Natural History of Inhibitor Recurrence Following Successful Immune Tolerance Induction Público

Abstract

The formation of factor VIII (fVIII) inhibitory antibodies is a major complication of hemophilia A. Immune tolerance induction (ITI) is successful in up to 70% of patients. The probability and predictors of inhibitor recurrence following successful ITI are unknown. The study's objectives are to determine the influence of discontinuation and adherence of post-ITI prophylaxis on inhibitor recurrence, and the probability of recurrence following successful ITI.

In this multicenter retrospective cohort study, 84 male patients with Hemophilia A who successfully completed ITI based on local institutional criteria were enrolled. Sixty four subjects with fVIII <2% who were considered tolerant following ITI based on a negative inhibitor titer and normalized recovery level and/or half-life were analyzed. Kaplan-Meier method and logistic regression models were used to estimate the probability of inhibitor recurrence at 1, 3 and 5 years and to determine the association between clinical characteristics, including adherence to post-ITI prophylaxis and inhibitor recurrence.

Sixty four (76%) patients with fVIII level < 2% met criteria for tolerance and were included in the analysis: 45 (70.3%) subjects did not have a recurrent inhibitor titer and 19 (29.7%) had at least one inhibitor titer > 0.6 BU/ml. The probability of recurrent inhibitor at 1 year was 0.17 (95% CI: [0.05, 0.20]); at 3 years was 0.27 (95% CI: [0.2, 0.4]) and 5 years was 0.35 (95% CI: [0.2, 0.5]). Adherence to prophylactic fVIII infusion was found not to be statistically significant associated with inhibitor-free status (p=0.88). However, the odds of inhibitor recurrence were 11.1 and 9.0 higher in patients who received immunosuppression and in those whose recovery level was < 85%, respectively.

ITI is currently the most effective treatment to eradicate fVIII inhibitors, however 5 years after ITI completion, 30-35% of patients will have at least one inhibitor titer > 0.6 BU/ml. A recurrent inhibitor is unlikely after 5 years of ITI. Adherence to post-ITI prophylaxis does not appear to be a major driver of inhibitor recurrence. FVIII recovery level with a cutoff of 85%, and immunosuppression concomitant with ITI were found to be associated with inhibitor recurrence.

Table of Contents

Introduction

1-2

Background

3-5

Methods

6-13

Results

14-21

Discussion

22-25

References

26-27

Tables and Figures

28-39

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Table 1

Table 2

Table 3

Table 4

Table 5-6

Table 7-8

Table 9

Table A

28

34

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38

29

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About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research Curriculum Program
Degree	MS
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Medicine and Surgery
Palabra Clave	hemophilia inhibitor recurrence immune tolerance induction
Committee Chair / Thesis Advisor	Kempton, Christine, Emory University
Committee Members	Esper, Annette , Emory University Manatunga, Amita, Emory University

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