The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Carção, Manuel; Escuriola‐Ettingshausen, C.; Santagostino, Elena; Oldenburg, Johannes; Liesner, Ri; Nolan, Beatrice; Bátorová, Angelika; Haya, Saturnino; Young, Guy

doi:10.1111/hae.13762

Cited by 80 publications

(152 citation statements)

References 36 publications

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“…Moreover, patients <8 years old and a time interval of <5 years between inhibitor detection and the start of ITI have been shown to be positive predictors of successful ITI . Thus, ITI remains an important strategy for inhibitor eradication and restoring the therapeutic benefit of fVIII for bleeds in patients with inhibitors …”

Section: Discussionmentioning

confidence: 99%

Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis

et al. 2019

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Haemophilia A is a rare congenital bleeding disorder caused by a deficiency of blood coagulation protein factor VIII (fVIII). Prophylactic fVIII infusions are the standard of care for the prevention of bleeds and their sequela. 1 However, 30% of individuals with severe deficiency will develop neutralizing antibodies, called inhibitors, against fVIII. 2 Most patients who develop inhibitors, particularly individuals with high titre inhibitors (titres ≥ 5 Bethesda units (BU) per mL), require immune tolerance induction (ITI) consisting of frequent and often high dose fVIII to induce peripheral tolerance. ITI is the standard of care for eradicating inhibitors with reported success Abstract Introduction: The formation of neutralizing antifactor VIII (fVIII) antibodies, called inhibitors, is the most common complication in modern haemophilia A care. Novel non-factor replacement therapies, such as emicizumab, have sought to address the limitations of bypassing agents for bleeding management in patients with inhibitors.However, immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII. Aim:The aim of this study was to review a case series of paediatric patients with haemophilia A and inhibitors who have received ITI for inhibitor eradication concomitantly with emicizumab prophylaxis for bleeding prevention.Methods: Single institution retrospective chart review of paediatric patients with severe haemophilia A receiving ITI and emicizumab.Results: Seven patients were included in this cohort. Six patients used three different recombinant fVIII products at 100 IU/kg three times per week, and one patient used a plasma-derived fVIII product at an initial dose of 50 IU/kg three times per week.

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Section: Discussionmentioning

confidence: 99%

Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis

et al. 2019

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“…In the last several years, novel therapeutics have been evaluated in clinical trials, among which the bispecific monoclonal antibody, emicizumab, has been licensed for the prevention of bleeding in children and adults with haemophilia with and without inhibitors. Recent studies indicate emicizumab is safe and effective for prophylaxis in infants with haemophilia A 15,16 and in immune tolerance induction (ITI) in inhibitor patients, 16,17 and, while costly, is cost-effective in those with inhibitors. 13,14 Whether bleed frequency and bleed severity, long-term joint health and quality of life are comparable to that achieved with factor VIII, therefore, remains unknown.…”

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confidence: 99%

“…13,14 Whether bleed frequency and bleed severity, long-term joint health and quality of life are comparable to that achieved with factor VIII, therefore, remains unknown. Recent studies indicate emicizumab is safe and effective for prophylaxis in infants with haemophilia A 15,16 and in immune tolerance induction (ITI) in inhibitor patients, 16,17 and, while costly, is cost-effective in those with inhibitors. 18 Yet, there is limited experience with emicizumab in breakthrough bleeding rates and surgical hemostasis in those with and without inhibitors.…”

