Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities to transform the care of people with hemophilia.

Background: Decades of research have transformed hemophilia from severely limiting children's lives to a manageable disorder compatible with a full, active life, for many in high-income countries. The direction of future research will determine whether exciting developments truly advance health equity for all people with hemophilia (PWH). National Hemophilia Foundation (NHF) and American Thrombosis and Hemostasis Network conducted extensive inclusive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them.

Gene Therapy and Hemophilia: Where Do We Go from Here?

Gene therapy for hemophilia using adeno-associated virus (AAV) derived vectors can reduce or eliminate patients' disease-related complications and improve their quality of life. Broad implementation globally will lead to societal gains and foster health equity. Several vector products each for factor IX (FIX) or factor VIII (FVIII) deficiency are in advanced clinical development.

Screening for inattention, hyperactivity and impulsivity in children with haemophilia: A quality improvement intervention.

Introduction: Children with haemophilia have been reported with increased rates of inattention (IN) and hyperactivity/impulsivity (HI) and, therefore, are particularly vulnerable to poor social and academic outcomes.

Aim: To examine the benefit of utilizing a formal screening process for IN/HI in children with haemophilia during comprehensive clinic visits using a quality improvement approach.

Methods: At a single haemophilia treatment centre, screening for psychosocial issues was expanded and formalised to include (1) the Conners 3 Edition (Conners3) screening tool for IN/HI symptoms administered during the standard psychosocial assessment (SPA) by the social worker and school advocacy coordinator, (2) formal pathways to diagnosis and intervention as indicated including psychology consultation, psychological testing, or referral to community-based mental health professionals, and in-person advocacy assistance in the patient's community school.

Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.

Background: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B.

Methods: In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses.

Haemophilia gene therapy-Update on new country initiatives.

Introduction: Gene therapy is emerging as a potential cure for haemophilia. Gene therapy is a one-time treatment that can elevate factor levels for many years and minimize or eliminate the need for clotting factor concentrate (CFC) replacement therapy. However, there is a paucity of reports on gene therapy efforts in countries outside of North America or Europe, especially in low-and-middle-income countries (LMIC).

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

Introduction: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL).

Aim: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment.

Methods: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1).

Reduced-intensity conditioning-based hematopoietic cell transplantation for dyskeratosis congenita: Single-center experience and literature review.

Background: Bone marrow failure in dyskeratosis congenita (DKC) is progressive, and allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. However, outcomes after HCT are suboptimal because of mucosal, vascular, pulmonary, and hepatic fragility, which can be exacerbated by chemotherapy conditioning and graft-versus-host disease (GVHD). These toxicities can be mitigated by reducing the intensity of the conditioning regimen.

The cost-effectiveness of gene therapy for severe hemophilia B: a microsimulation study from the United States perspective.

Adeno-associated virus (AAV)-mediated gene therapy is a novel treatment promising to reduce morbidity associated with hemophilia. Although multiple clinical trials continue to evaluate efficacy and safety, limited cost-effectiveness data have been published. This study compared the potential cost-effectiveness of AAV-mediated factor IX (FIX)-Padua gene therapy for patients with severe hemophilia B in the United States vs on-demand FIX replacement and primary FIX prophylaxis, using either standard or extended half-life FIX products.

Eltrombopag in children with severe aplastic anemia.

Background: Immunosuppressive therapy with horse antithymocyte globulin and cyclosporine currently remains the standard therapy for children with severe aplastic anemia (SAA) who lack human leukocyte antigen (HLA)-identical sibling. The thrombopoietin receptor agonist eltrombopag has been recently approved for SAA patients 2 years and older. However, there are limited data on its safety and efficacy in pediatric cohorts.

Limited sampling strategies for accurate determination of extended half-life factor VIII pharmacokinetics in severe haemophilia A patients.

Background: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in haemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring.

Objective: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs.

Use of recombinant activated factor VII for uncontrolled bleeding in a haematology/oncology paediatric ICU cohort.

: Bleeding among critically ill paediatric haematology/oncology (CIPHO) patients leads to significant morbidity and mortality. Recombinant activated factor VII (rFVIIa) has shown some benefits in previous reported off-label use when conventional therapies have failed. However, data in CIPHO are lacking.

Hemophilia gene therapy-New country initiatives.

Gene therapy is an opportunity for haemophilia patients to receive a one-time treatment and have lasting factor levels for years or decades instead of dependence on repeated administration within short intervals and on sustained supply of drug. Great strides have been made in the development of gene therapy for haemophilia in the last decade. Adeno-associated virus (AAV) vector-mediated gene transfer in haemophilia A and B has entered the phase III trial stage.

Gene therapy for haemophilia.

Background: Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy for haemophilia is a curative treatment modality currently under investigation.

Efficacy and Safety of Recombinant Activated Factor VII Off-label Use in a Pediatric Hematology/Oncology Cohort.

Background: Recombinant activated factor VII (rFVIIa) has been used off-label to treat or prevent severe bleeding in patients for whom conventional treatments are unsuccessful. However, studies in children remain limited.

Procedure: To examine the efficacy and safety of rFVIIa, we performed a retrospective analysis of rFVIIa off-label use in a pediatric hematology/oncology cohort at a single center from 2006 to 2014.

Platelet Transfusions in the PICU: Does Disease Severity Matter?

Objectives: Pediatric intensivists frequently prescribe platelet transfusions to critically ill children, but there are limited data on platelet transfusion practice and platelet transfusion-related outcomes in the PICU. In this study, we evaluated the current platelet transfusion practice and platelet transfusion-related outcomes in the PICU.

Design: Institutional review board-approved, retrospective cohort study from January 2010 to March 2016.

Safe Use of Low-Molecular-weight Heparin in Pediatric Acute Lymphoblastic Leukemia and Lymphoma Around Lumbar Punctures.

Children with acute lymphoblastic leukemia or lymphoma (ALL) undergo multiple lumbar punctures (LPs) and frequently require low-molecular-weight heparin (LMWH) for thromboembolic complications. We evaluated if withholding LMWH 24 hours before and after LPs prevented bleeding complications. Children (n=133) with ALL from who were: (1) treated at St.

Gene therapy for haemophilia.

Background: Haemophilia is a genetic disorder characterized by spontaneous or provoked, often uncontrolled, bleeding into joints, muscles and other soft tissues. Current methods of treatment are expensive, challenging and involve regular administration of clotting factors. Gene therapy has recently been prompted as a curative treatment modality.

New and improved AAVenues: current status of hemophilia B gene therapy.

Introduction: Hemophilia B is a sex linked, monogenic, coagulation disorder caused by a deficiency in functional factor IX protein. Gene therapy for this disorder via systemic administration of an adeno-associated virus (AAV) encoding an optimized factor IX construct has shown considerable success, ameliorating the bleeding phenotype in a number of patients. However challenges to sustained curative gene transfer in this patient population remain, and as such there are efforts in the field to improve long term factor IX expression, via optimisations to the AAV vector, transgene cassette and correction strategy.

Efficacy and safety of eculizumab in children and adolescents with paroxysmal nocturnal hemoglobinuria.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is rare in children, but represents a similarly serious and chronic condition as in adults. Children with PNH frequently experience complications of chronic hemolysis, recurrent thrombosis, marrow failure, serious infections, abdominal pain, chronic fatigue, and decreased quality of life with reduced survival. The terminal complement inhibitor eculizumab is proven to be effective and safe in adults and approved by the FDA for treatment of PNH.

PG4KDS: a model for the clinical implementation of pre-emptive pharmacogenetics.

Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Children's Research Hospital pre-emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay.