eltrombopag administration in Italian children with chronic ITP aims to extend follow-up of our previous study. Materials and methods: This retrospective multicenter study was conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). Patients were classified into three subgroups: group 1 included patients who discontinued treatment due to a stable platelet count; group 2 included patients who discontinued treatment due to ineffectiveness; group 3 included patients who did not permanently discontinue treatment. Results: 56 patients were eligible for analysis. The median duration of eltrombopag treatment was 40 months (7-71 months). Twenty patients (36%) discontinued permanently eltrombopag. The reasons of permanent discontinuation were adverse effects (n = 1), inefficacy (n = 10), stable platelet count (n = 9). All patients of group 1 maintained a durable response without additional treatments after eltrombopag discontinuation. We found that patients of group 2 were on treatment for less time (median treatment time: 13.5 months, min: 6.0 - max: 56.0) than patients of group 1 (median treatment time: 34 months, min: 16.0 - max: 62.0) (p < 0.05). Patients of group 2 mostly did not achieve a stable platelet count in the first 6 months of treatment and underwent concomitant therapies during follow-up respect of group 1 and group 3 (p < 0.01). Conclusion: Our study found that the benefits of eltrombopag treatment, in terms of platelet count improvement and use of additional therapies, are identifiable from the first 6 months of treatment.

"CHildren with Inherited Platelet disorders Surveillance" (CHIPS) retrospective and prospective observational cohort study by Italian Association of Pediatric Hematology and Oncology (AIEOP).

Background: Inherited thrombocytopenias (ITs) are rare congenital bleeding disorders characterized by different clinical expression and variable prognosis. ITs are poorly known by clinicians and often misdiagnosed with most common forms of thrombocytopenia. Material and methods: "CHildren with Inherited Platelet disorders Surveillance" study (CHIPS) is a retrospective - prospective observational cohort study conducted between January 2003 and January 2022 in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). The primary objective of this study was to collect clinical and laboratory data on Italian pediatric patients with inherited thrombocytopenias. Secondary objectives were to calculate prevalence of ITs in Italian pediatric population and to assess frequency and genotype-phenotype correlation of different types of mutations in our study cohort. Results: A total of 139 children, with ITs (82 male - 57 female) were enrolled. ITs prevalence in Italy ranged from 0.7 per 100,000 children during 2010 to 2 per 100,000 children during 2022. The median time between the onset of thrombocytopenia and the diagnosis of ITs was 1 years (range 0 - 18 years). A family history of thrombocytopenia has been reported in 90 patients (65%). Among 139 children with ITs, in 73 (53%) children almost one defective gene has been identified. In 61 patients a pathogenic mutation has been identified. Among them, 2 patients also carry a variant of uncertain significance (VUS), and 4 others harbour 2 VUS variants. VUS variants were identified in further 8 patients (6%), 4 of which carry more than one variant VUS. Three patients (2%) had a likely pathogenic variant while in 1 patient (1%) a variant was identified that was initially given an uncertain significance but was later classified as benign. In addition, in 17 patients the genetic diagnosis is not available, but their family history and clinical/laboratory features strongly suggest the presence of a specific genetic cause. In 49 children (35%) no genetic defect were identified. In ninetyseven patients (70%), thrombocytopenia was not associated with other clinically apparent disorders. However, 42 children (30%) had one or more additional clinical alterations. Conclusion: Our study provides a descriptive collection of ITs in the pediatric Italian population.

Focus on MicroRNAs as Biomarker in Pediatric Diseases.

BACKGROUND: MiRNAs are a class of small non-coding RNAs that are involved in the post-transcriptional regulation of gene expression. MiRNAs are considered a class of epigenetic biomarkers. These biomarkers can investigate disease at different stages: diagnosis, therapy or clinical follow-up. OBJECTIVE: The aim of this paper is to highlight the innovative use of miRNAs in several childhood diseases. METHODS: We conducted a literature review to search the usage of miRNAs in pediatric clinical routine or experimental trials. RESULTS: We found a possible key role of miRNAs in different pediatric illnesses (metabolic alterations, coagulation defects, cancer). CONCLUSION: The modest literature production denotes that further investigation is needed to assess and validate the promising role of miRNAs as non-invasive biomarkers in pediatric disorders.

Thrombopoietin Receptor Agonists in Children with Immune Thrombocytopenia: A New Therapeutic Era.

BACKGROUND AND OBJECTIVE: Immune thrombocytopenia (ITP) is a common bleeding disorder in childhood. The management of ITP in children is controversial, requiring personalized assessment of patients and therapeutic choices. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, have been shown to be safe and effective for the treatment of pediatric ITP. The aim of our research is to define the role of thrombopoietin receptor agonists in the management of pediatric ITP. METHODS: This review focuses on the use of TPO-RAs in pediatric ITP, in randomized trials and in clinical routine, highlighting their key role in the management of the disease. RESULTS: Eltrombopag and romiplostim appear effective treatment options for children with ITP. Several clinical studies have assessed that the use of TPO-RAs increases platelet count, decreases bleeding symptoms and improves health-related quality of life. Moreover, TPO-RAs are well tolerated with minor side effects. CONCLUSION: Although long term efficacy and safety of TPO-RAs still require further investigations, their use is gradually expanding in the clinical practice of children with ITP.

Fatigue perception in a cohort of children with chronic immune thrombocytopenia and their caregivers using the PedsQL MFS: Real-life multicenter experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP).

