Results of a prospective observation on the use of a coagulation factor concentrate VIII concentrate (Octanate®) for the induction of immunological tolerance in patients with an inhibitory form of hemophilia A

Relevance. Immune tolerance induction (ITI) is the only approach proven to eradicate inhibitors in hemophilia A patients. ITI with Octanate® (human VWF-stabilized FVIII) has been shown to be effective at eradicating inhibitors, even in poor-prognosis patients. Here we report interim data from two observational, prospective studies on the use of Octanate® for ITI in patients in Russia.

Purposes of research. The primary objective was to assess the efficacy of ITI. Secondary objectives included assessment of time to ITI success and inhibitor eradication.

Patients and methods. Patients of any age with any severity of hemophilia A and a FVIII inhibitor  0.6 BU/mL were eligible. The ITI regimen was at the discretion of the treating physician.

Results. The analysis included 73 patients. ITI outcomes were assessed in 63 patients who had completed the study, of whom 56 (89 %) had  1 poor prognostic factors. Inhibitor eradication was achieved by 77.1 % (37/48) of primary ITI patients and 71.4 % (45/63) of all patients, in a median of 2.4 months (range – 0.0–27.4) for both groups. Complete success was achieved by 72.9 % (35/48) of primary ITI patients in a median of 8.9 months (range – 2.4–28.0) and 66.7 % (42/63) of all patients in a median of 10.5 months (range – 2.4–28.0). No relapses were reported after complete or partial ITI success. Of the patients with  1 poor prognostic factors, 67.9 % achieved inhibitor eradication and 62.5 % complete success.

Conclusions. ITI with Octanate® in a real-world setting showed rapid and sustained success, even in patients with poor prognostic factors.

1. 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. doi: 10.3390/jcm6040046.

2. Garagiola I., Palla R., Peyvandi F. Risk factors for inhibitor development in severe hemophilia A. Thromb Res 2018;168:20–7. doi: 10.1016/j.thromres.2018.05.027.

3. Walsh C.E., Jimenez-Yuste V., Auerswald G., Grancha S. The burden of inhibitors in haemophilia patients. Thromb Haemost 2016;116:S10–7. doi: 10.1160/TH16-01-0049.

4. Di Minno M.N., Di Minno G., Di Capua M., Cerbone A.M., Coppola A. Cost of care of haemophilia with inhibitors. Haemophilia 2010;16:e190–201. doi: 10.1111/j.1365-2516.2009.02100.x.

5. Giangrande P.L.F., Hermans C., O’Mahony B., de Kleijn P., Bedford M., Batorova A., Blatný J., Jansone K.; 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;13:66. doi: 10.1186/s13023-018-0800-z.

6. Зозуля Н.И., Кумскова М.А., Полянская Т.Ю., Свирин П.В., Мамаев А.Н., Галстян Г.М. Национальные клинические рекомендации по лечению гемофилии. [Электронный ресурс]: http://www.cr.rosminzdrav.ru/#!/recomend/104. [Zozulya N.I., Kumskova M.A., Polyanskaya T.Yu., Svirin P.V., Mamaev A.N., Galstyan G.M. National clinical guidelines for the treatment of hemophilia. [Electronic resource]: http://www.cr.rosminzdrav.ru/#!/recomend/104 (In Russ.)].

7. Valentino L.A., Kempton C.L., Kruse-Jarres R., Mathew P., Meeks S.L., Reiss U.M., International Immune Tolerance Induction Study, Investigators. US Guidelines for immune tolerance induction in patients with haemophilia a and inhibitors. Haemophilia 2015;21:559–67. doi: 10.1111/hae.12730.

8. Collins P., Chalmers E., Alamelu J., Hay C., Liesner R., Makris M., Mathias M., Payne J., Rangarajan S., Richards M., Talks K., Tunstall O., Williams M., Hart D.P. 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;23:654–9. doi: 10.1111/hae.13264.

9. Santagostino E., Young G., Escuriola Ettingshausen C., Jimenez-Yuste V., Carcao M. Inhibitors: a need for eradication? Acta Haematol 2019;141:151–5. doi: 10.1159/000495454.

10. Kreuz W., Escuriola Ettingshausen C., Vdovin V., Zozulya N., Plyushch O., Svirin P., Andreeva T., Bubanska E., Campos M., Benedik-Dolnicar M., Jimenez-Yuste V., Kitanovski L., Klukowska A., Momot A., Osmulskaya N., Prieto M., Salek S.Z., Velasco F., Pavlova A., Oldenburg J., Knaub S., Jansen M., Belyanskaya L., Walter O.; 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;22:87–95. doi: 10.1111/hae.12774.

