Gene Therapy in Hemophilia A: Achievements, Challenges, and Perspectives.

Strides in advancements of care of persons with hemophilia include development of long-acting factor replacement therapies, novel substitution and hemostatic rebalancing agents, and most recently approved gene therapy. Several decades of preclinical and clinical trials have led to development of adeno-associated viral (AAV) vector-mediated gene transfer for endogenous production of factor VIII (FVIII) in hemophilia A (HA). Only one gene therapy product for HA (valoctocogene roxaparvovec) has been approved by regulatory authorities. Results of valoctocogene roxaparvovec trial show significant improvement in bleeding rates and use of factor replacement therapy; however, sustainability and duration of response show variability with overall decline in FVIII expression over time. Further challenges include untoward adverse effects involving liver toxicity requiring immunosuppression and development of neutralizing antibodies to AAV vector rendering future doses ineffective. Real-life applicability of gene therapy for HA will require appropriate patient screening, infrastructure setup, long-term monitoring including data collection of patient-reported outcomes and innovative payment schemes. This review article highlights the success and development of HA gene therapy trials, challenges including adverse outcomes and variability of response, and perspectives on approach to gene therapy including shared decision-making and need for future strategies to overcome the several unmet needs.

The benefits of gene therapy in people with haemophilia.

Haemophilia is an inherited bleeding disorder which causes significant morbidity and mortality, especially in the severe form. Prophylaxis with factor replacement has high efficacy in reducing bleeding but is limited by the need for frequent intravenous infusion and fluctuations in haemostasis between doses. Additional prophylaxis therapies are being developed which may overcome some of the current treatment barriers. Gene therapy (GT) is being developed to provide a functional cure such that there is sustained factor expression and minimal to no need for additional haemostatic therapy. There are now two approved gene therapies for haemophilia which may be transformative for many individuals. Benefits of GT should go beyond increasing factor activity and reducing bleeding as persons with haemophilia aim to achieve a 'haemophilia-free mind' and health equity with optimal health and well-being.

Novel Approach to Improve the Identification of the Bleeding Phenotype in Noonan Syndrome and Related RASopathies.

OBJECTIVES: To characterize the bleeding phenotype in Noonan syndrome (NS), to test the utility of following national guidelines in detecting this phenotype, to evaluate thromboelastography (TEG) as a diagnostic tool, and to evaluate the cohort for genotype-phenotype correlations. STUDY DESIGN: Participants with a clinical diagnosis of NS or related RASopathies were enrolled in a cohort study. Study procedures included clinical bleeding assessment, coagulation testing per guidelines, and hematology consultation. TEG was completed in a subset, and genetic testing was conducted for those without a molecular diagnosis. International Society of Haemostasis and Thrombosis Bleeding Assessment Tool scores were calculated with hematology consultation. Bleeding phenotype was defined as abnormal bleeding score. RESULTS: Twenty participants were enrolled; 12 completed clinical and laboratory evaluation, and five of whom met the definition for bleeding phenotype. Four of the five participants with a bleeding phenotype had platelet aggregation defects and at least one additional coagulation defect. TEG was performed in nine participants, four with bleeding phenotype and five without, and results were normal in all cases. No genotype-phenotype correlation was found. CONCLUSION: Five of the 20 participants had a bleeding phenotype identified. Based on available data, we do not recommend incorporating TEG into clinical practice for patients with NS. Platelet aggregation defects were the most common abnormalities, which would not be detected on tier 1 testing of current guidelines; therefore, we propose a new algorithm.

Development of a haemophilia A gene therapy shared decision-making tool for clinicians.

INTRODUCTION: As gene therapies are incorporated into clinical practice, shared decision-making (SDM) is recommended for implementation. AIM: To inform development of a clinician SDM tool for haemophilia A gene therapy. METHODS: Clinicians at US Hemophilia Treatment Centers completed semi-structured interviews about their experience with SDM and provided feedback on a clinician SDM tool prototype. Interviews were transcribed verbatim for coding and thematic content analysis. RESULTS: Ten participants enrolled, eight physicians and two haemophilia nurses. All participants care for adults with haemophilia (1-27 years of experience) and 7 have gene therapy trials open at their institution. Confidence in having a clinical discussion about gene therapy included none (N = 1), slight (N = 3), moderate (N = 5) and high (N = 1). All participants reported familiarity with SDM and agreed that the tool would be useful for their clinical practice. Key themes in participant feedback for the tool were (1) language and presentation; (2) content; and (3) implementation. Participants highlighted the importance of providing unbiased information and having companion tools with patient-centric language. CONCLUSION: These data highlight the need for SDM tools for haemophilia A gene therapy. Key information to include in the tool are safety, efficacy, cost and detailed information on the gene therapy process. Data should be provided in an unbiased format and allow comparison to other treatments. The tool will be evaluated in clinical practice and refined as clinical trial data and real-world experience mature.

