The treatment landscape for hemophilia has been rapidly changing with introduction of novel therapies. Gene therapy for hemophilia is a promising therapeutic option for sustained endogenous factor production to mitigate the need for prophylactic treatment to prevent spontaneous and traumatic bleeding. Etranacogene dezaparvovec is an investigational factor IX (FIX) gene transfer product that utilizes the adeno-associated virus (AAV) 5 vector with a liver-specific promoter and a hyperactive FIX transgene. Here, the development of etranacogene dezaparvovec and available efficacy and safety data from clinical trials are reviewed. Overall, etranacogene dezaparvovec provides sustained FIX expression for more than 2 years and allows for a bleed and infusion-free life in the majority of patients. Safety, efficacy, and quality-of-life data will inform shared decision-making for patients who are considering gene therapy. Long-term follow-up regarding duration of expression and safety are crucial.

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.

Purpose

As gene therapies for hemophilia are incorporated into clinical practice, shared decision-making (SDM) is recommended for implementation. SDM tools may facilitate informed decision-making for gene therapy and other novel therapies.

Objective

To inform the development of SDM tools for hemophilia gene therapy.

Patients and methods

Men with severe hemophilia were recruited from the National Hemophilia Foundation (NHF) Community Voices in Research (CVR). Semi-structured interviews were completed, and the interviews were transcribed verbatim for quantitative and qualitative analysis.

Results

Twenty-five men with severe hemophilia A participated. All participants reported treatment with prophylaxis, nine (36%) on continuous prophylaxis with clotting factor, one (4%) on intermittent prophylaxis with clotting factor, and 15 (60%) on continuous prophylaxis with emicizumab. Ten (40%) indicated that they are excited about gene therapy, 12 (48%) indicated that they are hopeful about gene therapy, one (4%) indicated that they are worried or scared about gene therapy, and one (4%) indicated that they do not have strong feelings about gene therapy. Participants reported engaging Hemophilia Treatment Center, family, and the hemophilia community in their decision-making process. The most reported information needs are efficacy, safety, cost/insurance, mechanism of action, and follow-up. In addition, key information themes that emerged were patient testimonials, hard data and statistics, and comparison to other products. Twenty-two (88%) indicated that a SDM tool would be useful when discussing gene therapy with their hemophilia team. Two indicated that they do their own research, and the tool would not add anything. One needed more information to provide an answer.

Conclusion

These data highlight the utility of a SDM tool for hemophilia gene therapy and key information needs. Data including comparison to other treatments should be provided along with patient testimonials in a transparent format. Patients will engage the Hemophilia Treatment Center, family, and community members in the decision-making process.

Medical decisions in hemophilia care are primarily related to the type of factor replacement and treatment regimen. With the growing number of treatment options for patients with hemophilia, decision making is more complex and requires careful consideration of benefits, risks, and patient goals. Shared decision making and decision-aid tools facilitate patient and healthcare provider communication. In this review, the overall role of shared decision making in medicine is outlined, with special emphasis on models for practical implementation. Examples of shared decision making in hemophilia are outlined, and application to new therapeutics is discussed through a case-based approach.

Prophylactic clotting-factor regimens reduce the occurrence of bleeding episodes and maintain joint health in individuals with moderate and severe hemophilia. However, these outcomes are only achieved with adherence to prescribed prophylaxis regimens. There are several types of barriers to adherence related to key patient, condition, treatment, health-care system, and/or socioeconomic variables. Notably, health-care professionals may not prescribe prophylaxis if they perceive that a patient will be nonadherent. Prophylactic treatment strategies should be developed with the patient and family, focused on individualized treatment goals. Personalized strategies are needed to reinforce the importance of and encourage confidence in administering the regular infusions required for prophylactic therapy. These strategies may include verbal and written information delivered by health-care professionals, peers, and inter-active media. The advent of extended half-life clotting factors requiring less frequent infusion may improve adherence.

