Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience

Carção, Manuel; Louis, Jean St.; Mc, Poon; Grunebaum, Eyal; Lacroix, Sébastien; Stain, Ann Marie; Blanchette, Victor S.; Rivard, Georges E.

doi:10.1111/j.1365-2516.2005.01170.x

Cited by 99 publications

(87 citation statements)

References 45 publications

(43 reference statements)

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“…Moreover, in many conditions, including hemophilia, ADA deficiency, Gaucher disease, and others, enzyme replacement therapy is used over the course of many years (37,(52)(53)(54); thus we anticipated that TAT-PNP may also be required for extended periods. Therefore we extended the treatment of TAT-PNP PTD in PNP -/-mice, which also provided additional confidence about the successful effect of TAT-PNP PTD treatment on mortality.…”

Section: Figurementioning

confidence: 99%

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TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

Toro-Montoya¹,

Grunebaum²

2006

Journal of Clinical Investigation

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Defects in purine nucleoside phosphorylase (PNP) enzyme activity result in abnormal nucleoside homeostasis, severe T cell immunodeficiency, neurological dysfunction, and early death. Protein transduction domain (PTD) can transfer molecules into cells and may help restore PNP activity in cases of PNP deficiency. However, long-term use of PTD to replace enzymes in animal models or patients has not previously been described. We fused human PNP to the HIV-TAT PTD and found that the fusion with TAT changed the retention and distribution of PNP in PNP-deficient mice. TAT induced rapid intracellular delivery of PNP into tissues, including the brain, prevented urinary excretion of PNP, and protected PNP from neutralizing antibodies, resulting in significant extension of the enzyme's biological activity in vivo. Frequent TAT-PNP injections in PNP-deficient mice corrected the metabolic disorder and immune defects with no apparent toxicity. TAT-PNP remained effective over 24 weeks of treatment, resulting in continued improvement in immune function and extended survival. Our data demonstrate that TAT changes the properties of PNP in vivo and that long-term intracellular delivery of PNP by TAT corrects PNP deficiency in mice. We provide evidence to promote further use of PTD to treat diseases that require repeated intracellular enzyme or protein delivery.

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Section: Figurementioning

confidence: 99%

“…Additionally, full-length TAT has been shown previously to induce an immune response (34,35); thus fusion with TAT could also increase the immunogenicity of proteins. Indeed, neutralizing antibodies have limited several enzyme and protein replacement therapies such as ADA, insulin, or factor VIII (36,37).…”

Section: Introductionmentioning

confidence: 99%

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

Toro-Montoya¹,

Grunebaum²

2006

Journal of Clinical Investigation

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“…41,42 This product depletes all forms of B lymphocytes from pre-B cells to mature activated B cells. In the studies reported to date, success rates of inhibitor eradication have ranged from 50-80%, but many questions remain about the optimal use of this agent in this context.…”

Section: Administration Of Iti Protocolsmentioning

confidence: 99%

The Role of Immunomodulation in the Management of Factor VIII Inhibitors

Lillicrap¹

2006

Hematology

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With the development of factor VIII (FVIII) concentrates for which the risk of infectious agent transmission is negligible, the principal treatment-related complication in hemophilia A is now the formation of anti-FVIII antibodies (FVIII inhibitors).1 The occurrence of a FVIII inhibitor in a person with hemophilia significantly influences the clinical care of the patient from two aspects: the requirement of alternative approaches to effect hemostasis through the use of bypassing agents, and the need to initiate immunomodulatory therapy to induce immunological tolerance to FVIII. This review will address recent developments in this latter area of clinical management. Factor VIII Inhibitors: Background and PathogenesisSince their earliest recognition in the 1940s, the pathobiology and treatment of FVIII inhibitors has been an area of intense activity for the scientific and clinical hemophilia communities. The incidence of this adverse immunological event ranges in the literature from 15-50%, 2-5 thus prompting questions about why such diverse results have been obtained in these various studies. It is clear that a number of variables are likely to have contributed to this wide range of results. These include the frequency of testing for inhibitors, the type of laboratory test being used, the type of FVIII concentrate and its mode of administration, and the mix of patients in the study population.Best characterized of the patient variables is the FVIII genotype, with a spectrum of inhibitor risks ranging from > 75% for multi-domain deletions through a 20-30% risk with the common intron 22 inversion mutation, to < 10%

