LISA N BOGGIO, MS, MDRUSH UNIVERSITY MEDICAL CENTER

Inhibitors in Congenital Hemophilia

Faculty Disclosure

CSL Behring – Advisory Board, InvestigatorNovo Nordisk – InvestigatorBaxter – Advisory Board, InvestigatorBayer – InvestigatorBiogen-Idec - Investigator

Educational Objectives

Identify patients at risk for developing factor VIII (FVIII) and factor IX (FIX) inhibitors

Evaluate treatment options for the management of acute bleeding episodes in patients with inhibitors

Discuss therapeutic options for the prevention of bleeding in the surgical and nonsurgical setting

Introduction

Congenital bleeding disorder X-linked

Deficiency of FVIII or factor IX 80%-85% FVIII deficiency (hemophilia A) 60% is severe hemophilia

15% moderate 25% mild

Recurrent Joint Bleeding

©2009 Rush University Medical Center.

Right Left

Inhibitors

Occur in up to 30% of patients with severe (<1% FVIII) hemophilia A 0.9%-7% of those with mild to moderate hemophilia A 3% of those with hemophilia B

Do not increase mortality, but bleeding more difficult to control Uncontrollable hemorrhage, devastating joint disease

and disability

What Is an Inhibitor?

Antibody to FVIII molecule IgG4 subclass

Does not fix complement No immune complex disease

Measured in Bethesda units (BU) Normal, <0.6 BU

Low-responding inhibitor, 0.6-5 BU Transient or persistent

High-responding inhibitor, >5 BU Anamnestic response

Mechanisms of FVIII Inhibitor Action

Scandella D. Vox Sang. 1999;77 (suppl 1):17-20.

FXinteraction

A2A3

FIXa Interactions

C1

C2 Phospholipid interaction

FVIIIa

A1

Bethesda Unit

Kasper CK et al. Thromb Diath Haemorrh. 1975;34:869-872.

BU per mL Plasma

1 BU = amount of inhibitor that inactivates half of FVIII in incubation mixture

Re

sid

ua

l FV

III (

% o

f co

ntr

ol)

100

75

50

25

10

0 0.4 1 2

Genetics of FVIII Inhibitors

Schwaab R et al. Thromb Haemost. 1995;74:1402-1406.Oldenburg J, Pavlova A. Haemophilia. 2006;12(suppl 6):15-22.

Certain molecular abnormalities are highly associated with inhibitor development Large deletions (69% risk) Stop mutation (35% risk) Inversion of intron 22 (39% risk)

Absence of protein may be associated with inhibitor development

Inhibitor Prevalence in Hemophilia A

Oldenburg J, Pavlova A. Haemophilia.2006;12 (suppl 6):15-22.

Multidomain 88%

Largedeletions 41%

Intron 22/1inversions 21%/17%

Single domain 25%

Light chain 40%

Nonsense 31%

Heavy chain 40%

Non–A-Run21%

Smalldeletions

16%Splice site

17%

A-Run3%

C1-C2MissenseNon–C1-C2

10%5%3%

100

75

50

25

0

Inh

ibit

or

Pre

vale

nce

(%

)

Incidence of Inhibitors

Lusher JM et al. N Engl J Med. 1993;328:453-459. Bray G. Ann Hematol. 1994;68(suppl 3):S29-S34.

FVIII: 15%-30%Less pure products may produce lower titer

inhibitor Intermediate purity, 20% Monoclonal products, 16%

Recombinant products, 24% 25%: transient inhibitor 30%: low-responding inhibitor 45%: high-responding inhibitor

Onset of Bleeding and Inhibitors in Patients With Severe Hemophilia

Pollmann H et al. Eur J Pediatr. 1999;158(suppl 3):S166-S170.

<5 BU >5 BU

100

80

60

40

20

0P

atie

nts

(%

)FVIII Exposure (days)

0 50 100 150 200 250

% W

ith

Ble

edin

g

100

80

60

40

20

0

Age (years)0 1 2 3 4 5

BleedingAll patientsJoint

Other

White GC II et al. Am J Hematol. 1982;13:335-342.

Inhibitor Development

Lusher JM et al. N Engl J Med. 1993;328:453-459; Bray G. Ann Hematol. 1994;(suppl 3):S29-S34; McMillan CW et al. Blood. 1988;71:344-348.

Inhibitors usually develop in young patients Median, 20 months for pure products

Present later in life for less pure product 2% incidence for previously treated adults

Inhibitor development occurs in severe hemophilia (<2% FVIII activity) Mild-moderate (2.5% incidence)

Inhibitors develop early after exposure: median, 9 doses

Treatment-Related Risk Factors for Inhibitor

Gouw SC et al. Blood. 2007;109:4648-4654.

CANAL: Retrospective cohort study in 366 patients with severe hemophilia A

Age at first exposure Incidence ↓ from 41% in patients treated within first

month of age to 18% in patients first treated after 18 months

Association largely disappeared after adjustment for treatment intensity

↑ risk associated with surgical procedures and peak treatments

60% lower risk in patients on prophylactic vs on-demand treatment

Risk Factors for Inhibitor Development

Viel KR et al. N Engl J Med. 2009;360:1618-1627; Ragni MV et al. Haemophilia. 2009;15:1074-1082.