Gene therapy preferences and informed decision-making: Results from a National Hemophilia Foundation Community Voices in research survey.

INTRODUCTION: To inform education and treatment discussions, it is important to understand how persons with haemophilia prefer to learn about and discuss new therapies and to identify variables that influence decision-making. AIM: The aim of this study was to evaluate preferences and variables which influence decision-making related to gene therapy and other novel haemophilia therapies. METHODS: An online survey was sent to men with severe haemophilia enrolled in the National Hemophilia Foundation Community Voices in Research online platform for patient-powered research. RESULTS: One hundred four men completed the survey including 33% Hispanics, 96 who had had not gene therapy and 71/96 (74%) who were on prophylaxis. Ninety-five percent were somewhat or very familiar with gene therapy. Men with haemophilia obtain information about new therapies from several sources, most commonly their haemophilia treatment team, patient advocacy groups and self-study. Participants identified safety and efficacy as well as other educational needs to inform decision-making. Of those without prior gene therapy, 73% indicated a high likelihood of considering gene therapy. Hispanic ethnicity and government-issued insurance were associated with a higher likelihood of considering gene therapy as a treatment option. CONCLUSION: Haemophilia Treatment Centers and patient advocacy groups must be able to educate persons with haemophilia about aspects of novel therapies which are important to the individual, especially short- and long-term safety and efficacy. Further research is needed to determine how patient activation and health literacy influence decision-making and how to achieve equitable access and valid informed consent for novel therapies.

Consensus definition of essential, optimal, and suggested components of a pediatric sickle cell disease center.

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

Improving vitamin D testing and supplementation in children with newly diagnosed cancer: A quality improvement initiative at Rady Children's Hospital San Diego.

BACKGROUND: Vitamin D deficiency and insufficiency have been associated with poorer health outcomes. Children with cancer are at high risk for vitamin D deficiency and insufficiency. At our institution, we identified high variability in vitamin D testing and supplementation in this population. Of those tested, 65% were vitamin D deficient/insufficient. We conducted a quality improvement (QI) initiative with aim to improve vitamin D testing and supplementation among children aged 2-18 years with newly diagnosed cancer to ≥80% over 6 months. METHODS: An inter-professional team reviewed baseline data, then developed and implemented interventions using Plan-Do-Study-Act (PDSA) cycles. Barriers were identified using QI tools, including lack of automated triggers for testing and inconsistent supplementation criteria and follow-up testing post supplementation. Interventions included an institutional vitamin D guideline, clinical decision-making tree for vitamin D deficiency, insufficiency and sufficiency, electronic medical record triggers, and automated testing options. RESULTS: Baseline: N = 26 patients, four (15%) had baseline vitamin D testing; two (8%) received appropriate supplementation. Postintervention: N = 33 patients; 32 (97%) had baseline vitamin D testing; 33 (100%) received appropriate supplementation and completed follow-up testing timely (6-8 weeks post supplementation). Change was sustained over 24 months. CONCLUSIONS: We achieved and sustained our aim for vitamin D testing and supplementation in children with newly diagnosed cancer through inter-professional collaboration of hematology/oncology, endocrinology, hospital medicine, pharmacy, nursing, and information technology. Future PDSA cycles will address patient compliance with vitamin D supplementation and impact on patients' vitamin D levels.

Diagnostic and Treatment Challenges for Acquired Hemophilia A in Pediatrics: Report of 2 Cases.

