PB0649 - Results From the RESIST Study for Tolerance Induction in Patients With Poor Prognosis for ITI Success

Monday, June 26, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Christoph Koenigs, Dr. Dr.

Professor
University Hospital Frankfurt, Department of Paediatrics and Adolescent Medicine, Frankfurt, Germany
Frankfurt, Hessen, Germany

Co-Author(s)

AS

Anja Schmidt

Postdoctoral Researcher
Goethe University Frankfurt, University Hospital, Department of Paediatrics and Adolescent Medicine, Clinical and Molecular Haemostasis, Frankfurt am Main, Germany
Frankfurt am Main, Hessen, Germany
ES

Emilia Salzmann-Manrique

Statistician
Goethe University Frankfurt, University Hospital, Department of Pediatrics, Frankfurt am Main, Germany
Frankfurt am Main, Hessen, Germany
AO

Aleksander Orlowski

leitender techn. Assistent
Goethe University Frankfurt, University Hospital, Department of Paediatrics and Adolescent Medicine, Clinical and Molecular Haemostasis, Frankfurt am Main, Germany
Frankfurt am Main, Hessen, Germany
DS

Diana Stichel

technical assistant
Goethe University Frankfurt, University Hospital, Department of Paediatrics and Adolescent Medicine, Clinical and Molecular Haemostasis, Frankfurt am Main, Germany
Frankfurt am Main, Hessen, Germany
Manuel Carcao, MD, FRCPC

Professor
Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
Toronto, Ontario, Canada
Anthony KC. Chan, MBBS

Professor
McMaster University, McMaster Children’s Hospital, Hamilton, Canada
Hamilton, Ontario, Canada
MG

Michael Guerrera

Physician
Department of Pediatrics, Children’s National Hospital, Washington, USA
Washington DC, District of Columbia, United States
MJ

Michael R Jeng

Physician
Department of Pediatrics, Stanford University School of Medicine, USA
Palo Alto, California, United States
RK

Robert J. Klaassen, MD, FRCP(C)

Scientist, CHEO Research Institute; Professor, Department of Pediatrics
Children’s Hospital of Eastern Ontario
Ottawa, Ontario, Canada
RK

Roshni Kulkarni

Physician
Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, USA
East Lansing, Michigan, United States
Madhvi Rajpurkar, MD

Physician
Department of Pediatrics, Central Michigan University, Mount Pleasant, Michigan, USA
Mount Pleasant, Michigan, United States
UR

Ulrike Reiss

Physician
Hemophilia Treatment Center, Department of Hematology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
Memphis, Tennessee, United States
JS

Joann Sanders

Physician
Cook Children's Hematology and Oncology, Fort Worth, Texas, USA
Fort Worth, Texas, United States
ES

Elena Santagostino

Physician
Bianchi Bonomi Hemophilia and Thrombosis Center, Maggiore Hospital Policlinico, Milan, Italy
Milan, Lombardia, Italy
LV

Leonard A. Valentino

Physician
Rush Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, Illinois, USA
New York, New York, United States
NE

Nadia Ewing

Physician
Department of Pediatrics, City of Hope National Medical Center, Duarte, California, USA
Duarte, California, United States

Background: Immune tolerance induction (ITI) therapy routinely is used to tolerize hemophilia A patients towards FVIII after the development of inhibitory FVIII-specific antibodies. Within the prospective RESIST study, a total of 18 patients with severe hemophilia A and inhibitors with either previous ITI failure (experienced) or with bad prognostic factors for ITI success (naïve) were enrolled for tolerance induction.

Aims: Aim of this study was to analyze the impact of plasma-derived FVIII on achieving tolerance. In addition, the impact of FVIII-specific antibody characteristics on FVIII inhibitor dynamics was analyzed to identify potential prognostic factors for ITI success.

Methods: Informed consent was obtained from all subjects and the study was approved by the local ethics committees of involved hospitals. Patients were treated with daily 200 IU/kg FVIII. FVIII-specific antibodies were analyzed by Bethesda Assay and ELISAs to characterize binding domain and IgG subclasses. Survival analysis and mixed effects were used as appropriate.

Results: Eleven out of 18 patients achieved a Bethesda titer < 0.6 BU/ml during the study (Table 1). Patients with lower initial titers were more likely to reach titer < 0.6 BU/ml (Hazard ratio per 10 BU/ml= 0.21; p< 0.036). None of the patients achieved complete ITI success within their follow-up. The Bethesda titer positively correlated with FVIII-specific IgG4 antibodies and with those specific for the FVIII light chain.

Conclusion(s): Despite the limitation of this study due to the small number of patients treated with recombinant or plasma-derived FVIII, statistical analysis points out that the titer at start of ITI is a prognostic marker for ITI success. Furthermore, light chain-specific antibodies and antibodies of subclass IgG4 have a high impact on the Bethesda titer. A larger cohort study is needed to determine if these characteristics can prognosticate ITI success.