Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors

A. Coppola, M. Margaglione, E. Santagostino, A. Rocino, E. Grandone, P. M. Mannucci, G. Di Minno

Research output: Contribution to journalArticle

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Abstract

Background: Immune tolerance induction (ITI) is the only therapeutic approach that can eradicate factor VIII (FVIII) inhibitors in patients with hemophilia A. Predictors of ITI outcome are still debated, and the role of F8 gene mutations in this is not well established. Objectives: To investigate the relationship between F8 genotype and ITI outcome in patients with severe hemophilia A and high-responding inhibitors. Patients and Methods:F8 mutations were identified in 86 patients recruited as part of the Italian ITI registry (the PROFIT study). ITI outcome was centrally reviewed according to the following definitions: success (undetectable inhibitor and normal FVIII pharmacokinetics), partial success (inhibitor titer <5 BU mL-1 and/or abnormal FVIII pharmacokinetics), and failure. Results:F8 mutations known to be associated with a high risk of inhibitor development (large deletions, inversions, nonsense mutations and splice site mutations) were found in 70 patients (81%); among these, the intron 22 inversion was present in 49 patients (57%). In 16 patients (19%) lower-risk F8 defects (small insertions/deletions and missense mutations) were identified. The latter group of patients showed a significantly higher ITI success rate than those carrying high-risk mutations [13/16 (81%) vs. 33/70 (47%); risk ratio 1.7, 95% confidence interval (CI) 1.1-2.1, P = 0.01]. On multivariate analysis, the mutation risk class remained a significant predictor of success [adjusted odds ratio (OR) 6.2, 95% CI 1.1-36.0, P = 0.04], as were inhibitor titer at ITI start (<5 BU mL-1, OR 11.8, 95% CI 3.5-40.2, P <0.001), and peak titer during ITI (<100 BU mL-1, OR 11.4, 95% CI 3.2-40.8, P <0.001). Conclusions: ITI success is influenced by F8 genotype. This knowledge should contribute to the stratification of prognosis, and to the clinical choices made for ITI in patients with high-responding inhibitors.

Original languageEnglish
Pages (from-to)1809-1815
Number of pages7
JournalJournal of Thrombosis and Haemostasis
Volume7
Issue number11
DOIs
Publication statusPublished - Nov 2009

Fingerprint

Immune Tolerance
Factor VIII
Hemophilia A
Mutation
Genes
Odds Ratio
Confidence Intervals
Pharmacokinetics
INDEL Mutation
Genotype
Nonsense Codon
Missense Mutation
Introns
Registries
Multivariate Analysis

Keywords

  • F8 gene mutations
  • Hemophilia
  • Immune tolerance induction
  • Inhibitors
  • Prognostic factors

ASJC Scopus subject areas

  • Hematology

Cite this

Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors. / Coppola, A.; Margaglione, M.; Santagostino, E.; Rocino, A.; Grandone, E.; Mannucci, P. M.; Di Minno, G.

In: Journal of Thrombosis and Haemostasis, Vol. 7, No. 11, 11.2009, p. 1809-1815.

Research output: Contribution to journalArticle

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abstract = "Background: Immune tolerance induction (ITI) is the only therapeutic approach that can eradicate factor VIII (FVIII) inhibitors in patients with hemophilia A. Predictors of ITI outcome are still debated, and the role of F8 gene mutations in this is not well established. Objectives: To investigate the relationship between F8 genotype and ITI outcome in patients with severe hemophilia A and high-responding inhibitors. Patients and Methods:F8 mutations were identified in 86 patients recruited as part of the Italian ITI registry (the PROFIT study). ITI outcome was centrally reviewed according to the following definitions: success (undetectable inhibitor and normal FVIII pharmacokinetics), partial success (inhibitor titer <5 BU mL-1 and/or abnormal FVIII pharmacokinetics), and failure. Results:F8 mutations known to be associated with a high risk of inhibitor development (large deletions, inversions, nonsense mutations and splice site mutations) were found in 70 patients (81{\%}); among these, the intron 22 inversion was present in 49 patients (57{\%}). In 16 patients (19{\%}) lower-risk F8 defects (small insertions/deletions and missense mutations) were identified. The latter group of patients showed a significantly higher ITI success rate than those carrying high-risk mutations [13/16 (81{\%}) vs. 33/70 (47{\%}); risk ratio 1.7, 95{\%} confidence interval (CI) 1.1-2.1, P = 0.01]. On multivariate analysis, the mutation risk class remained a significant predictor of success [adjusted odds ratio (OR) 6.2, 95{\%} CI 1.1-36.0, P = 0.04], as were inhibitor titer at ITI start (<5 BU mL-1, OR 11.8, 95{\%} CI 3.5-40.2, P <0.001), and peak titer during ITI (<100 BU mL-1, OR 11.4, 95{\%} CI 3.2-40.8, P <0.001). Conclusions: ITI success is influenced by F8 genotype. This knowledge should contribute to the stratification of prognosis, and to the clinical choices made for ITI in patients with high-responding inhibitors.",
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T1 - Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors

AU - Coppola, A.

