title: Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study.
abstract: BACKGROUND
  Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence after successful ITI are not well understood.
  
  
  OBJECTIVE
  To determine the association of clinical characteristics, particularly adherence to factor VIII (FVIII) prophylaxis after ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant after ITI.
  
  
  METHODS
  In this multicenter retrospective cohort study, 64 subjects with FVIII level < 2% who were considered successfully tolerant after ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression.
  
  
  RESULTS
  A recurrent inhibitor titer ≥ 0.6 BU mL(-1) occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5%, respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2-22.4) and FVIII recovery of < 85% at the end of ITI (OR 2.6, 95% CI 1.3-5.9) but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR 0.5, 95% CI 0.06-4.3).
  
  
  CONCLUSIONS
  The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence after successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Antun
authors.affiliation: Department of Pediatrics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: P E
authors.initials: PE
authors.lastname: Monahan
authors.affiliation: Hemophilia and Thrombosis Center and Children's Hospital Colorado, University of Colorado, Aurora, CO, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Manco-Johnson
authors.affiliation: Children's Hospital of Michigan, Detroit, MI, USA.
authors.forename: M U
authors.identifier: http://orcid.org/0000-0003-3540-2838
authors.initials: MU
authors.lastname: Callaghan
authors.affiliation: Children's Hospital of Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kanin
authors.affiliation: Phoenix Children's Hospital, Phoenix, AZ, USA.
authors.forename: C
authors.initials: C
authors.lastname: Knoll
authors.affiliation: Children's Mercy Hospital, Kansas City, MO, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Carpenter
authors.affiliation: Department of Pediatrics, University of Miami, Miami, FL, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Davis
authors.affiliation: Children's National Medical Center, Washington, DC, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Guerrera
authors.affiliation: Department of Medicine, Tulane University, New Orleans, LA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Kruse-Jarres
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Ragni
authors.affiliation: Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Witmer
authors.affiliation: Department of Pediatrics, Emory University, Atlanta, GA, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: McCracken
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Kempton
mesh_terms: D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D005260:Female; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007223:Infant; D007518:Isoantibodies / Q000096:biosynthesis* / Q000097:blood / Q000276:immunology; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D055118:Medication Adherence; D018448:Models, Immunological; D010956:Plasmapheresis; D057216:Propensity Score; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D007518:Isoantibodies; D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII
keywords: hemophilia; immune tolerance; incidence; prophylaxis; recurrence