BACKGROUND: Fatigue is an important clinical and psychological aspect for a significant number of children affected by immune thrombocytopenia (ITP). To date, few studies have explored fatigue and its relationship with chronic ITP in pediatric age. The aim of the present multicentric pilot study is to determine fatigue perception in a large group of children with chronic ITP and their caregivers using the PedsQL Multidimensional Fatigue Scale (PedsQL MFS), and to compare the results with those of healthy control subjects. PROCEDURE: Children with chronic ITP aged 5-18 years and/or caregivers of children aged 2-18 years were enrolled. Child/adolescent self-report was used for patients aged 5-18 years, and parent proxy-report for patients aged 2-18 years. The questionnaire was offered as online survey. PedsQL MFS is composed of 18 items covering three dimensions: General Fatigue Scale, Sleep/Rest Fatigue Scale, and Cognitive Fatigue Scale. RESULTS: One hundred ninety-one patients affected by chronic ITP and 248 caregivers answered the PedsQL MFS. We have highlighted that lower values of PedsQL MFS scores are obtained in the 13-18 age group. Moreover, sleep/rest fatigue domain appears to be more compromised in all age groups. For all PedsQL MFS scores, pediatric patients with chronic ITP and their caregivers reported statistically significant worse fatigue than healthy children. CONCLUSIONS: This study suggests that fatigue is relevant among children and adolescents affected by chronic ITP. The PedsQL MFS represents an adequate instrument for measuring fatigue in patients with chronic ITP. Therefore, symptoms of fatigue should be routinely assessed in clinical practice.

Venous Thromboembolism in Children: From Diagnosis to Management.

Venous thromboembolism (VTE) in children is a rare occurrence, although in recent decades we have seen an increase due to several factors, such as the rise in survival of subjects with chronic conditions, the use of catheters, and the increased sensitivity of diagnostic tools. Besides inherited thrombophilia, acquired conditions such as cardiovascular diseases, infections, chronic disorders, obesity and malignancy are also common risk factors for paediatric VTE. The treatment of paediatric VTE consists of the use of heparins and/or vitamin K antagonists to prevent dissemination, embolization, and secondary VTE. Randomized clinical trials of direct oral anticoagulants in paediatric VTE are ongoing, with the aim to improve the compliance and the care of patients. We reviewed the physiological and pathological mechanisms underlying paediatric thrombosis and updated the current diagnosis and treatment options.

Use of Eltrombopag in Children With Chronic Immune Thrombocytopenia (ITP): A Real Life Retrospective Multicenter Experience of the Italian Association of Pediatric Hematology and Oncology (AIEOP).

Background: The thrombopoietin receptor agonist eltrombopag has been shown to be safe and effective for children with chronic immune thrombocytopenia (ITP). The aim of the present study was to characterize eltrombopag use in current clinical practice. Material and Methods: This is a retrospective multicenter study conducted in 17 centers affiliated to the Italian Association of Pediatric Hematology and Oncology (AIEOP). The primary objective of the study was to determine the prevalence of eltrombopag use in Italian children affected by chronic ITP, after EMA authorization for pediatric age. The secondary objective was to assess efficacy in the first 6 months and safety during the whole period of eltrombopag treatment in current clinical practice. A total of 386 children with chronic ITP were retrospectively enrolled and eligible for analysis. Among these patients, 71 received eltrombopag. Results: The prevalence of eltrombopag use was 19% (95% CI 0.15-0.23). Thirty-one patients (44%) were male and 40 patients (56%) were female. The median age at the first dose of eltrombopag was 12 years (3-17 years). The median duration of eltrombopag treatment was 11 months (1-32 months) and the median starting dose was 50 mg/day (12, 5-75 mg/day). Thirty-two patients (45%) required one or more concomitant ITP medications during the first 6 months of treatment with eltrombopag. Thirty-nine patients (55%) never required concomitant medications. Median platelet counts and proportion of patients achieving the target platelet count of at least 30 × 109/L and 100 × 109/L significantly increased during the first 6 months of treatment (p < 0.0001). Additionally, eltrombopag has been proved effective in the absence of concomitant therapies. The most common Adverse Events were headache (7%) and thrombocytosis (6%). Conclusion: Our study highlighted the crucial role of eltrombopag as second line treatment in children with chronic ITP.

Can Anti-Thyroid Antibodies Influence the Outcome of Primary Chronic Immune Thrombocytopenia in Children?

BACKGROUND: Immune thrombocytopenia (ITP) is an acquired immune mediated disorder characterized by isolated thrombocytopenia. Pediatric ITP patients can develop autoantibodies such as anti-thyroglobulin (TG) and anti-thyroperoxidase (TPO), even in the absence of clinical signs of autoimmune disease. OBJECTIVE: The purpose of this article is to provide a review about: 1) the prevalence of positivity of anti-thyroid antibodies (TPO and TG) in pediatric patients with chronic ITP; 2) the role of autoimmune thyroiditis on the outcome of chronic ITP. METHODS: The authors individually completed a review of the literature for this article. Retrospective and prospective clinical studies with pediatric cohorts were considered. RESULTS: From the analysis of data, we found 4 papers which included studies only on pediatric population, and which corresponded to selected criteria. Pediatric ITP patients have been shown to have a statistically significant prevalence of anti-thyroid antibodies over healthy controls (11.6-36% versus 1.2-1.3%). No correlation has been found between the platelet count and the prevalence of positive anti-thyroid antibodies at any time of the follow up. CONCLUSION: The results of our bibliographic research demonstrated that: a) pediatric patients with chronic ITP tend to have a statistically significant prevalence of anti-thyroid antibodies positivity respect to general pediatric population; b) there are no clear data about the role of autoimmune thyroiditis as prognostic factor for chronic course of ITP in pediatric age.