First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study

Kreuz, W.; Ettingshausen, Carmen Escuriola; Vdovin, Vladimír; Zozulya, Nadezhda; Plyushch, O. P.; Svirin, Pavel; Andreeva, Tatiana; Bubanská, Eva; Campos, M.; Benedik-Dolničar, Majda; Jiménez‐Yuste, Víctor; Kitanovski, Lidija; Klukowska, Anna; Момот, А. П.; Osmulskaya, N; Prieto, M.; Šalek, Silva Zupančić; Velasco, Francisco; Pavlova, A.; Oldenburg, Johannes; Knaub, Sigurd; Jansen, Martina; Belyanskaya, Larisa; Walter, Olaf

doi:10.1111/hae.12774

Cited by 50 publications

(91 citation statements)

References 29 publications

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“…It has been suggested that reducing bleeding during ITI can shorten the time to tolerance. Interim results from the international, open‐label, uncontrolled, observational immune tolerance induction (ObsITI) study showed a significant correlation between the monthly bleeding rate during ITI and the time to achievement of complete success with ITI ( P = .0005) . Patients with 0 bleeds, or ≤0.5 bleeds per month during ITI, achieved complete success faster than patients experiencing >0.5 bleeds per month .…”

Section: Iti Therapymentioning

confidence: 99%

“…Interim results from the international, open‐label, uncontrolled, observational immune tolerance induction (ObsITI) study showed a significant correlation between the monthly bleeding rate during ITI and the time to achievement of complete success with ITI ( P = .0005) . Patients with 0 bleeds, or ≤0.5 bleeds per month during ITI, achieved complete success faster than patients experiencing >0.5 bleeds per month . Furthermore, Rocino et al 2016 also showed that the number of breakthrough bleeding events during ITI was significantly associated with the length of time to achieve successful tolerance ( P = .0035).…”

Section: Iti Therapymentioning

confidence: 99%

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Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII

Carpenter

Khair

Gringeri³

et al. 2018

Haemophilia

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The development of high-titre inhibitory antibodies (inhibitors) against factor VIII (FVIII) remains a challenge in the management of patients with haemophilia A (HA). Patients with high-titre inhibitors are more likely to experience uncontrolled bleeding, physical disability from chronic arthropathy and premature death compared with those without this complication. Immune tolerance induction (ITI), utilizing repeated infusions of FVIII, is an effective therapeutic approach to eliminating inhibitory antibodies. This strategy can eradicate FVIII inhibitors, so that FVIII-specific tolerance is induced. However, patients undergoing ITI are still vulnerable to the development of serious and/or repeated bleeding events. The efficacy of bypassing agents in preventing bleeding episodes has been widely proven in patients with HA and inhibitors to FVIII. Evidence suggests that reducing bleeding during ITI can also shorten the time to tolerance. There are concerns with the use of bypassing agents, including the cost of treatment, short half-life, management of non-responders and the risk of thrombosis. Despite these concerns, and the still limited evidence from prospective studies and consensus reports, the use of prophylaxis with bypassing agents during ITI has been gaining support. This review presents a rationale and current data supporting the use of prophylactic bypassing agents as effective and safe therapies to reduce the incidence of joint bleeding due to inhibitors and improve quality of life in patients with HA undergoing ITI.

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Section: Iti Therapymentioning

confidence: 99%

Section: Iti Therapymentioning

confidence: 99%

Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII

Carpenter

Khair

Gringeri³

et al. 2018

Haemophilia

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“…A number of studies suggest that the presence of von Willebrand factor (VWF) in the preparations of therapeutic FVIII concentrates results in increased effectiveness in both primary and rescue ITI [9][10][11][12][13]. In the Grifols ITI (G-ITI) study [14], 60 patients recruited between 1996 and 2008 in Germany, Italy and Spain who underwent primary or rescue ITI using a VWF-containing plasma-derived (pdFVIII) product were analysed retrospectively.…”