Acquired hemophilia A (AHA) occurs rarely in children. We report 2 cases of adolescent females with AHA. The first case underwent bone marrow aspiration/biopsy during workup, which was complicated by bleeding. Bleeding resolved after initiation of therapy with cyclophosphamide and glucocorticoid, but despite the addition of rituximab, she did not achieve complete remission until treatment with intravenous immunoglobulin. In the second case, we observed that a mixing study without incubation will not detect an acquired factor VIII inhibitor, but further workup based on suspicion for AHA led to the correct diagnosis. Both had significant medication toxicity which required treatment modification.

Effect of Poloxamer 188 vs Placebo on Painful Vaso-Occlusive Episodes in Children and Adults With Sickle Cell Disease: A Randomized Clinical Trial.

Importance: Although effective agents are available to prevent painful vaso-occlusive episodes of sickle cell disease (SCD), there are no disease-modifying therapies for ongoing painful vaso-occlusive episodes; treatment remains supportive. A previous phase 3 trial of poloxamer 188 reported shortened duration of painful vaso-occlusive episodes in SCD, particularly in children and participants treated with hydroxyurea. Objective: To reassess the efficacy of poloxamer 188 for vaso-occlusive episodes. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled, multicenter, international trial conducted from May 2013 to February 2016 that included 66 hospitals in 12 countries and 60 cities; 388 individuals with SCD (hemoglobin SS, SC, S-ß0 thalassemia, or S-ß+ thalassemia disease) aged 4 to 65 years with acute moderate to severe pain typical of painful vaso-occlusive episodes requiring hospitalization were included. Interventions: A 1-hour 100-mg/kg loading dose of poloxamer 188 intravenously followed by a 12-hour to 48-hour 30-mg/kg/h continuous infusion (n = 194) or placebo (n = 194). Main Outcomes and Measures: Time in hours from randomization to the last dose of parenteral opioids among all participants and among those younger than 16 years as a separate subgroup. Results: Of 437 participants assessed for eligibility, 388 were randomized (mean age, 15.2 years; 176 [45.4%] female), the primary outcome was available for 384 (99.0%), 15-day follow-up contacts were available for 357 (92.0%), and 30-day follow-up contacts were available for 368 (94.8%). There was no significant difference between the groups for the mean time to last dose of parenteral opioids (81.8 h for the poloxamer 188 group vs 77.8 h for the placebo group; difference, 4.0 h [95% CI, -7.8 to 15.7]; geometric mean ratio, 1.2 [95% CI, 1.0-1.5]; P = .09). Based on a significant interaction of age and treatment (P = .01), there was a treatment difference in time from randomization to last administration of parenteral opioids for participants younger than 16 years (88.7 h in the poloxamer 188 group vs 71.9 h in the placebo group; difference, 16.8 h [95% CI, 1.7-32.0]; geometric mean ratio, 1.4 [95% CI, 1.1-1.8]; P = .008). Adverse events that were more common in the poloxamer 188 group than the placebo group included hyperbilirubinemia (12.7% vs 5.2%); those more common in the placebo group included hypoxia (12.0% vs 5.3%). Conclusions and Relevance: Among children and adults with SCD, poloxamer 188 did not significantly shorten time to last dose of parenteral opioids during vaso-occlusive episodes. These findings do not support the use of poloxamer 188 for vaso-occlusive episodes. Trial Registration: ClinicalTrials.gov Identifier: NCT01737814.

The Evaluation of Hematologic Screening and Perioperative Management in Patients with Noonan Syndrome: A Retrospective Chart Review.

OBJECTIVES: To assess the potential impact of using screening recommendations for bleeding disorders in patients with Noonan syndrome on perioperative bleeding complications. STUDY DESIGN: We performed a retrospective, single-site cohort study; patients were identified by query of the electronic medical record. All patients with a clinical diagnosis of Noonan syndrome over a 10-year period were included. Data on surgeries, hematologic evaluation, bleeding symptoms, and bleeding complications were extracted. Surgeries were graded as major or minor. RESULTS: We identified 101 patients with Noonan syndrome, 70 of whom required surgery for a total of 164 procedures. Nine patients (9/70; 12.8%) had bleeding complications, occurring in those without comprehensive testing or perioperative intervention and undergoing major or dental surgery. Based on these findings, the risk of a bleeding complication for patients with Noonan syndrome who did not have comprehensive testing or perioperative intervention was 6.2% (95% CI 2.3%-10.1%), indicating the number needed to treat or screen would be 16 to prevent 1 bleeding complication (95% CI 9.9-43.9). The majority of patients had either no or incomplete evaluation (59 of 101; 58.4%). CONCLUSIONS: With proper evaluation and management, the bleeding risk in patients with Noonan syndrome can be minimized. Efforts are needed to address the knowledge and implementation gap in this evaluation.