Hemophilia is characterized by a deficiency in coagulation factors VIII or IX. The general standard of care for severe hemophilia is frequent intravenous recombinant or plasma-derived factor replacement to prevent bleeding. While this treatment is effective in preventing bleeding, frequent infusions are burdensome for patients. Nonadherence to the therapeutic regimen leaves people with hemophilia at risk for spontaneous and traumatic bleeds into joints as well as life-threatening bleeds such as intracranial hemorrhage. The chronicity of the disorder often leads to the formation of target joints, causing long-term pain and impairing mobility. As a monogenic disorder with well-understood genetics, hemophilia is an ideal disorder for implementing innovations in gene therapies. Indeed, recent approvals of two gene therapy products have the potential to shift the hemophilia treatment paradigm. Valoctocogene roxaparvovec and etranacogene dezaparvovec-drlb are gene therapies for hemophilia A and B, respectively. These therapies, given as a single intravenous infusion, may improve patients quality of life, decreasing treatment burden and resulting in factor expression that virtually eliminates the need for factor replacement. Since both treatments involve viral vectors targeted to the liver, short- and long-term safety and efficacy monitoring involves monitoring liver enzymes to track liver health. Long-term monitoring of efficacy, durability of gene expression, and safety are ongoing. Gene therapy presents a promising new therapeutic option for patients with hemophilia and warrants continued innovation and investigation.

Venous thromboembolism (VTE) in children is multifactorial and most often related to a combination of inherited and acquired thrombophilias. Children with cancer and blood disorders are often at risk for VTE due to disease-related factors such as inflammation and abnormal blood flow and treatment-related factors such as central venous catheters and surgery. We will review risk factors for VTE in children with leukemia, lymphoma, and solid tumors. We will also review risk factors for VTE in children with blood disorders with specific focus on sickle cell anemia and hemophilia. We will present the available evidence and clinical guidelines for prevention and treatment of VTE in these populations.

A delayed hemolytic transfusion reaction (DHTR) is a potential complication for patients with sickle cell disease (SCD) who develop red blood cell (RBC) alloimmunization to foreign antigens from allogeneic transfusions, potentially resulting in life-threatening hemolytic anemia between 24 hours and 28 days after the transfusion. Guidelines have suggested obtaining an extended RBC antigen profile by genotyping in patients with SCD to provide increased accuracy for antigen matching. We present a pediatric patient with SCD and a rare RBC phenotype that was not identified by serology who developed DHTR after her second lifetime transfusion and highlight the potential advantages of molecular genotyping. She was successfully managed by transfusion with least incompatible packed RBCs and aggressive medical management per American Society of Hematology clinical guidelines. Molecular genotyping is advantageous over serologic phenotyping because it can provide additional antigen information, such as increased accuracy for C antigen determination and Fyb antigen matching. Having RBC genotyping results on file for patients with SCD can facilitate care in two ways-by preventing alloimmunization with potential hemolytic transfusion reaction and by responding rapidly to request rare donors when complicating antibodies arise.

Introduction

This is the first published report of a young girl with co-inherited sickle cell-β+ thalassemia and cystic fibrosis. Although a small subset of patients with co-inherited cystic fibrosis and other hemoglobinopathies have been reported, this patient developed early hematologic and pulmonary complications that were more severe than the previous cases. To assess pulmonary co-morbidities, we used infant pulmonary function testing through the raised volume rapid thoracoabdominal compression technique as both an established study of early cystic fibrosis and also as a newer study of mechanism for early sickle cell lung disease. This further serves as the first report of the raised volume rapid thoracoabdominal compression technique to determine raised volume forced expiratory flows and fractional lung volumes in a patient with a hemoglobinopathy.

Case presentation

A 2-year-old African-American girl with co-inherited cystic fibrosis and sickle cell-β+ thalassemia developed severe hematologic complications (recurrent vaso-occlusive events, hepatic sequestration, and acute chest syndrome) during periods of cystic fibrosis pulmonary exacerbations and weight loss. Because cystic fibrosis and sickle cell-β+ thalassemia both confer distinct patterns of pulmonary disease, infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique was used to define respiratory pathophysiology and guide treatment options. Infant pulmonary function testing data demonstrated moderate-to-severe lower airways obstruction, moderate air trapping, and no evidence of restrictive lung disease.

Conclusions

Infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique guided therapy in this patient with cystic fibrosis and sickle cell-β+ thalassemia. Although this is an original case report on a unique patient, this case highlights the need to evaluate early respiratory pathophysiology in a broader population of young patients with hemoglobinopathies and screen those at risk for early pulmonary co-morbidities.