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CC BY 4.0 · TH Open 2022; 06(02): e124-e134
DOI: 10.1055/s-0042-1748756
Original Article

Immune Tolerance Induction (ITI) with a pdFVIII/VWF Concentrate (octanate) in 100 Patients in the Observational ITI (ObsITI) Study

Carmen Escuriola Ettingshausen
1   HZRM, Hämophilie-Zentrum Rhein Main, Mörfelden-Walldorf, Germany
,
Vladimír Vdovin
2   Morozovskaya Children's Hospital, Moscow, Russian Federation
,
Nadezhda Zozulya
3   National Research Center for Hematology, Moscow, Russian Federation
,
Pavel Svirin
2   Morozovskaya Children's Hospital, Moscow, Russian Federation
,
Tatiana Andreeva
4   City Center for the Treatment of Hemophilia Patients, City Polyclinic N° 37, St. Petersburg, Russian Federation
,
Majda Benedik-Dolničar
5   Children's Hospital Oncology-Hematology Unit, University Medical Center Ljubljana, Ljubljana, Slovenia
,
Victor Jiménez-Yuste
6   Servicio de Hematología, Hospital Univeristario La Paz, Autónoma University, Madrid, Spain
,
Lidija Kitanovski
5   Children's Hospital Oncology-Hematology Unit, University Medical Center Ljubljana, Ljubljana, Slovenia
,
Silva Zupancic-Šalek
7   Division of Haematology, Haemophilia Centre, University Hospital REBRO, Zagreb, Croatia
,
Anna Pavlova
8   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
Angelika Bátorová
9   Department of Hematology and Transfusion Medicine, National Hemophilia Center, Faculty of Medicine of the Comenius University and University Hospital, Bratislava, Slovak Republic
,
Cesar Montaño Mejía
10   Hemolife and Universidad Tecnológica de Pereira, Pereira, Colombia
,
Gulnara Abdilova
11   Scientific Center of Pediatrics and Pediatric Surgery, Almaty, Kazakhstan
,
Sigurd Knaub
12   Octapharma AG, Lachen, Switzerland
,
Martina Jansen
13   Octapharma Pharmazeutika Produktionsges.mbH, Vienna, Austria
,
Shannely Lowndes
12   Octapharma AG, Lachen, Switzerland
,
Larisa Belyanskaya
12   Octapharma AG, Lachen, Switzerland
,
Olaf Walter
12   Octapharma AG, Lachen, Switzerland
,
Johannes Oldenburg
8   Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
,
on behalf of the ObsITI Study Group › Author Affiliations Funding The ObsITI study is funded by Octapharma and Swedish Orphan Biovitrum.
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Abstract

Background Immune tolerance induction (ITI) with repeated factor VIII (FVIII) administration is the only strategy proven to eradicate inhibitors. The observational ITI study is evaluating ITI with a range of FVIII products.

Methods This subgroup analysis reports prospective interim data for patients treated with a plasma-derived, von Willebrand factor-stabilized FVIII concentrate (pdFVIII/VWF, octanate). Complete success (CS) of ITI required achievement of three criteria: inhibitor titer < 0.6 BU/mL; FVIII recovery ≥ 66%; FVIII half-life ≥6 hours. Partial success (PS) required achievement of two criteria and partial response (PR) one. ITI success was defined as CS or PS. Data were analyzed for patients who achieved CS, had 36 months' observation, or failed ITI.

Results One-hundred prospectively enrolled patients were included in the analysis; 91 had poor prognosis factors for ITI success. The mean (standard deviation) daily ITI dose was 116.4 (61.1) IU FVIII/kg in 14 low responders (< 5 BU/mL) and 173.7 (112.0) IU FVIII/kg in 86 high responders (≥ 5 BU/mL). Inhibitor titers < 0.6 BU/mL were achieved in 71% of patients in a median of 4.01 months, accompanied by a 93% reduction in bleeding rate. ITI success was achieved by 70% of patients and 56 of 72 (78%) primary (first-line) ITI patients. PR was achieved by 5 patients; ITI failed in 25 patients. PS and CS were achieved in a median of 5.55 and 11.25 months, respectively.

Conclusions ITI with pdFVIII/VWF led to rapid eradication of FVIII inhibitors, normalization of FVIII pharmacokinetics in the majority of patients, and a significant reduction in bleeding rates.

