Successful second ITI with factor IX and combined immunosuppressive therapy

K. Holstein; R. Schneppenheim; J. Schrum; C. Bokemeyer; F. Langer

doi:10.5482/HAMO-14-01-0010

Hämostaseologie, Table of Contents

Hamostaseologie 2014; 34(S 01): S5-S8
DOI: 10.5482/HAMO-14-01-0010

Case report

Schattauer GmbH

Successful second ITI with factor IX and combined immunosuppressive therapy

A patient with severe haemophilia B and recurrence of a factor IX inhibitorErfolgreiche zweite Immuntoleranzinduktion mit Faktor IX und kombinierter Immunsuppression beiEinem Patienten mit schwerer Hämophilie B und Inhibitor-Rezidiv

K. Holstein

¹II. Medizinische Klinik und Poliklinik, Universitätsklinikum Eppendorf, Hamburg, Germany

,

R. Schneppenheim

²Pädiatrische Hämatologie und Onkologie, Universitätsklinikum Eppendorf, Hamburg, Germany

,

J. Schrum

²Pädiatrische Hämatologie und Onkologie, Universitätsklinikum Eppendorf, Hamburg, Germany

,

C. Bokemeyer

¹II. Medizinische Klinik und Poliklinik, Universitätsklinikum Eppendorf, Hamburg, Germany

,

F. Langer

¹II. Medizinische Klinik und Poliklinik, Universitätsklinikum Eppendorf, Hamburg, Germany

› Author Affiliations

Abstract

Summary

Immune tolerance induction (ITI) in patients with haemophilia B and inhibitors may be complicated by anaphylactic reactions and nephrotic syndrome with lower success rates than in haemophilia A (25% vs. 50–90%). According to case reports, immunosuppressive therapy in addition to high doses of factor IX (FIX) appears to be promising. We report an 18-year-old patient with severe haemophilia B and a FIX inhibitor with a maximum titre of 2.6 Bethesda units and allergic skin reactions to FIX infusions. At 5 years of age, this patient already had a FIX inhibitor with allergic reactions to FIX and activated prothrombin complex concentrate. ITI at 11 years of age with high-dose FIX, de-xamethasone, rituximab, mycophenolate mofetil and intravenous immunoglobulins had induced a sustained response until the current presentation.

The patient was restarted on the same ITI regimen with aforementioned immunosup-pressants, which were initiated one week before high-dose FIX. No allergic reactions, nephrotic syndrome or serious infection occurred during ITI. The FIX inhibitor was unde-tectable after five weeks of treatment and remained so until 19 months of follow-up.

Zusammenfassung

Im Vergleich zu Inhibitorpatienten mit Hämo-philie A führt die Immuntoleranzinduktion (ITI) bei Patienten mit Hämophilie B und Inhibitor seltener zum Erfolg und häufiger zu Kompli-kationen wie allergischen Reaktionen oder nephrotischem Syndrom. Nach Fallberichten scheint die zusätzliche Immunsuppression vielversprechend.

Wir berichten über einen 18-jährigen Patien-ten mit schwerer Hämophilie B und einem Faktor IX (FIX)-Inhibitor von maximal 2,6 Be-thesda-Einheiten sowie allergischer Hautre-aktion auf FIX-Infusion. Bereits im Alter von 5 Jahren hatte dieser Patient einen FIX-Inhibitor mit allergischer Reaktion auf FIX und ak-tiviertes Prothrombinkomplex-Konzentrat. Im Alter von 11 Jahren führte eine ITI mit hoch-dosiertem FIX, Rituximab, Dexamethason, Mycofenolat-Mofetil (MMF) und intraven-ösen Immunglobulinen zu einer sieben Jahre anhaltenden Remission.

Aktuell wurde eine erneute ITI mit o. g. immun suppressiver Therapie, die eine Woche vor FIX-Gabe begonnen wurde, durchgeführt, ohne dass es erneut zu Allergie, Infektion oder nephrotischem Syndrom kam. Der FIX-Inhibitor war nach fünf Wochen negativ und die Remission anhaltend über den Beobach-tungszeitraum von 19 Monaten.