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confidence: 99%

Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors

et al. 2019

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Introduction Emicizumab is a bispecific monoclonal antibody that mimics factor VIII (FVIII) by binding to factors IXa and X to promote hemostasis in haemophilia A (HA) and HA with inhibitors (HA‐I). As emicizumab differs biochemically from FVIII, there is interest in its real‐world haemostatic efficacy. Aim To describe real‐world patient experience with emicizumab by retrospective chart review. Methods We reviewed medical records of patients cared for at the Hemophilia Center of Western PA, who initiated emicizumab following its licensure, and on whom bleeding events and factor use were available. Comparisons between groups were done by Student's t test for continuous data and by chi‐square or Fisher's exact test for discrete data. Results A total of 42 patients whose charts were reviewed included 18 (42.9%) with HA and 24 (52.1%) with HA‐I. Groups were similar in age, 17 (40.5%) <18 years, race, and haemophilia severity, and initiated weekly subcutaneous emicizumab 1.5 mg/kg, following 4‐week induction. Fourteen (33.3%) experienced at least one breakthrough bleed, of which 11 (44.0%) were joint bleeds, with an annualized bleed rate (ABR), 0.9 ± 0.3, not different between groups, P = .251. Surgical procedures were performed in 10 (23.8%), of whom 4 (40.0%) had postoperative bleeding and one developed postoperative thrombosis in association with FEIBA despite emicizumab discontinuation 1 month preoperatively. Local skin reactions occurred in three and headache in one. Overall, 85.0% of those who rated their health indicated it was improved. Discussion Despite breakthrough bleeds and postoperative thrombosis associated with emicizumab, most HA and HA‐I experienced improved health.

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“…These early data suggested that ITI can be performed accompanied with emicizumab prophylaxis without safety concerns. In this context, Carcao et al 43 from the Future of Immunotolerance Treatment (FIT) Study Group discussed ITI in the modern era of nonfactor therapies. They proposed starting FVIII at a low dose (50 IU/kg) and low frequency (3 times weekly) escalating to 200 IU/kg daily if the inhibitor titer rises.…”

Section: Questions For the Wider Use Of Emicizumab In The Postmarketimentioning

confidence: 99%

“…Nevertheless, given the limited information and experience in this field, it is difficult to define precise maintenance treatment. The FIT study group recommended continued regular infusions of FVIII once or twice a week for at least 6 months after ITI success 43 . Furthermore, emicizumab alone may be an option, considering the marked reduction in ABR, the burden of frequent FVIII infusions, and catheter‐related thrombotic and infection risks.…”

Section: Questions For the Wider Use Of Emicizumab In The Postmarketimentioning

confidence: 99%

Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

Shima

2020

Research and Practice in Thrombosis and Haemostasis

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Regular prophylaxis has markedly improved the treatment for patients with hemophilia A, especially after the introduction of highly purified factor VIII (FVIII) concentrates. However, frequent intravenous infusions and the development of FVIII inhibitors remain as unsolved difficulties. To overcome these unmet needs, a bispecific antibody mimicking activated FVIII has been developed in Japan. This bispecific antibody, emicizumab, recognizes activated factor IX (FIXa) and activated factor X (FXa), and promotes FIXa‐catalyzed activation of FX in the absence of FVIII. Emicizumab initially reacts with FIXa generated by the action of factor VIIa/tissue factor complexes. Subsequently, thrombin generation is enhanced in the presence of higher amounts of FIXa derived from FXIa‐dependent mechanisms. Hence, emicizumab‐driven FXa and thrombin generation is maintained by a FXI activation loop in the intrinsic coagulation pathway. Reactions downstream of emicizumab are regulated by natural anticoagulants including activated protein C, antithrombin, and tissue factor pathway inhibitor. Phase 3 studies (HAVEN 1‐4 and HOHOEMI studies) demonstrated a remarkable reduction in bleeding rates together with a high percentage of patients with zero treated bleeds irrespective of the presence of inhibitors. In general, emicizumab proved to be well tolerated, although isolated thromboembolic and thrombotic microangiopathic complications were observed in the HAVEN 1 studies, and 3 out of a total of 400 patients developed neutralizing antidrug antibodies. In addition, several questions remain to be discussed with respect to open‐use clinical practice, including when to start treatment, how to monitor therapy, and optimum dosage for surgical procedures and immune tolerance induction.

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The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Cited by 80 publications

References 36 publications

Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis

Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis

Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors

Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

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