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“…The use of rituximab, a genetically engineered human-mouse chimaeric monoclonal immunoglobulin (Ig)G1 antibody, is now being considered to eradicate inhibitors in haemophilia A and has shown potential in five cases. 19 There are major differences in inhibitor management, and the implementation of ITI regimens varies widely between centres. 20 This reflects a lack of knowledge of a successful ITI regimen.…”

Section: Immune Tolerance Induction Therapymentioning

confidence: 99%

Recent Developments in Immune Tolerance Induction in Haemophilia A

Kreuz¹,

Ettingshausen²

2007

European Oncology &Amp; Haematology

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ethnic origin/race, 5 family history of inhibitors and immunogenotypic differences, 6,7 age at first exposure 8,9 and therapy regimen. 10 The management of bleeding episodes in high-titre inhibitor patients is through the use of bypassing agents, mainly activated prothrombin complex concentrates (aPCCs) and recombinant factor VIIa (rFVIIa). These treatments are satisfactory for achieving haemostasis. However, in arthropathy and disability in long-standing inhibitor patients this is difficult to achieve. Eradication of inhibitors through immune tolerance induction (ITI) is accepted as the superior treatment because it allows the resumption of FVIII replacement therapy and prophylaxis of bleeding episodes. 11 Currently, ITI through various regimens has been successful in approximately 60-90% of patients with inhibitors. 12-17 However, there is not enough scientific evidence to guide a successful ITI regime. Immune Tolerance Induction TherapyITI is a method of treating inhibitors in patients with haemophilia A that involves several protocols of long-term administration of low-and high-dose FVIII. ITI was first utilised in 1974, when a high-titre inhibitor patient with a serious haemorrhage was treated with a high dose of FVIII concentrate and aPCC. This treatment resulted in control of the haemorrhage and a reduction in inhibitors. 18 Between the late 1970s and 1990, patients were treated with plasma-derived FVIII products for ITI.Since 1990, recombinant and monoclonal products have been introduced and are the most common forms used today. ITI in most institutions involves either the use of the recombinant product and/or the plasma-derived product, depending on patient requirements.Investigators have also examined alternative unconventional ITI regimens.These regimens include the use of immunosuppressive agents that non-specifically target the humoral or cellular immune system in addition to neutrophils, macrophage and natural killer cells. However, the use of such chemotherapeutic agents is associated with both short-and long-term toxicity. The use of rituximab, a genetically engineered human-mouse chimaeric monoclonal immunoglobulin (Ig)G1 antibody, is now being considered to eradicate inhibitors in haemophilia A and has shown potential in five cases. 19 There are major differences in inhibitor management, and the implementation of ITI regimens varies widely between centres. 20 This reflects a lack of knowledge of a successful ITI regimen. 17,[21][22][23] Studies identify variables affecting ITI, but they do not allow for successful comparison between different regimens.Consequently, an optimal protocol is far from being decided. A consensus agreement is required to define an optimal ITI regimen in terms of both efficacy and pharmacoeconomics. Identified Factors Affecting the Outcome of Immune Tolerance Induction TherapyOne of the most important factors affecting the success of ITI is the inhibitor titre at the beginning of treatment, which also has an effect on the time taken to achieve tolerance. An inhibitor t...

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Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience

Cited by 99 publications

References 45 publications

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

TAT-mediated intracellular delivery of purine nucleoside phosphorylase corrects its deficiency in mice

The Role of Immunomodulation in the Management of Factor VIII Inhibitors

Recent Developments in Immune Tolerance Induction in Haemophilia A

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