11. Zozulya N., Vdovin V., Andreeva T., Shiller E., Svirin P. Thirteen years of clinical experience with Immune Tolerance Induction (ITI) using a plasma-derived FVIII containing von Willebrand Factor (pdFVIII/VWF). Research and Practice in Thrombosis and Haemostasis 2019;3(Issue S1):PB0732. doi: 10.1002/rth2.12229.

12. Kreuz W., Escuriola-Ettingshausen C., Auerswald G., Heidemann P., Kemkes-Matthes B., Schneppenheim R., Behnisch W., Kobelt R., Martinez Saguer I., Mentzer D., Gnekow A., Klingebiel T. Immune tolerance induction (ITI) in haemophilia A – patients with inhibitors – the choice of concentrate aff ecting success. Haematologica 2001;86:16–22. doi: 10.1111/hae.12774.

13. Auerswald G., Spranger T., Brackmann H.H. The role of plasmaderived factor VIII/von Willebrand factor concentrates in the treatment of hemophilia A patients. Haematologica 2003;88:EREP05. PMID: 12826531.

14. Brackmann H.H., White II G.C., Berntorp E., Andersen T., Escuriola-Ettingshausen C. Immune tolerance induction: What have we learned over time? Haemophilia 2018;24(Suppl. 3):3–14. doi: 10.1111/hae.13445.

15. Verbruggen B., Novakova I., Wessels H., Boezeman J., van den Berg M., Mauser-Bunschoten E. The Nijmegen modifi cation of the Bethesda assay for factor VIII: C inhibitors: improved specifi city and reliability. Thromb Haemost 1995;73:247–51. PMID: 7792738.

16. Brackmann H.H., Oldenburg J., Schwaab R. Immune tolerance for the treatment of factor VIII inhibitors - twenty years’ 'bonn protocol'. Vox Sang 1996;70:30–5. doi: 10.1111/j.1423-0410.1996.tb01346.x.

17. Di Michele D.M., Hoots W.K., Pipe S.W., Rivard G.E., Santagostino E. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007;13:1–22. doi: 10.1111/j.1365-2516.2007.01497.x.

18. Blanchette V.S., Key N.S., Ljung L.R., Manco-Johnson M.J., van den Berg H.M., Srivastava A., Subcommittee on Factor Viii, Factor I.X., Rare Coagulation Disorders of the, Scientifi c, Standardization Committee of the International Society on, Thrombosis, Hemostasis. Defi nitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014;12:1935–9. doi: 10.1111/jth.12672.

19. Carcao M., Shapiro A., Staber J.M., Hwang N., Druzgal C., Lieuw K., Belletrutti M., Thornburg C.D., Ahuja S.P., Morales-Arias J., Dumont J., Miyasato G., Tsao E., Jain N., Pipe S.W. Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis. Haemophilia 2018;24:245–52. doi: 10.1111/hae.13413.

20. Oldenburg J., Jimenez-Yuste V., Peiro-Jordan R., Aledort L.M., Santagostino E. Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWFcontaining plasma-derived FVIII concentrate. Haemophilia 2014;20:83–91. doi: 10.1111/hae.12263.

21. Hay C.R., Di Michele D.M., International Immune Tolerance S. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012;119:1335–44. doi: 10.1182/blood-2011-08-369132.

22. Mariani G., Ghirardini A., Bellocco R. Immune tolerance in hemophilia-principal results from the International Registry. Report of the factor VIII and IX Subcommittee. Thrombosis and haemostasis 1994;72:155–8. PMID: 7974364.

23. Antun A., Monahan P.E., Manco-Johnson M.J., Callaghan M.U., Kanin M., Knoll C., Carpenter S.L., Davis J.A., Guerrera M.F., Kruse-Jarres R., Ragni M.V., Witmer C., McCracken C.E., Kempton C.L. Inhibitor recurrence after immune tolerance induction: a multicenter retrospective cohort study. J Thromb Haemost 2015;13:1980–8. doi: 10.1111/jth.13143.

24. Escuriola Ettingshausen C., Kreuz W.. A review of immune tolerance induction with Haemate P in haemophilia A. Haemophilia 2014;20:333–9. doi: 10.1111/hae.12288.

25. 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(2):e110–3. doi: 10.1111/hae.13676.

26. Rangarajan S., Jiménez-Yuste V., Santagostino E. Adult haemophilia A patients with inhibitors: successful immune tolerance induction with a single FVIII/VWF product. Haemophilia 2014;20:e414–7. doi: 10.1111/hae.12521.

27. Octapharma AG. Octanate Summary of Product Characteristics, 2015.