scholarly journals Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BrazIT) Study protocol

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256265
Author(s):  
Ricardo Mesquita Camelo ◽  
Daniel Gonçalves Chaves ◽  
Luciana Werneck Zuccherato ◽  
Suely Meireles Rezende ◽  
Keyword(s):  
Immune Tolerance ◽  
Low Dose ◽  
Clinical Laboratory ◽  
Tolerance Induction ◽  
High Dose ◽  
Haemophilia A ◽  
Clinical Genetic ◽  
Immune Tolerance Induction ◽  
Immune Biomarkers ◽  
Treatment Centre

The development of inhibitors is the main complication of haemophilia A (HA) treatment. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. We describe the methodology of the Brazilian Immune Tolerance Induction (BrazIT) Study, aimed to identify clinical, genetic, and immune biomarkers associated with response to ITI and inhibitor recurrence. This cohort study includes people with HA (PwHA) and inhibitors (a) who require bypassing agents to treat and/or prevent bleeding, and (b) who are at any stage of ITI treatment. Patients are included in each haemophilia treatment centre (HTC). Factor VIII (FVIII) and inhibitor assessments are performed at local laboratories of each HTC. The ITI regimen followed the national protocol of the Brazilian Ministry of Health. All PwHA starts with low-dose ITI (50 IU/kg three times weekly); high-dose regimen (100 IU/kg daily) is used if there is lack of response to the low-dose ITI. Outcomes are classified as total or partial success, and failure. Standardized case report forms with clinical, laboratory, and treatment data are collected from medical files and interviews. Blood samples are collected for genetic and immune biomarkers at the time of inclusion in the study and at the end of ITI. The study is ongoing and, currently, 202/250 (80.8%) PwHA from 15 HTCs have been included. BrazIT Study is the largest cohort of PwHA and inhibitor under treatment with the same ITI regimen reported to date. This study is likely to contribute with novel predictors of ITI response.

Successful low dose immune tolerance induction in severe haemophilia A with inhibitors below 40 Bethesda Units

Haemophilia ◽  
2009 ◽  
Vol 16 (102) ◽  
pp. 71-79 ◽  
Author(s):  
P. C. TER AVEST ◽  
K. FISCHER ◽  
S. C. GOUW ◽  
K. VAN DIJK ◽  
E. P. MAUSER-BUNSCHOTEN
Keyword(s):  
Immune Tolerance ◽  
Low Dose ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Immune Tolerance Induction

Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors

2017 ◽  
Vol 117 (12) ◽  
pp. 2274-2282 ◽  
Author(s):  
Maria Elisa Mancuso ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Johannes Oldenburg ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Risk Factors ◽  
Immune Tolerance ◽  
Laboratory Data ◽  
Tolerance Induction ◽  
High Titre ◽  
High Dose ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Immune Tolerance Induction ◽  
Potential Risk Factors

AbstractIn children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

ITI with a VWF-Stabilised FVIII Concentrate in Haemophilia A Patients with Inhibitors and a Poor Prognosis for ITI Success: Progress Report on octanate® in the Observational ObsITI Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3310-3310
Author(s):  
Carmen Escuriola-Ettingshausen ◽  
Vladimir Vdovin ◽  
Nadezhda Zozulya ◽  
Olga Plyushch ◽  
Wolfhart Kreuz ◽  
...  
Keyword(s):  
Partial Response ◽  
Replacement Therapy ◽  
Immune Tolerance ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Tolerance Induction ◽  
High Dose ◽  
Haemophilia A ◽  
Immune Tolerance Induction ◽  
Cox Regression Analysis

Abstract Abstract 3310 FVIII inhibitors that neutralise FVIII efficacy are the most serious complication of FVIII replacement therapy in patients with haemophilia A (HA) and can be overcome with high-dose FVIII (Bonn protocol) during immune tolerance induction (ITI) therapy. The ongoing investigator-initiated Observational Immune Tolerance Induction (ObsITI) study systematically documents the tolerisation process, retrospectively and prospectively, in patients with HA and inhibitors, including those with a poor prognosis for ITI success. Here we report interim data on Octanate®, a human plasma-derived, von Willebrand factor-stabilised FVIII product. Data were analysed for a subgroup of 18 prospective patients who received octanate® as the sole FVIII replacement therapy for a treatment/follow-up period of 36 months. ITI success was determined by fulfilment of three stringent criteria: (I) inhibitor titre < 0.6 Bethesda Units, (II) incremental in vivo recovery ≥ 80% of 1.5% per IU/kg body weight reference and (III) FVIII half-life ≥ 7 hours. According to the criteria fulfilled, patients achieved the following: partial response (I), partial success (I, II), complete success (I, II, III) or failure. Following complete success, patients received prophylaxis with octanate® every second day. Of 18 patients, with at least one risk factor for a poor ITI outcome, 14 patients (77.8%) achieved complete success; 2 patients (11.1%) had partial response and 2 patients (11.1%) failed the ITI. Cox regression analysis of time to achievement of treatment outcome, suggested that both commencing ITI at ≤ 7 years of age and having had no prior ITI attempt appear to be positive prognostic factors for earlier ITI success in this population. Despite the stringent success criteria, complete or partial ITI success was achieved in 77.8 % of the patients. Treatment with octanate® administered according to the Bonn protocol is safe and effective in the induction of immune tolerance, even in patients with a poor-prognosis for ITI success. Disclosures: Schwartz: Octapharma usa: Employment.

Low-dose Immune Tolerance Induction in Hemophilia

2019 ◽  
Vol 41 (6) ◽  
pp. e355-e358 ◽  
Author(s):  
Bulent Zulfikar ◽  
Basak Koc ◽  
Nihal Ozdemir
Keyword(s):  
Immune Tolerance ◽  
Low Dose ◽  
Tolerance Induction ◽  
Immune Tolerance Induction
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