Keywords

Haemophilia B inhibitors - immune tolerance induction - immunosuppression

Schlüsselwörter

Hämophilie B - Inhibitor - Immuntoleranz -induktion - Immunsuppression

Full Text

References

References
1 Alexander S, Hopewell S, Hunter S, Chuksey A. Rituximab and desensitation for a patient with severe factor IX-deficiency, inhibitors and history of anaphylaxis. J Pediatr Haematol Oncol 2008; 30: 93-95.
2 Barnes C, Davis A, Furmedge J. et al. Induction of immune tolerance using rituximab in a child with severe haemophilia B with inhibitors and anaphylaxis to factor IX. Haemophilia 2010; 16: 840-841.
3 Batorova A, Morongova A, Tagariello G. et al. Challenges in the management of hemophilia B with inhibitor. Semin Thromb Hemost 2013; 39: 767-771.
4 Beutel K, Hauch H, Rischewski J. et al. ITI with high-dose FIX and combined immunosuppressive therapy in a patient with severe haemophilia B and inhibitor. Hämostaseologie 2009; 29: 155-157.
5 Castaman G, Bonetti E, Messina M. et al. on behalf of Italian Association of Haemophilia Centers. Inhibitors in haemophilia B: the Italian experience. Hamophilia 2013; 19: 686-690.
6 Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibitors in factor IX deficiency: a report of the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia 2009; 15: 1027-1031.
7 Chuansumrit A, Moonsup Y, Sirachainan N. et al. The use of rituximab as an adjuvant for immune tolerance therapy in a hemophilia B boy with inhibitor and anaphylaxis to factor IX concentrate. Blood Coagul Fibrinolysis 2008; 19: 208-211.
8 Collins PW, Chalmers E, Hart DP. et al. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia. 4th ed. UK Haemophilia Centres Doctors Organisation. Br J Haematol. 2013. 160: 153-170.
9 Curry NS, Misbah SA, Giangrande PL, Keeling DM. Achievement of immune tolerance in a patient with haemophilia B and inhibitory antibodies, complicated by an anaphylactoid reaction. Haemophilia 2007; 13: 328-330.
10 Di Michele D, Kroner BL. The North American Immune Tolerance Registry: Practices, outcomes, outcome predictors. Thromb Haemost 2002; 87: 52-57.
11 DiMichele The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy. Haemophilia 2009; 15: 320-328.
12 Ewenstein BM, Takemoto C, Warrier I. et al. Nephrotic syndrome as a complication of immune tolerance in hemophilia B. Blood 1997; 89: 1115-1116.
13 Freiburghaus C, Berntorp E, Ekman M. et al. Tolerance induction using the Malmö treatment model 1982-1995. Haemophilia 1999; 05: 32-39.
14 Gamerman S, Singh AM, Makhija M, Sharathkumar A. Successful eradication of inhibitor in a patient with severe haemophilia B and anaphylaxis to factor IX concentrates: is there a role for Rituximab and desensitization therapy?. Haemophilia 2013; 19: e382-e385.
15 Klarmann D, Martinez ISaguer, Funk MB. et al. Immune tolerance induction with mycophenolatemofetil in two children with haemophilia B and inhibitor. Haemophilia 2008; 14: 44-49.
16 Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factor VIII and IX. Haemophilia 2006; 12 (Suppl. 06) 15-22.
17 Verghese P, Darrow S, Kurth M. et al. Successful management of factor IX inhibitor-associated nephrotic syndrome in a hemophilia B patient. Pediatr Nephrol 2013; 28: 823-826.
18 Warrier I, Ewenstein BM, Koerper MA. et al. Factor IX inhibitors and anaphylaxis in haemophilia B. J Pediatr Hematol Oncol 1997; 19: 23-27.