The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Management of Patients with Haemophilia and Inhibitors in Australia

Chris Barnes

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Inhibitors

Following the widespread introduction of recombinant clotting factor concentrates, development of inhibitors is the most significant complication affecting the patients with haemophilia

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Inhibitor Patients In Australia

ABDR data (January 2007)Total of patients with past or current inhibitor

High 74Low 39Transient 3Total 116

Tolerised 31

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Inhibitor Patients In Australia

Approximate incidence of High TitreInhibitors in Australia

Severe haemophilia A 14.0%

Severe haemophilia B 2.6%

High Titre Inhibitor Patients by HTC

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The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Inhibitors

Presence of an inhibitor renders clotting factor replacement ineffective

Management of patients with inhibitors focused on

Management of bleeding episodesEradication of inhibitors (immune tolerance)

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Management of Bleeding Episodes

Bypassing agentsNovo VII

FEIBA

Common to these agentsDifficult to monitor

Risk of thrombosis

Reported as being effective in 80 – 90% of bleeding episodes

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Management of Bleeding Episodes

FEIBA NovoVII comparative study (FENOC)

Cross over non blinded trial of single dose FEIBA versus 2 doses Novo VII 2 hours apart

Primary outcome; patient report of efficacy at 6 hours to be the primary outcome

Astermark J. et al Blood. 109(2):546-51, 2007 Jan 15.

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

FENOC study

ConclusionSimilar effect of two products

Efficacy may be assessed differently

Astermark J. et al Blood. 109(2):546-51, 2007 Jan 15.

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Management of Bleeding Episodes

Non responding patientsSequential FEIBA / NOVO VII (within 6 hours of each dose)

Retrospective report of 5 children unresponsive to single therapy all had bleeding controlled with sequential therapy

Schneiderman, J et al Haemophilia. 2004 Jul;10(4):347-51.

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Management of Bleeding Episodes - Surgery

Major SurgeryFEIBA 75–100 U/kg every 8 h (not to exceed 200 U/kg per 24-h period. Novo VII 90 μg/kg every 2 h on the day of surgery, then every 4 h for 3 days or as long as necessary.

Minor SurgeryFEIBA 75–100 U/kg daily as needed (plus antifibrinolytic for oral surgery) 6 h after the last dose of FEIBArFVIIa 90 μg/kg every 2 h for three doses (plus antifibrinolytic for oral surgery) 6 h after the last dose of FEIBA

Di Paola J et al Haemophilia. 12(6):591-7, 2006 Nov.

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Management of Bleeding Episodes - Prophylaxis

Reports of both successful reduction in bleeding events for patients managed with prophylaxis with FEIBA and Novo VII

Pro-FEIBA studyRandomised cross over trial comparing 6 months on demand versus 6 months three times per week FEIBA @ 85 units / kg per dose

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Immune Tolerance Induction (ITT)

First described in 1977 with numerous protocols subsequently being developed

All rely on frequent exposure to FVIII/FIX +/-immune modulation

According to the results from three large ITT registries, 56–79% of patients ultimately respond to ITT

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

ITT registries

68.4%38SR

69.2%130NAITR

25% 48.7%263 IITR

16%78.6%126GITR

Reported failure rate

Success rate (95% CI)

Number of patients

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

ITT Success

Favourable outcome associated with1. Low titre inhibitor immediately prior to ITT2. Historical low titre inhibitor3. Young age?4. Duration from inhibitor to commencement ITT

UncertainFactor VIII / IX dosageType of clotting factor concentrate

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

ITT – Dose of FVIII

International Immune Tolerance StudyHigh dose versus low dose

World wide study

< 7 years, < 12 months from inhibitor diagnosis

Peak titre 5 – 200 BU

Randomised to 50 U/kg three times per week or 200 U/kg per day

www.itistudy.com

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

ITT - Mabthera

Case reports and small case series of Mabthera (anti CD20 molecule) being effective in the eradication of inhibitors

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

ITT - Mabthera

Potential for immune dysregulation (and lymphoproliferative disorders in later life)

Should not be used as first line ITT (may be helpful in difficult ITT cases)

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Inhibitors in FIX deficiency

Lower frequency (4 – 5%)

Most are high responder inhibitors

Occur after a shorter median period

Unusual clinical featuresAnaphylaxis to FIX containing products

More difficult to ITT

May develop nephrotic syndrome during ITT

The Henry Ekert Haemophilia Treatment CentreRoyal Children’s Hospital Melbourne

Tolerisation Advisory Committee (TAC)

Sub-committee of AHCDOTo provide clinical advice on cases of immune tolerisation for clinicians managing patients with haemophilia and inhibitors in Australia To monitor the ongoing progress of cases of patients with haemophilia and inhibitors within AustraliaTo liaise with the supplying agencies (NBA) regarding upcoming cases immune tolerisation casesEncourage cases of immune tolerance to be included in clinical trialsTelephone conferences will be held between members of the TAC every month and arranged by the Chair of the TAC with assistance from the Project Officer AHCDO.