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. RESEARCH DESIGN AND METHODS: Working group (WG) 1 of the NHF State of the Science Research Summit distilled the community-identified priorities for hemophilia A and B into concrete research questions and scored their feasibility, impact, and risk. RESULTS: WG1 defined 63 top priority research questions concerning arthropathy/pain/bone health, inhibitors, diagnostics, gene therapy, the pediatric to adult transition of care, disparities faced by the community, and cardiovascular disease. This research has the potential to empower PWH to thrive despite lifelong comorbidities and achieve new standards of wellbeing, including psychosocial. CONCLUSIONS: Collaborative research and care delivery will be key to capitalizing on current and horizon treatments and harnessing technical advances to improve diagnostics and testing, to advance health equity for all PWH.

Hemophilia is the best known of the inherited bleeding disorders (BD). This is a rare condition that causes disproportionate bleeding, often into joints and vital organs. Factor replacement, injecting recombinant or plasma-based clotting factor products directly into the vein, became commonplace to control the disorder in the 1990s and 2000s. Prophylaxis, or injecting replacement factor every few days into people with hemophilia (PWH), has revolutionized patients' lives. In the last few years, other advances in new therapies have entered this space, such as non-factor replacement therapies and gene therapy. With many more research advances on the horizon, the National Hemophilia Foundation (NHF) initiated a State of the Science Research Summit in 2020. This event was attended by over 880 interested parties to help design an agenda of research priorities for inherited BDs for the next decade, based on community consultations. NHF formed multiple Working Groups (WG), each exploring a theme resulting from the community consultations, and presenting their results at the Summit. Led by 2 hematologists who manage and treat PWH daily, the 21-community member WG1 assigned to hemophilia A and B divided into 7 subgroups to identify and organize research priorities for different topic areas. The outcomes focused on prioritizing patients' needs, technological advances, and research in the areas of greatest potential for PWH and those who care for them. The results are a roadmap for the future execution of a research plan that truly serves the community.

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 3rd 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. RESULTS: Forty-four patients, age 9.9 ± 4.8 years (range 3-16) were targeted. The initial screening approach was modified to improve the communication with caretakers during assessments and streamline diagnostic pathways if no, moderate or significant behavioural concerns were identified. Eleven patients had pre-existing mental health diagnoses. Thirteen of the remaining 33 patients (39.4%) received a new mental health diagnosis, ADHD in 8/33 (24.2%). Of the total cohort, 54.5% were found to have a mental health diagnosis. The rate of ADHD (29.5%) was significantly higher than reported in the general population. CONCLUSION: The described process, developed through a QI approach, allowed formal and objective screening for IN/HI, streamlined a pathway to diagnosis and intervention, and identified undiagnosed disabilities in children with haemophilia improving their access to services.

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. Safety data are reassuring. Efficacy data for up to 8 and 5 years, respectively, vary considerably among vector types and among individuals, but indicate significant reduction in bleeds and factor use. Products will soon be approved for marketing. This review highlights the relevant considerations for implementation of hemophilia gene therapy, specifically across a broad range of socioeconomic backgrounds globally, based on recent publications and our own experience. We address the current efficacy and safety data and relevant aspects of vector immunology. We then discuss pertinent implementation steps including pre-implementation and readiness assessments, considerations on cost, cost-effectiveness and payment models, approaches to education and informed consent, and the operational needs as well as the need for monitoring of health outcomes and implementation outcomes. To prevent a lag or complete lack of establishing access to this life-changing therapy option for all patients with hemophilia worldwide, adaptable pathways supported by collaborative and international efforts of all stakeholders are needed.

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). All indications are that gene therapy will be one of standard care treatments for haemophilia in the future. Still, it may not be accessible to many countries due to various barriers and challenges. At the same time, each country may formulate solutions that may be used globally. AIM: To summarize the approaches taken to establish haemophilia gene therapy in Japan, China, India, South Africa, and Brazil, and to describe the US-initiated multi-LMIC haemophilia gene therapy development program to include Peru, Vietnam, Thailand, Nepal, and Sri Lanka. METHODS: A review of related published information or as accessible by each country's author. RESULTS: Different starting conditions, differing input and level of support from the multitude of stakeholders, and strong leadership have led to various approaches for facilitating research and developing needed infrastructure and regulatory and financing models. Gene therapy programs are at various stages of development and include both adeno-associated viral and lentiviral vectors. CONCLUSION: Global partnerships and collaboration, exchange of knowledge and experience, and alignment of processes across borders will promote further progress towards global access to gene therapy for haemophilia.