Keywords

factor VIII - von Willebrand factor - FVIII inhibitors - hemophilia A - immune tolerance

Addendum

This research was performed by the ObsITI Study Group in collaboration with the ObsITI Committee. ObsITI Study Group members contributing patients to this analysis were M. Anar, T. Andreeva, A. Bátorová, S. Bayart, M. Benedik-Dolničar E. Benz-Lemoine, C. Berger, E. Bilic, B. Boggia, E. Bubanská, M. Campos, H. Chambost, M.S. Cruz, B. Freitas, J. Hak, T. Henni, V. Jiménez-Yuste, A. Klukowska, W. Kreuz, R. Lassila, V. Li-Thiao-Te, A. Mamaev, S. Morais, A. Momot, C. Montaño Mejía, K. Orgulas, N. Osmulskaya, O. Plyushch, M. Prieto, K. Prunnsild, O. Pyatkova, M. Quintana Molina, I. Rodriguez, C. Rothschild, S. Saulyte-Trakymiene, R. Turello, V. Vdovin, F. Velasco, N. Zozulya, S. Zupančić Salek.


Authors' Contributions

Carmen Escuriola Ettingshausen prepared the first draft of the manuscript. All authors made a substantial contribution to the study design and/or analysis of the data, critically revised the manuscript, and approved the final submitted version.