Management and outcomes of pediatric septic thrombophlebitis: a case series.

Septic thrombophlebitis is a potentially life-threatening condition. Pediatric hematologists are often consulted to provide recommendations regarding anticoagulation management. We conducted a ten-year retrospective, single-center study of hospitalized pediatric patients who were treated for septic thrombophlebitis. Our primary outcome was resolution of thrombophlebitis. Twenty-eight patients were included in the study. Eighty-nine percent of patients received both antibiotic and anticoagulation therapy. The median durations of intravenous and total antibiotic therapy were 47.5 days (range 14-120) and 65 days (range 14-281), respectively, and median duration of anticoagulation therapy was 92 days (range 41-268). Resolution of thrombosis defined by magnetic resonance imaging, computed tomography, or ultrasound imaging was documented in 16 of 28 (57%) patients. Despite the high rate of persistent thrombosis, there was a low risk of relapse of infection in cases where antibiotic and/or anticoagulation was discontinued prior to complete resolution of the thrombus. Further research is needed to determine if duration of antibiotic and/or anticoagulation treatment can be shortened.

Sociodemographic and clinical characteristics associated with vitamin D status in newly diagnosed pediatric cancer patients.

Vitamin D deficiency and insufficiency are associated with serious sequelae in childhood cancer survivors. However, data on vitamin D deficiency in children with newly diagnosed cancer are scarce and the role of sociodemographic factors and vitamin D supplementation is largely unknown. We assessed vitamin D status and its socio-demographic and clinical correlates in 163 children with newly diagnosed cancer, using 25-hydroxy vitamin D (25(OH)D) concentrations and assessed longitudinal changes following vitamin D supplementation. Sixty-five percent of the patients with newly diagnosed cancer had low 25(OH)D concentrations. Fifty-two patients (32%) were vitamin D deficient (≤20 ng/mL 25(OH)D concentration), and 53(33%) were insufficient (21-29 ng/mL 25(OH)D concentration). Age over 10 (P = 0.019), Hispanic ethnicity (P = 0.002), and female sex (P = 0.008) were significantly associated with lower 25(OH)D concentration at diagnosis. Vitamin D supplementation resulted in significant increase in 25(OH)D concentrations (P < 0.001). However, following supplementation in the longitudinal analysis, this increase was less pronounced in Hispanic patients vs. non-Hispanic (P = 0.007), and in children with solid tumors vs. hematological malignancies (P = 0.003). Vitamin D deficiency and insufficiency are common in children with newly diagnosed cancer. Hispanic patients, females and older children were at higher risk for vitamin D deficiency and insufficiency. Although supplementation appeared to increase 25(OH)D concentrations over time, this increase was not as pronounced in certain subsets of patients. Prospective trials of the effects of vitamin D supplementation on bone health in children with newly diagnosed cancer are warranted, particularly in Hispanics and patients with solid tumors.

Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia.

BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) and IX (FIX) products are intended to decrease the burden of prophylaxis for patients with haemophilia A or B. Whether these newer concentrates have led to meaningful clinical practice change remains vague. AIM: To characterize the longitudinal use of standard (SHL) and EHL factor concentrates at haemophilia treatment centres (HTCs), using the ATHNdataset, a US database of 138 ATHN-affiliated HTCs. METHODS: Factor concentrate use among moderate and severe haemophilia A and B patients without inhibitors was analysed at three time points over 18 months. RESULTS: Use of EHL concentrates rose from 10% of patients to 22% during this study. EHL FVIII prophylaxis is prescribed to the minority of patients, 28%; EHL FIX now predominates for prophylaxis, 52%. Rates of prescribed EHL products varied significantly by age group and HTC region. Median prescribed prophylaxis for SHL compared to EHL products was FVIII 6240 and 5200 and FIX 6968 and FIX 3900 IU/kg/y, respectively. On-demand EHL use has grown but has minimal contribution to overall usage (2%). CONCLUSION: Haemophilia treatment centre region and patient age impact the rate of adoption of EHL products; however, EHL prescribing continues to rise nationally, particularly for EHL FIX. Careful attention to annual cost of prophylaxis is imperative as the decrease in median EHL prophylaxis consumption is not offset by the higher unit cost of these products. It is unclear how further growth in use of EHLs will be impacted by emerging non-factor replacement and gene therapies.