AU - Margaglione, M.

AU - Santagostino, E.

AU - Rocino, A.

AU - Grandone, E.

AU - Mannucci, P. M.

AU - Di Minno, G.

PY - 2009/11

Y1 - 2009/11

N2 - Background: Immune tolerance induction (ITI) is the only therapeutic approach that can eradicate factor VIII (FVIII) inhibitors in patients with hemophilia A. Predictors of ITI outcome are still debated, and the role of F8 gene mutations in this is not well established. Objectives: To investigate the relationship between F8 genotype and ITI outcome in patients with severe hemophilia A and high-responding inhibitors. Patients and Methods:F8 mutations were identified in 86 patients recruited as part of the Italian ITI registry (the PROFIT study). ITI outcome was centrally reviewed according to the following definitions: success (undetectable inhibitor and normal FVIII pharmacokinetics), partial success (inhibitor titer <5 BU mL-1 and/or abnormal FVIII pharmacokinetics), and failure. Results:F8 mutations known to be associated with a high risk of inhibitor development (large deletions, inversions, nonsense mutations and splice site mutations) were found in 70 patients (81%); among these, the intron 22 inversion was present in 49 patients (57%). In 16 patients (19%) lower-risk F8 defects (small insertions/deletions and missense mutations) were identified. The latter group of patients showed a significantly higher ITI success rate than those carrying high-risk mutations [13/16 (81%) vs. 33/70 (47%); risk ratio 1.7, 95% confidence interval (CI) 1.1-2.1, P = 0.01]. On multivariate analysis, the mutation risk class remained a significant predictor of success [adjusted odds ratio (OR) 6.2, 95% CI 1.1-36.0, P = 0.04], as were inhibitor titer at ITI start (<5 BU mL-1, OR 11.8, 95% CI 3.5-40.2, P <0.001), and peak titer during ITI (<100 BU mL-1, OR 11.4, 95% CI 3.2-40.8, P <0.001). Conclusions: ITI success is influenced by F8 genotype. This knowledge should contribute to the stratification of prognosis, and to the clinical choices made for ITI in patients with high-responding inhibitors.

AB - Background: Immune tolerance induction (ITI) is the only therapeutic approach that can eradicate factor VIII (FVIII) inhibitors in patients with hemophilia A. Predictors of ITI outcome are still debated, and the role of F8 gene mutations in this is not well established. Objectives: To investigate the relationship between F8 genotype and ITI outcome in patients with severe hemophilia A and high-responding inhibitors. Patients and Methods:F8 mutations were identified in 86 patients recruited as part of the Italian ITI registry (the PROFIT study). ITI outcome was centrally reviewed according to the following definitions: success (undetectable inhibitor and normal FVIII pharmacokinetics), partial success (inhibitor titer <5 BU mL-1 and/or abnormal FVIII pharmacokinetics), and failure. Results:F8 mutations known to be associated with a high risk of inhibitor development (large deletions, inversions, nonsense mutations and splice site mutations) were found in 70 patients (81%); among these, the intron 22 inversion was present in 49 patients (57%). In 16 patients (19%) lower-risk F8 defects (small insertions/deletions and missense mutations) were identified. The latter group of patients showed a significantly higher ITI success rate than those carrying high-risk mutations [13/16 (81%) vs. 33/70 (47%); risk ratio 1.7, 95% confidence interval (CI) 1.1-2.1, P = 0.01]. On multivariate analysis, the mutation risk class remained a significant predictor of success [adjusted odds ratio (OR) 6.2, 95% CI 1.1-36.0, P = 0.04], as were inhibitor titer at ITI start (<5 BU mL-1, OR 11.8, 95% CI 3.5-40.2, P <0.001), and peak titer during ITI (<100 BU mL-1, OR 11.4, 95% CI 3.2-40.8, P <0.001). Conclusions: ITI success is influenced by F8 genotype. This knowledge should contribute to the stratification of prognosis, and to the clinical choices made for ITI in patients with high-responding inhibitors.

KW - F8 gene mutations

KW - Hemophilia

KW - Immune tolerance induction

KW - Inhibitors

KW - Prognostic factors

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