Section: Introductionmentioning

confidence: 99%

Long‐term outcome of haemophilia A patients after successful immune tolerance induction therapy using a single plasma‐derived FVIII/VWF product: the long‐term ITI study

Jiménez‐Yuste

Oldenburg²,

Rangarajan

et al. 2016

Haemophilia

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Introduction: Immune tolerance induction (ITI) is a standard intervention to eradicate inhibitors in haemophilic patients. However, information on the long-term condition of patients who eradicated the inhibitor totally or partially after ITI is scarce. Aim: To perform a long-term follow-up to describe the status of patients reported as ITI success in the G-ITI study. Methods: This was an international, multicentre, observational, retrospective study of the 57 haemophilic patients who were reported as ITI success in the G-ITI study. Demographics and post-ITI clinical data recorded until January 2015 were extracted from the medical records. A descriptive analysis was undertaken. Results: Forty-four patients were evaluable. Post-ITI follow-up was 9.1 years in average. Thirtyseven target joints were affected in 21 patients; 38 patients presented bleeding with a mean of 1.0 AE 1.2 episodes year À1, most of them (271/330) treated with Fanhdi â (Grifols). Around half of the patients underwent at least one surgical procedure. Most venous access complications were of expected nature, requiring hospital stay in practically all cases. Fanhdi was used in 42 patients as the regular haemophilia treatment after ITI, mainly prophylactically. Three patients (6.8%) who were being treated with Fanhdi (prophylaxis), Kogenate (prophylaxis) and Emoclot (on demand), respectively, showed inhibitor relapse (at 29, 53 and 13 months after ITI, with 0.9, 3.65 and 12.5 BU respectively). All of them were successfully tolerized after rescue ITI. Conclusion: After ITI success, all patients continued with regular successful FVIII treatment for haemophilia for more than 9 years. The few inhibitor relapses were successfully overcome after rescue ITI.

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“…However, both groups ultimately achieved similar ITI success rates, suggesting that the higher frequency of bleeding did not reduce the ITI success rate. In contrast, the ongoing Observational Immune Tolerance Induction study (ObsITI) showed an association between increased bleeding frequency and reduced ITI success rate [20]. It might be that bleeding frequency on ITI is related to patients’ inhibitor titers; higher inhibitor titers are associated with more bleeding and with a lower rate of ITI success.…”

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confidence: 99%

Inhibitors: A Need for Eradication?

Santagostino¹,

Ettingshausen²,

Jiménez‐Yuste³

et al. 2019

Acta Haematol

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The development of inhibitors against factor VIII (FVIII) concentrates represents a significant treatment complication for hemophilia. Immune tolerance induction (ITI) therapy eradicates inhibitors in 60–80% of patients, resulting in a normal FVIII response. This article, based on presentations at the 6th International Coagulation Meeting, held in Barcelona, Spain, in September 2017, provides an overview of management approaches for patients with inhibitors and briefly tabulates four cases of ITI therapy (first-line or rescue ITI therapy in pediatric and adult patients) with successful outcomes. Switching FVIII product from recombinant FVIII to plasma-derived FVIII/VWF concentrate may be helpful in eradicating inhibitors. The rate of decline of inhibitor titer in the initial stages of ITI therapy is a good indicator of the success or failure of therapy, although prognostic biomarkers are needed. The development of the bispecific monoclonal antibody emicizumab, which was recently shown to reduce bleeding in inhibitor patients, offers a potential alternative therapeutic option. However, the benefits of inhibitor eradication, including a wider choice of cheaper therapeutic products for preventing and treating bleeds, suggest that at least one attempt of ITI therapy should be offered to patients who develop inhibitors.

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First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study

Cited by 50 publications

References 29 publications

Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII

Prophylactic bypassing agent use before and during immune tolerance induction in patients with haemophilia A and inhibitors to FVIII

Long‐term outcome of haemophilia A patients after successful immune tolerance induction therapy using a single plasma‐derived FVIII/VWF product: the long‐term ITI study

Inhibitors: A Need for Eradication?

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