How we approach: Training pediatric coagulationists.

Unique expertise is required for the care of children, adolescents, and young adults with bleeding and clotting disorders. A number of Hemophilia Treatment Centers have developed pediatric hemostasis and thrombosis fellowship programs to facilitate subspecialty training and recruitment and retention in this field. This manuscript reviews an approach to training pediatric coagulationists including a description of current programs, sample curriculum, funding sources, and expected outcomes.

Hematologic Manifestations of Nutritional Deficiencies: Early Recognition is Essential to Prevent Serious Complications.

Nutritional deficiencies, including deficiencies of vitamin B12, copper, and vitamin C, may result in cytopenias and hematologic symptoms. Early recognition of these deficiencies is imperative for prompt treatment and improvement in hematologic and other manifestations. We describe 5 cases which illustrate the hematologic manifestations of nutritional deficiencies and challenges to initial diagnosis and management. Supplementation of the deficient vitamin or micronutrient in all of these cases resulted in rapid resolution of cytopenias, hemorrhage, and other associated hematologic symptoms. We also review other nutritional deficiencies that manifest with hematologic symptoms and compile recommendations on treatment and expected time to response.

Risk factors for cardiovascular disease in children and young adults with haemophilia.

INTRODUCTION: The origins of cardiovascular disease (CVD) begin in childhood. The primary objective of this cross-sectional cohort study was to determine the prevalence of cardiovascular risk factors in patients with congenital haemophilia A or B followed at Rady Children's Hospital San Diego Hemophilia and Thrombosis Treatment Center (HTC). We hypothesized that cardiovascular risk factors could be identified as part of a comprehensive clinic visit. MATERIALS AND METHODS: Standardized measurement of weight, height, waist circumference and blood pressure plus non-fasting glucose and lipid panel were performed. Participants and/or caregivers completed questionnaires about family history, medical history and lifestyle. Clinical data were abstracted from the medical record. Descriptive statistics, Student's t test, correlation, Mann-Whitney U test and chi-square test were performed to analyse the data. RESULTS: Forty-three males (mean 12 years, range 5-20 years) enrolled. High rates of overweight and obesity, (pre)hypertension and abnormal lipids were identified. Subjects with normal weight had more days of >60 minutes of physical activity compared with those with overweight or obesity (5.2 ± 2.4 vs. 3.8 ± 2.5 day; P = 0.07). Higher weight was correlated with higher factor consumption (cor = 0.88; P < 0.001). There was no difference in target joints based on weight category (30% in normal weight vs. 25% in overweight or obese, χ2 = 0.11, P = 0.74), which may be attributed to high rates of prophylaxis. CONCLUSIONS: Modifiable risk factors for CVD were identified as part of the study during comprehensive clinic visits. The HTC team may develop behavioural interventions to target cardiovascular risk reduction as part of the comprehensive care model.

How I approach: Previously untreated patients with severe congenital hemophilia A.

Previously untreated patients with severe hemophilia A are a vulnerable population at risk for severe bleeding which is currently managed with exogenous clotting factor replacement. The primary burden of current treatment is high-titer inhibitor development. Evolving data on current treatment products as well as emerging therapeutics may inform treatment decisions to prevent bleeding and inhibitor formation. Considerations for diagnosis, education, and shared decision-making related to product choice and treatment regimen are discussed.

Children with sickle cell disease migrating to the United States from sub-Saharan Africa.

Sickle cell disease (SCD) is an inherited red blood cell disorder that occurs worldwide and results in significant morbidity and mortality. In addition to affected children who are born in the US, an increasing number of children with SCD are migrating to the US with their families or through international adoption. Children arriving as immigrants or refugees have unique medical and psychosocial challenges that require a multidisciplinary team approach which takes into account the family's primary language, culture, and health beliefs. This review focuses on the special challenges for children with SCD who emigrate from sub-Saharan Africa to the US.