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). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

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. A microsimulation Markov model was constructed, and transition probabilities between health states and utilities were informed by using published data. Costs were aggregated by using a microcosting approach. A time horizon from 18 years old until death, from the perspective of a third-party payer in the United States, was conducted. Gene therapy was more cost-effective than both alternatives considering a $150 000/quality-adjusted life-year threshold. The price for gene therapy was assumed to be $2 000 000 in the base case scenario; however, one of the 1-way sensitivity analyses was conducted by using observed manufacturing, administration, and 5-year follow-up costs of $87 198 for AAV-mediated gene therapy vector as derived from the manufacturing facility and clinical practice at St Jude Children's Research Hospital. One-way sensitivity analyses revealed 10 of 102 scenarios in which gene therapy was not cost-effective compared with alternative treatments. Notably, gene therapy remained cost-effective in a hypothetical scenario in which we estimated that the discounted factor concentrate price was 20% of the wholesale acquisition cost in the United States. Probabilistic sensitivity analysis estimated gene therapy to be cost-effective at 92% of simulations considering a $150 000/quality-adjusted life-year threshold. In conclusion, based on detailed simulation inputs and assumptions, gene therapy was more cost-effective than on-demand treatment and prophylaxis for patients with severe hemophilia B.

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. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modelled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error <10%). When samples are only collected during a single visit (i.e., predose + peak), inclusion of prior dose information reduces median half-life error from >20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-h trough from 25% to <12% in the youngest population. CONCLUSIONS: The PK of rFVIIIFc can be accurately estimated using only peak and trough samples, provided that knowledge of prior doses is incorporated and the PK study is planned on an appropriate day within the dosing regimen.

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 transfer by lentiviral vector or gene editing technologies using factor VIII (FVIII) or IX (FIX) genes are now entering clinical evaluation. It is expected that the first FVIII and FIX gene therapy products will soon be approved and distributed in major markets. Global access to gene therapy is a critical goal. This review presents new and ongoing efforts towards this goal in countries other than North America and Europe. In Japan, researchers, regulators and funders have established a promising gene therapy development platform for multiple diseases including haemophilia. Decades of scientific and clinical research in haemophilia gene therapy in China have led to a recently registered clinical trial of AAV-mediated gene therapy for haemophilia B. Other countries are in earlier phases of building gene therapy programmes or participate in international trials. A phase 2 feasibility trial of AAV-mediated FIX gene therapy in low- and middle-income countries aims to demonstrate that gene therapy could become available in resource-constrained socio-economic settings. The different strategies for establishing gene therapy provide opportunities for closing the global gap in haemophilia care.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

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. We retrospectively studied (2006-2014) the efficacy and outcomes in CIPHO patients younger than 21 years who received at least one rFVIIa dose for bleeding in the ICU. Of 39 patients, the majority had leukaemia (59%), bone marrow transplantation (77%) and a life-threatening bleed (80%) with most common site being pulmonary haemorrhage (44%). Most needed invasive mechanical ventilation (87%) or vasopressor support (59%). After rFVIIa administration, 56% had cessation or decreased bleeding. Packed red blood cell transfusion requirements decreased significantly 48-72 h after rFVIIa administration. Lower baseline prothrombin time and more rFVIIa doses were related to bleeding control. A favourable response was associated with higher survival (55% in responders versus 18% in nonresponders, P = 0.019). Overall, bleeding-related mortality was 37.5%, highest in pulmonary haemorrhage. Two patients had thromboembolic events. Use of rFVIIa for CIPHO patients appears to be well tolerated with low adverse events. Despite half of the patients having a favourable response of cessation or decrease in bleeding after rFVIIa administration, mortality was high. These findings highlight the need for prospective studies to evaluate interventions to improve outcomes in this population.

