Description of the condition
Hemophilia is a rare, inherited, X-linked, recessive disorder in which the blood does not clot normally (NHLBI 2011). Treatment consists of administering concentrated FVIII (for hemophilia A) or FIX (for hemophilia B) as required (when bleeding occurs), or prophylactically to prevent bleeding (Iorio 2011 Coppola 2012). Inhibitors can occur when the body's immune system stops accepting clotting factor concentrates as a normal part of the blood (WFH 2013). These inhibitors reduce the efficacy of, or even eliminate, clotting factor concentrates. There are several known risk factors for the occurrence of inhibitors; either genetic risk factors (nature of gene defect, ethnicity) or non-genetic risk factors (intensive factor exposure at the time of surgery, and prophylactic or on-demand treatment regimens) (Iorio 2010a). The source of FVIII used for replacement therapy may also have an effect on inhibitor development. Studies have shown that for previously untreated patients (PUPs) with severe hemophilia A, high-dose (HD) intensive FVIII treatment increases the risk for inhibitor development, but low-dose (LD) prophylactic treatment decreases it, especially in patients with low-inhibitor-risk FVIII genotype mutations (Gouw 2007a; Gouw 2013a). There is no significant difference in the risk of inhibitor development between recombinant or plasma-derived therapy (Gouw 2007b; Gouw 2013b).
Blood screening tests can show the presence of a bleeding disorder. The activated partial thromboplastin time (APTT) test often suggests the presence of inhibitors, either when the sample is non-coagulable or has a prolonged clotting time, which is not corrected (either at all or partially) by mixing with normal plasma. The Nijmegen assay is performed to confirm diagnosis, which can determine the titer of inhibitors (Verbruggen 1995). The amount of inhibitors in the blood is measured in Bethesda units (BU), where a level of more than five BU is referred to as 'high titer' and less than five BU as 'low titer' (WFH 2012a). Inhibitors usually occur between the first 10 to 20 treatments and therefore most often develop in childhood. Approximately 30% of children with hemophilia A (Gouw 2013b), and 1% to 6% of individuals with hemophilia B (WFH 2012b), develop inhibitors against the clotting factor. Sometimes the bleeding is spontaneous; surgical operations and strenuous exercise can be precipitating factors to acute bleeding.
Hemophilia patients with inhibitors commonly receive bypassing agents for acute bleeding episodes and immune tolerance induction (ITI) to eliminate inhibitors. Bypassing agents, such as recombinant FVIIa concentrate (rFVIIa) or activated prothrombin complex concentrate (aPCC), are insensitive to inhibitors (Iorio 2010b). As an alternative, and where resources are not a limitation, bypassing agents can be used prophylactically (Leissinger 2011). The standard treatment, ITI, is the regular infusion of FVIII in an attempt to achieve immunogenic acceptance (immunologic tolerance). Success is no different between using a HD or LD of therapy, although HD therapy can achieve success more rapidly (Hay 2012). Patients with hemophilia B and high-titer FIX inhibitors may also be treated with ITI, although this approach is successful far less frequently than in patients with hemophilia A (DiMichele 2007). However, ITI is expensive and not always effective for everyone; it requires specialized medical expertise over a long period of time.
Patients with inhibitors continue to have significantly more issues with morbidity and mortality, with treatment costs being considerable. The ultimate eradication of inhibitors remains the most challenging treatment issue in this group of patients.
Description of the intervention
Many immunomodulatory approaches have been studied in the search for more effective techniques to eliminate clotting factor inhibitors. The chimeric monoclonal antibody, rituximab, shows particular promise. In 1997, the USA's Food and Drug Administration (FDA) approved rituximab, also known as MabThera® (F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Basel, Switzerland) and Rituxan® (IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA), for use in adult CD20+ B-cell lymphomas (Kavcic 2013). So far, this treatment is licensed for the following indications in adults: non-Hodgkin's lymphoma (NHL); chronic lymphocytic leukemia (CLL); rheumatoid arthritis (RA); granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis); and microscopic polyangiitis (MPA) (FDA 2013). In pediatric hematology-oncology departments, rituximab is widely used off-label (Yadav 2012) to treat such diseases as chronic immune thrombocytopenia (ITP) (Grace 2012), systemic lupus erythematosus (SLE) (Nwobi 2008) and autoimmune hemolytic anemia (Kuzmanovic 2012). Although given its off-label use, studies in the pediatric population are limited. The standard single dose of rituximab for inhibitors is 375 mg/m2, administered intravenously on a weekly schedule for four weeks. Rituximab currently is available in a 10 mg/mL concentrate of either 10 mL (100 mg, average wholesale price $568) or 50 mL (500 mg average wholesale price $2840) (Pescovitz 2006). It is an expensive drug and not covered by many insurance plans or by government funding.
How the intervention might work
Rituximab is a chimeric mouse-human monoclonal immunoglobulin G1 antibody against the CD20 antigen on the surface of B lymphocytes (Borker 2011). The binding of rituximab to CD20, which is a B-cell differentiation maker, may cause B-cell death that produces inhibitors in three ways, including complement-dependent cytotoxicity (CDC), stimulation of apoptosis, or antibody-dependent cell-mediated cytotoxicity (ADCC) (Selewski 2010). Rituximab targets the CD20+ B-cells, with a rapid and sustained elimination. Generally, rituximab is used as second-line treatment for inhibitors, if a patient is resistant to ITI. It is hypothesized that rituximab can reduce inhibitor titre to facilitate ITI in resistant inhibitor cases. A national cohort in the UK has showed the efficacy of this treatment (Collins 2009). Rituximab has been used for treating people with hemophilia with inhibitors with a response rate of up to 63% (Borker 2011).
Why it is important to do this review
Two non-Cochrane systematic reviews have examined the literature on rituximab for treating children with hemophilia who express clotting factor inhibitors. One review, published in 2008, was based on studies including only patients with congenital hemophilia, and it did not report conclusions specifically about children (Franchini 2008). Another review, published in 2007, included eight children with hemophilia (Giulino 2007). These two reviews included only case reports and case series involving a relatively small number of patients, making the reviews potentially biased and imprecise. The two reviews were unable to draw definitive conclusions or make recommendations about using rituximab to manage hemophilia in children with clotting factor inhibitors.
Although rituximab has become widely available as a therapy option, its high price and the lack of definitive evidence about its efficacy and safety remain barriers to its acceptance by patients and physicians. To guide both groups as they decide on the most appropriate hemophilia treatment, we will undertake a Cochrane systematic review to evaluate the efficacy and safety of rituximab to eradicate inhibitors complicating congential hemophilia treatment in children.