Angela Thomas

Factor VIII Products and Inhibitor Development in Severe Hemophilia A

BACKGROUND For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.).

Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia

The role of 6‐mercaptopurine (6MP) in the treatment of childhood acute lymphoblastic leukaemia (ALL) is well established. However, the efficacy of 6MP is significantly influenced by inactivation by the polymorphic enzyme thiopurine methyltransferase (TPMT). In the general population 89–94% have high TPMT activity, 6–11% have intermediate activity, and approximately 0.3% have low activity. Individuals with low‐activity experience severe or fatal toxicity with standard 6MP doses. Prospective identification of this group of patients might prevent this problem.

Use of recombinant factor VIIa (NovoSeven®) in patients with Glanzmann thrombasthenia

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

Does isochromosome 7q mandate bone marrow transplant in children with Shwachman–Diamond syndrome?

Summary. We report on nine children with Shwachman–Diamond syndrome (SDS), eight of whom had clonal abnormalities of chromosome 7. Seven children had an isochromosome 7 [i(7)(q10)] and one a derivative chromosome 7, all with an apparently identical (centromeric) breakpoint. Children with SDS are predisposed to myelodysplasia (MDS) and acute myeloid leukaemia (AML) often with chromosome 7 abnormalities. Allogeneic transplants have been used to treat these children, however, they are a high‐risk transplant group and require careful evaluation. Three of the children were transplanted but only one survived, who to our knowledge remains the longest surviving SDS transplant patient (4·5 years +). The six non‐transplanted children are well. In classic MDS, chromosome 7 abnormalities are associated with rapid progression to acute leukaemia; however, we present evidence to suggest that isochromosome 7q may represent a separate disease entity in SDS children. This is a particularly interesting finding given that the SDS gene has recently been mapped to the centromeric region of chromosome 7. Our studies indicate that i(7)(q10) is a relatively benign rearrangement and that it is not advisable to offer allogeneic transplants to SDS children with i(7)(q10) alone in the absence of other clinical signs of disease progression.

Interleukin-15 enhances cellular proliferation and upregulates CNS homing molecules in pre-B acute lymphoblastic leukemia

Genome-wide association studies have consistently implicated the interleukin-15 (IL-15) gene in acute lymphoblastic leukemia (ALL) biology, including associations with disease susceptibility, and increased risk of central nervous system (CNS) involvement. However, whether pre-B ALL blasts directly respond to IL-15 is unknown. Here, we show that most pre-B ALL primary samples and cell lines express IL-15 and components of its receptor and that primary pre-B ALL cells show increased growth in culture in response to IL-15. Investigation of mechanisms of action using IL-15-responsive SD-1 cells shows this growth advantage is maximal under low-serum conditions, mimicking those found in cerebrospinal fluid. IL-15 also upregulates PSGL-1 and CXCR3, molecules associated with CNS trafficking. Investigation of downstream signaling pathways indicates that IL-15 induces signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinase (ERK) 1/2, and to a lesser extent phosphatidylinositol 3-kinase (PI3K) and nuclear factor κB (NF-κB) phosphorylation. The IL-15-mediated growth advantage is abolished by mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK), PI3K, and NF-κB inhibitors but preserved in the presence of STAT5 inhibition. Together, these observations provide a mechanistic link between increased levels of IL-15 expression and leukemogenesis, high-risk disease, and CNS relapse and suggest potential therapeutic targets.

The European Medicines Agency review of eltrombopag (Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: summary of the scientific assessment of the Committee for Medicinal Products for Human Use

On 11th March 2010, the European Commission issued a marketing authorization valid throughout the European Union for Revolade for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura. Revolade is an orphan medicinal product indicated for splenectomized patients with immune (idiopathic) thrombocytopenic purpura who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) and as second-line treatment for non-splenectomized patients where surgery is contraindicated. The active substance of Revolade is eltrombopag (ATC code B02BX05). Eltrombopag increases platelet production through activation of the thrombopoietin receptor. The recommended oral dose is 50 mg once daily to achieve and maintain a platelet count of the 50×109/L or more necessary to reduce or prevent the risk of bleeding. The benefit of Revolade is a durable response in maintaining platelet levels. The most common side effects include headache, nausea, hepatobiliary toxicity, diarrhea, fatigue, paresthesia, constipation, rash, pruritus, cataract, arthralgia and myalgia. The decision to grant the marketing authorization was based on the favorable recommendation of the Committee for Medicinal Products for Human Use of the European Medicines Agency. The objective of this paper is to describe the data submitted to the European Medicines Agency and to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (www.ema.europa.eu).

Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades.

Prophylaxis for hemophilia is the scheduled infusion of the missing clotting factor with pre-specified dose, with the intention of preventing bleeds and subsequent hemophilic arthropathy. It is the treatment of choice for patients with severe hemophilia A in countries with available resources.[1][1

Protein assays for diagnosis of Wiskott–Aldrich syndrome and X-linked thrombocytopenia

Mutations in the gene encoding the Wiskott–Aldrich syndrome protein (WASp) give rise to Wiskott–Aldrich syndrome (WAS), a condition that exhibits a wide spectrum of clinical severity. Patients may develop mild thrombocytopenia or suffer from a wide range of associated disorders including eczema, immune dysfunction, autoimmune disease and malignancy. The clinical diagnosis of Wiskott–Aldrich syndrome (WAS) can be difficult and is usually supported by the detection of WASp gene mutations using genetic analysis. Recently, protein‐based assays have been used to demonstrate the absence of WASp in patients known to have WASp gene mutations. We have now reversed this approach and report on the use of immunoblot assays to rapidly diagnose WAS in 13 patients. There was a complete absence of WASp in 10 out of 13 patients and an abnormal protein form was detected in the remaining three patients. In all cases, subsequent genetic analysis confirmed the presence of a WASp gene mutation. We believe that protein‐based assays should be employed as the first line of investigation in the diagnosis of WAS spectrum disorders.

Joe Burchenal and the birth of combination chemotherapy

When Joe Burchenal started studying medicine at the University of Pennsylvania in 1934, antibiotics had not been discovered and the survival of patients diagnosed with acute leukaemia was <4 months. By the time he retired in 1983, 58% of children with acute lymphoblastic leukaemia survived 5 years with the majority being cured of their disease. His early work in infectious diseases and antimicrobials equipped him well, both clinically and scientifically. The approach to developing antibiotics to conquer previously incurable infection was an inspiration and model for his pioneering work when searching for drugs with activity against cancer. Trials of sequential and then combination chemotherapy followed. Success in treating lymphoid malignancies in children led him to develop treatment regimens for other more resistant cancers, and as an advocate of collaborative working he introduced multimodal therapy to tackle bulky or metastatic cancers, replacing inevitable relapse with a chance of true cure.

Patterns of bruising in preschool children with inherited bleeding disorders: a longitudinal study

Objective The extent that inherited bleeding disorders affect; number, size and location of bruises in young children <6 years. Design Prospective, longitudinal, observational study. Setting Community. Patients 105 children with bleeding disorders, were compared with 328 without a bleeding disorder and classified by mobility: premobile (non-rolling/rolling over/sitting), early mobile (crawling/cruising) and walking and by disease severity: severe bleeding disorder factor VIII/IX/XI <1 IU/dL or type 3 von Willebrand disease. Interventions Number, size and location of bruises recorded in each child weekly for up to 12 weeks. Outcomes The interventions were compared between children with severe and mild/moderate bleeding disorders and those without bleeding disorders. Multiple collections for individual children were analysed by multilevel modelling. Results Children with bleeding disorders had more and larger bruises, especially when premobile. Compared with premobile children without a bleeding disorder; the modelled ratio of means (95% CI) for number of bruises/collection was 31.82 (8.39 to 65.42) for severe bleeding disorders and 5.15 (1.23 to 11.17) for mild/moderate, and was 1.81 (1.13 to 2.23) for size of bruises. Children with bleeding disorders rarely had bruises on the ears, neck, cheeks, eyes or genitalia. Conclusions Children with bleeding disorder have more and larger bruises at all developmental stages. The differences were greatest in premobile children. In this age group for children with unexplained bruising, it is essential that coagulation studies are done early to avoid the erroneous diagnosis of physical abuse when the child actually has a serious bleeding disorder, however a blood test compatible with a mild/moderate bleeding disorder cannot be assumed to be the cause of bruising.