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. This is an update of a published Cochrane Review. OBJECTIVES: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of last search: 17 April 2020. SELECTION CRITERIA: Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX. DATA COLLECTION AND ANALYSIS: No trials of gene therapy for haemophilia matching the inclusion criteria were identified. MAIN RESULTS: No trials of gene therapy for haemophilia matching the inclusion criteria were identified. AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in clinical investigation and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.

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. RESULTS: Of 58 patients identified, 46 (79.3%) received rFVIIa to treat bleeding and 12 (20.7%) to prevent bleeding. Thirty-three (71.7%) patients had life-threatening bleeding. In the treatment group, 63.0% patients were responders (ie, bleeding decreased or stopped) and 37.0% were nonresponders (ie, bleeding did not change). Blood products usage was similar between responders and nonresponders. After rFVIIa administration, prothrombin time, partial thromboplastin time and lactate were significantly lower, but fibrinogen was significantly higher in responders than nonresponders. Venous thromboembolism developed in 5.2% (3/58) patients, but its relation to rFVIIa remains unclear. Responders had significantly lower mortality than nonresponders (17.2% vs. 82.4%, P<0.0001). CONCLUSIONS: rFVIIa controlled most bleeding events in this cohort, despite predominance of life-threatening bleeding, suggesting good efficacy. Venous thromboembolism rate was low. Further studies are warranted to identify predictors of favorable response to rFVIIa in similar patients.

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. SETTING: Tertiary-level PICU. PATIENTS: Children less than 19 years old who received platelet transfusions in the PICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-six percent (1,547/4,339) of platelet transfusions in the institution were given to 2.4% of PICU patients (232/9,659). The patients who received a platelet transfusion (platelet transfusions, n = 232) compared with those who did not receive platelets (no platelet transfusions, n = 9,427) were younger, had similar gender distribution, had a higher median Pediatric Risk of Mortality-3 score, and stayed longer in the PICU. Fifty percent of platelet transfusions were prescribed prophylactically for thrombocytopenia to patients without extracorporeal membrane oxygenation support. The mortality was higher for platelet transfusions group (30% vs 2.3%) with an 18 times increased unadjusted odds of mortality when compared with no platelet transfusion group (odds ratio, 18.2; 95% CI, 13.3-24.8; p < 0.0001). In a multiple logistic regression analysis, the predicted probability of dying for platelet transfusion group compared with no platelet transfusion group depended on the median Pediatric Risk of Mortality-3 score. Patients who received platelet transfusion versus no platelet transfusion have increased odds of dying at lower median Pediatric Risk of Mortality-3 scores, but decreased odds of dying at higher median Pediatric Risk of Mortality-3 scores. CONCLUSIONS: This PICU cohort demonstrates that the odds or predicted probability of dying change in patients who received platelet transfusions based on underlying disease severity measured by Pediatric Risk of Mortality-3 score compared with patients who did not receive platelet transfusions. A large, prospective trial is required to confirm this association and determine whether to consider underlying disease severity in estimating risks and benefits of prophylactic platelet transfusions in critically ill children.

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. Jude Children's Research Hospital, (2) received LMWH (2×/day of ~1 mg/kg) between January 2004 until December 2012, and (3) underwent a LP were analyzed. Spinal hematoma was defined as a clinical suspicion leading to diagnostic imaging. Traumatic LP was defined as ≥10 red blood cells per microliter of cerebrospinal fluid. In 1708 LPs, no hematomas occurred. For each child treated with LMWH, the probability of experiencing a spinal hematoma during the entire ALL treatment course was 0% (95% confidence interval [CI], 0.0%-2.7%), and in each LP, assuming no intrapatient correlation, the probability of spinal hematoma was 0% (95% CI, 0.0%-0.2%). Traumatic LPs were more common when performed when children were not receiving LMWH therapy (odds ratio [OR], 1.5; 95% CI, 1.1-2.2) which may be explained by clinician optimization of known risk factors for traumatic cerebrospinal fluid before the procedures. Withholding LMWH for 24 hours before and after LPs in children being treated for ALL is safe.

