Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A.

Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.  Emicizumab, ein bispezischer Antikörper, der wie aktivierter Faktor VIII (FVIII) wirkt, ist zugelassen zur Blutungsprophylaxe bei Patienten mit Hämophilie A ohne und mit FVIII-Inhibitor. Aufgrund substanzieller Unterschiede zwischen Emicizumab und FVIII hat die „Ständige Kommission Hämophilie“ der deutschen, österreichischen und schweizerischen Gesellschaft für Thrombose- und Hämostaseforschung (GTH) beschlossen, einen praxisorientierten Leitfaden für den Einsatz von Emicizumab bei Patienten mit Hämophilie A (PWHA) zu entwickeln.  Daten aus der Literatur (systematische Literaturrecherche in PubMed) und persönliche Erfahrungen wurden zusammengetragen und daraus Empfehlungen entwickelt. Diese wurden in der „Ständigen Kommission Hämophilie“ diskutiert und entsprechend revidiert. Die finalen Empfehlungen wurden von allen Autoren mittels Delphi-Abstimmung freigegeben.  Die Empfehlungen beziehen sich auf Patienten ohne und mit FVIII-Inhibitor und beinhalten generelle Aspekte, Patientenaufklärung, Blutungsbehandlung, Operationen, Anwendung von Emicizumab bei zuvor unbehandelten Patienten (PUPs), Patienten mit neudiagnostizierten Inhibitoren und älteren Patienten. Patienten sollten in spezialisierten Behandlungszentren behandelt werden und adäquate Labortests zum Monitoring von Emicizumab, einer Faktor VIII-Substitution oder von FVIII-Inhibitoren sollten zur Verfügung stehen. Erste Erfahrungen mit Protokollen zu Immuntoleranz -Induktion in Kombination mit Emicizumab und die begrenzte Erfahrung mit sehr jungen Kindern wird berichtet. Bis jetzt wurden keine thrombotischen Komplikationen bei der zusätzlichen Blutungsbehandlung mit rFVIIa oder FVIII berichtet. aPCC-Dosierungen von > 100 U/kg über > 24 Stunden müssen vermieden werden, wegen des Risikos von Thrombosen und/oder thrombotischer Mikroangiopathien.  Die Empfehlungen wurden anhand der aktuell verfügbaren Erfahrung entwickelt als Leitfaden für Hämophiliebehandler, die Emicizumab bei PWHA einsetzen. Mit weiterer Erfahrung und neuen Studien ist ein regelmäßiges Überarbeiten der Empfehlungen erforderlich.

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K.H. received honoraria for advisory boards, travel grants and/or speaker fees from Bayer, Biotest, Chugai, CSL Behring, NovoNordisk, Pfizer, Roche, Shire/Takeda and Sobi, and unrestricted research grants from Bayer, CSL Behring and Pfizer. M.A. received honoraria for advisory boards, travel grants, speaker fees and/or research funding from Biogen, Biotest, Novo Nordisk, Roche, Shire and Sobi. C.B. received honoraria for advisory boards, travel grants, research funding and/or speaker fees from Bayer, Biotest, CSL Behring, NovoNordisk, Pfizer, Roche, Shire/Takeda and Sobi. C.B. is investigator in the STASEY Trial (Roche). C.B. and C.K. are principal investigators of the German Pediatric Haemophilia Research Database (GEPHARD). GEPHARD is funded by manufacturers of haemophilia drugs. S.Ha. received honoraria for advisory boards or speaker's fees from Bayer, Baxalta/Shire/Takeda, Biotest, CSL Behring, Novartis, Novo Nordisk, Octapharma and Pfizer, and research grants from Bayer, Shire/Takeda, Biotest, CSL Behring, Novo Nordisk, Octapharma and Pfizer. S.He. received honoraria for advisory boards or speaker's fees from Bayer, Shire/Takeda, CSL Behring, Biotest, NovoNordisk, Pfizer, Roche and Sobi. R.K. has acted as a consultant, received speaker's fees and/or research funding from Bayer Healthcare, Biomarin, Biotest, CSL Behring, Grifols, Octapharma, Pfizer, NovoNordisk, Sanofi, Shire/Takeda, Sobiand Roche/Chugai. C.K. received honoraria for advisory boards, travel grants and/or speaker fees from Bayer, BFSH, Biotest, Bioverativ, CSL Behring, MSD, NovoNordisk, Pfizer, Roche, Shire and Sobi, and unrestricted research grants from the European Union, FP7 IMI, DFG, BMBF, FSKK-Foundation, Abbvie, Bayer, Biotest, Bioverativ, CSL Behring, Gilead, Intersero, Jansen, NovoNordisk, PENTA Foundation, Pfizer, Roche/Chugai, Shire and Sobi. K.K. received grants, travel support and/or lecture fees from Bayer, Biotest, CSL Behring, NovoNordisk, Roche, Sobi, Shire/Takeda and honoraria for advisory board from Shire/Takeda. C.M. has received personal honoraria (consultancy, speaker, chair) from Bayer, Biotest, CSL Behring, NovoNordisk, Roche; fees to the institution for study participation from Bayer, Shire/Takeda, Biotest, CSL Behring, NovoNordisk, Sobi; unrestricted grants to institution from Biotest, CSL Behring; travel support from Bayer, Biotest, CSL Behring, NovoNordisk. J.O. received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or honoraria for consulting, and/or funds for research from Bayer, Biogen Idec, Biotest, Chugai, CSL-Behring, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, Swedish Orphan Biovitrum and Takeda. W.S. has received honoraria and research funding from Biotest, Octapharma, Pfizer, Sobiand Shire/Takeda. W.S. has been a member of expert panels and advisory committees from NovoNordisk, Roche, Sobi and Shire/Takeda. C.W. is an employee at Werlhof-Institut, received honoraria from Bayer, Biotest, CSL-Behring, LFB, Novo Nordisk, Pfizer, Shire and Sobi, and acted as a consultant in advisory boards for Bayer, CSL-Behring, Novo Nordisk, Pfizer, Shire and Sobi. C.E.E has acted as a consultant, received speaker's fees and/or research funding from Bayer Healthcare, Biotest, CSL Behring, Grifols, Octapharma, NovoNordisk, Shire/Takeda, Sobi, Roche/Chugai, Alnylam and Kedrion.