Supplementary Material



Publication History

Received: 20 August 2021

Accepted: 02 February 2022

Article published online:
26 May 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Carcao M, Escuriola Ettingshausen C, Santagostino E. et al; Future of Immunotolerance Treatment Group. The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia 2019; 25 (04) 676-684
    CrossrefPubMedGoogle Scholar
  • 2 Walsh CE, Jiménez-Yuste V, Auerswald G, Grancha S. The burden of inhibitors in haemophilia patients. Thromb Haemost 2016; 116 (Suppl. 01) S10-S17
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Di Minno MN, Di Minno G, Di Capua M, Cerbone AM, Coppola A. Cost of care of haemophilia with inhibitors. Haemophilia 2010; 16 (01) e190-e201
    CrossrefPubMedGoogle Scholar
  • 4 Carcao M, Re W, Ewenstein B. The role of previously untreated patient studies in understanding the development of FVIII inhibitors. Haemophilia 2016; 22 (01) 22-31
    CrossrefPubMedGoogle Scholar
  • 5 Oldenburg J, Lacroix-Desmazes S, Lillicrap D. Alloantibodies to therapeutic factor VIII in hemophilia A: the role of von Willebrand factor in regulating factor VIII immunogenicity. Haematologica 2015; 100 (02) 149-156
    CrossrefPubMedGoogle Scholar
  • 6 Garagiola I, Palla R, Peyvandi F. Risk factors for inhibitor development in severe hemophilia a. Thromb Res 2018; 168: 20-27
    CrossrefPubMedGoogle Scholar
  • 7 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (11) 1935-1939
    CrossrefPubMedGoogle Scholar
  • 8 Rocino A, Franchini M, Coppola A. Treatment and prevention of bleeds in haemophilia patients with inhibitors to factor VIII/IX. J Clin Med 2017; 6 (04) E46
    CrossrefPubMedGoogle Scholar
  • 9 Giangrande PLF, Hermans C, O'Mahony B. et al; European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD). European principles of inhibitor management in patients with haemophilia. Orphanet J Rare Dis 2018; 13 (01) 66
    CrossrefPubMedGoogle Scholar
  • 10 Valentino LA, Kempton CL, Kruse-Jarres R, Mathew P, Meeks SL, Reiss UM. International Immune Tolerance Induction Study Investigators. US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. Haemophilia 2015; 21 (05) 559-567
    CrossrefPubMedGoogle Scholar
  • 11 Collins P, Chalmers E, Alamelu J. et al. First-line immune tolerance induction for children with severe haemophilia A: a protocol from the UK Haemophilia Centre Doctors' Organisation Inhibitor and Paediatric Working Parties. Haemophilia 2017; 23 (05) 654-659
    CrossrefPubMedGoogle Scholar
  • 12 Ljung R, Auerswald G, Benson G. et al. Inhibitors in haemophilia A and B: management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. Eur J Haematol 2019; 102 (02) 111-122
    CrossrefPubMedGoogle Scholar
  • 13 Gringeri A, Musso R, Mazzucconi MG. et al; RITS-FITNHES Study Group. Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response. Haemophilia 2007; 13 (04) 373-379
    CrossrefPubMedGoogle Scholar
  • 14 Kreuz W, Escuriola Ettingshausen C, Vdovin V. et al; ObsITI study group, ObsITI committee. First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study. Haemophilia 2016; 22 (01) 87-95
    CrossrefPubMedGoogle Scholar
  • 15 Hay CR, DiMichele DM. International Immune Tolerance Study. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119 (06) 1335-1344
    CrossrefPubMedGoogle Scholar
  • 16 Kreuz W, Escuriola Ettingshausen C, Auerswald G. et al. Immune tolerance induction (ITI) in haemophilia A - patients with inhibitors - the choice of concentrate affecting success. Haematologica 2001; 86 (Suppl. 04) 16-22
    PubMedGoogle Scholar
  • 17 Auerswald G, Spranger T, Brackmann HH. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients. Haematologica 2003; 88 (06) P05
    PubMedGoogle Scholar
  • 18 Brackmann HH, White II GC, Berntorp E, Andersen T, Escuriola Ettingshausen C. Immune tolerance induction: what have we learned over time?. Haemophilia 2018; 24 (Suppl. 03) 3-14
    CrossrefPubMedGoogle Scholar
  • 19 Franchini M, Lippi G. Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review. Thromb Haemost 2010; 104 (05) 931-940
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Brackmann HH, Oldenburg J, Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors–twenty years' 'bonn protocol'. Vox Sang 1996; 70 (Suppl. 01) 30-35
    PubMedGoogle Scholar
  • 21 Verbruggen B, Novakova I, Wessels H, Boezeman J, van den Berg M, Mauser-Bunschoten E. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost 1995; 73 (02) 247-251
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13 (Suppl. 01) 1-22
    CrossrefPubMedGoogle Scholar
  • 23 Benson G, Auerswald G, Elezović I. et al. Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice. Eur J Haematol 2012; 88 (05) 371-379
    CrossrefPubMedGoogle Scholar
  • 24 Oldenburg J, Jiménez-Yuste V, Peiró-Jordán R, Aledort LM, Santagostino E. Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF-containing plasma-derived FVIII concentrate. Haemophilia 2014; 20 (01) 83-91
    CrossrefPubMedGoogle Scholar
  • 25 Carcao M, Shapiro A, Hwang N. et al. Real-world data of immune tolerance induction using recombinant factor VIII Fc fusion protein in patients with severe haemophilia A with inhibitors at high risk for immune tolerance induction failure: a follow-up retrospective analysis. Haemophilia 2021; 27 (01) 19-25
    CrossrefPubMedGoogle Scholar
  • 26 Escobar M, Shaffer L, Holguin M, McCavit T, Amega NS, Rajan SK. Immune tolerance induction with antihaemophilia factor (human) in poor prognosis patients with haemophilia A. Haemophilia 2021; 27 (03) e393-e397
    CrossrefPubMedGoogle Scholar
  • 27 Rocino A, Cortesi PA, Scalone L, Mantovani LG, Crea R, Gringeri A. European Haemophilia Therapy Strategy Board (EHTSB), European Haemophilia Therapy Strategy Board EHTSB. Immune tolerance induction in patients with haemophilia a and inhibitors: effectiveness and cost analysis in an European Cohort (The ITER Study). Haemophilia 2016; 22 (01) 96-102
    CrossrefPubMedGoogle Scholar
  • 28 Santagostino E, Rangarajan S, Oldenburg J, Peiró-Jordan R, Jiménez-Yuste V. Rapid and sustained immune tolerance to inhibitors induced by a plasma-derived, VWF-containing FVIII concentrate. Haemophilia 2019; 25 (02) e110-e113
    CrossrefPubMedGoogle Scholar
  • 29 Oldenburg J, Mahlangu JN, Kim B. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818
    CrossrefPubMedGoogle Scholar
  • 30 Escuriola Ettingshausen C, Auerswald G, Königs C. et al. Optimizing the management of patients with haemophilia A and inhibitors in the era of emicizumab: recommendations from a German expert panel. Haemophilia 2021; 27 (03) e305-e313
    CrossrefPubMedGoogle Scholar
  • 31 Santagostino E, Young G, Escuriola Ettingshausen C, Jimenez-Yuste V, Carcao M. Inhibitors: a need for eradication?. Acta Haematol 2019; 141 (03) 151-155
    CrossrefPubMedGoogle Scholar
  • 32 Srivastava A, Santagostino E, Dougall A. et al; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia 2020; 26 (Suppl. 06) 1-158
    CrossrefPubMedGoogle Scholar
  • 33 Batsuli G, Zimowski KL, Tickle K, Meeks SL, Sidonio Jr RF. Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia 2019; 25 (05) 789-796
    CrossrefPubMedGoogle Scholar