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. This is an update of a published Cochrane Review. OBJECTIVES: To evaluate the safety and efficacy of gene therapy for treating people with haemophilia A or B. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis & Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Date of last search: 18 August 2016. SELECTION CRITERIA: Eligible trials include randomised or quasi-randomised clinical trials, including controlled clinical trials comparing gene therapy (with or without standard treatment) with standard treatment (factor replacement) or other 'curative' treatment such as stem cell transplantation for individuals with haemophilia A or B of all ages who do not have inhibitors to factor VIII or IX. DATA COLLECTION AND ANALYSIS: No trials of gene therapy for haemophilia were found. MAIN RESULTS: No trials of gene therapy for haemophilia were identified. AUTHORS' CONCLUSIONS: No randomised or quasi-randomised clinical trials of gene therapy for haemophilia were identified. Thus, we are unable to determine the safety and efficacy of gene therapy for haemophilia. Gene therapy for haemophilia is still in its nascent stages and there is a need for well-designed clinical trials to assess the long-term feasibility, success and risks of gene therapy for people with haemophilia.

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. AREAS COVERED: In this article we review the current state of AAV mediated gene therapy for hemophilia B in the clinic, detail progress since the first successful trial, and discuss alternative approaches from the AAV gene therapy field. EXPERT OPINION: AAV mediated gene therapy for hemophilia B is safe and efficacious; however, to achieve gene therapy success on a global scale, improvements to large scale production and alternative AAV serotype approaches need to be designed. With the current means of AAV gene therapy treatment entering the market concomitantly with the advent of long half-life clotting factor products, the quality of life for hemophilia patients worldwide is likely to improve significantly.

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. PROCEDURE: This 12-week, open-label, multi-center phase I/II study evaluated pharmacokinetics, pharmacodynamics, efficacy, and safety in seven children with PNH 11-17 years of age. Eculizumab was intravenously administered at 600 mg weekly for 4 weeks, 900 mg in week 5, and 900 mg every 2 weeks thereafter (http://clinicaltrials.gov NCT00867932). RESULTS: Eculizumab therapy resulted in complete and sustained inhibition of hemolysis in all participants with a reduction of lactate dehydrogenase to normal levels. All hematological parameters stabilized. No definitive, study drug-related adverse events were observed. Only one severe SAE of hospitalization due to aplastic anemia occurred, which was not study drug-related. CONCLUSION: Eculizumab appears to be a safe and effective therapy for children with 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. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1,559 patients have been enrolled, and four gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high-risk drugs. Of the 1,016 patients with genotype test results available, 78% of them had at least one high-risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support-gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre-emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable.

Diagnosis and treatment of pediatric acquired aplastic anemia (AAA): an initial survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC).

BACKGROUND: Randomized clinical trials in pediatric aplastic anemia (AA) are rare and data to guide standards of care are scarce. PROCEDURE: Eighteen pediatric institutions formed the North American Pediatric Aplastic Anemia Consortium to foster collaborative studies in AA. The initial goal of NAPAAC was to survey the diagnostic studies and therapies utilized in AA. RESULTS: Our survey indicates considerable variability among institutions in the diagnosis and treatment of AA. There were areas of general consensus, including the need for a bone marrow evaluation, cytogenetic and specific fluorescent in situ hybridization assays to establish diagnosis and exclude genetic etiologies with many institutions requiring results prior to initiation of immunosuppressive therapy (IST); uniform referral for hematopoietic stem cell transplantation as first line therapy if an HLA-identical sibling is identified; the use of first-line IST containing horse anti-thymocyte globulin and cyclosporine A (CSA) if an HLA-identical sibling donor is not identified; supportive care measures; and slow taper of CSA after response. Areas of controversy included the need for telomere length results prior to IST, the time after IST initiation defining a treatment failure; use of hematopoietic growth factors; the preferred rescue therapy after failure of IST; the use of specific hemoglobin and platelet levels as triggers for transfusion support; the use of prophylactic antibiotics; and follow-up monitoring after completion of treatment. CONCLUSIONS: These initial survey results reflect heterogeneity in diagnosis and care amongst pediatric centers and emphasize the need to develop evidence-based diagnosis and treatment approaches in this rare disease.