• Mismatched recombinant FVIII replacement therapy may be a risk factor for inhibitor development in black patients

• In a prevalent case-control study of 950 patients with hemophilia A enrolled in the Hemophilia Inhibitor Study (HIS), the following are risk factors for inhibitor development– High intensity product exposure– CNS bleeding– African-American race– Lack of missense mutations

Treatment Modalities

Control Bleeding High dose factor replacement Porcine factor VIII Bypassing agents

Prothrombin complex concentrates Recombinant factor VIIa

Eradicate inhibitor Immune tolerance induction

Control Bleeding

High dose factor Only helpful for low titer inhibitors

Bypassing products Porcine factor VIII Activated prothrombin complex concentrate (aPCC) Recombinant factor VIIa (rFVIIa)

Porcine Factor VIII

Morrison et al. Blood 1993: 1513

Not currently availableCan follow factor VIII activityComplications: inhibitor, thrombocytopenia, DIC

Study of 64 patients with acquired inhibitorBleeding control

Excellent 26 Good 24 Fair or poor 14

Average dose 90 U/kg q12 hours

Activated Prothrombin Concentrates

Sjamsoedin LJ et al. N Engl J Med. 1981;305:717-721; Hilgartner MW et al. Blood. 1983;61:36-40.

• More effective than prothrombin concentrates (PCC)

• Dose: 50-75 U/kg, every 12 hours as needed for bleeding resolution

• 36% of patients respond to a single dose of aPCC 50 U/kg within 12 hours

• Doses >200 U/kg/d associated with increased risk for thrombosis

• Complications more prevalent than with PCC– Especially disseminated intravascular coagulation– Rare complications: MI, PE, DVT, allergic reactions

Recombinant Factor VIIa

Young G et al. Haemophilia. 2008;14:287-294; Kavakli K et al. Thromb Haemost. 2006;95:600-605.

Mechanism of action: activation of FIX and FX Thrombin generation (amount and rate) essential

Conventional dosing: 90 µg/kg every two hours until hemostasis achieved Recent studies demonstrated that 270 μg/kg

single dose similar to 90 μg/kg x 3 Gradually increase dosing interval as patient improves

Recombinant FVIIa Dosing

Key NS et al. Thromb Haemost. 1998;80:912-918; Lusher JM. Blood Coag Fibrinolysis. 2000;11 (suppl 1):S45-S49.

Package insert: dose, 90-120 µg/kgClinical studies indicate that an average of

2.2 doses are needed to control a bleed at these doses

Earlier treatment results in better outcome23% of patients respond to a single dose of

rFVIIa 90 µg/kg within 3 hours

aPCC vs rFVIIa

Astermark J et al. Blood. 2007;109:546-551; Young G et al. Haemophilia. 2008;14:287-294.

Each alone is effective in about 70%-90% of bleeds

Two prospective studies compared aPCC and rFVIIa head to head FENOC study (investigator-initiated sponsored by

Baxter)1

F7Haem-2068 (industry-initiated sponsored by Novo Nordisk)2

FENOC Study

FENOC = FEIBA NovoSevenComparative .Astermark J et al. Blood. 2007;109:546-551.

• Randomized, open-label study comparing single dose of aPCC 75-100 U/kg vs 2 doses of rFVIIa 90-120 µg/kg

• Primary end points– Hemostatic efficacy– Pain

• Results – aPCC and rFVIIa appear to exhibit a similar effect on

joint bleeds– Statistical criterion of equivalence not met

FENOC Study: Efficacy Outcomes

No statistically significant differences in the distribution of outcomes by treatment at any time point

Primary endpoint of equivalence not met

Astermark J et al. Blood. 2007;109:546-551.

Frequency

50

40

30

20

10

04836

Effective

Poorly effective

Not effective

Partially effective

aPCCHourTreatment

2 6 12 24 2 6 12 24 36 48

rFVIIa

F7Haem-2068: Study Design

The rFVIIa doses were blinded and placebo-controlled.

First bleedT0 T+3h T+6h

27 patients with

hemophilia+ inhibitors

rFVIIa 270 μg/kg

Placebo

Placebo

rFVIIa 90 μg/kg

rFVIIa 90 μg/kg

rFVIIa 90 μg/kg

aPCC 75 U/kg

rFVIIa 270 μg/kg

Placebo

Placebo

rFVIIa 90 μg/kg

rFVIIa 90 μg/kg

rFVIIa 90 μg/kg

aPCC 75 U/kg

rFVIIa 270 μg/kg

Placebo

Placebo

rFVIIa 90 μg/kg

rFVIIa 90 μg/kg

rFVIIa 90 μg/kg

aPCC 75 U/kg

Second bleedT0 T+3h T+6h

Third bleedT0 T+3h T+6h

Young G et al. Haemophilia. 2008;14:287-294.

F7Haem-2068: Hemostasis Achieved

Key et al, 92%; Kavakli et al, 90.5%; Young G et al. Haemophilia. 2008;14:287-294.

91.7 90.9

0

20

40

60

80

100

Pa

tie

nts

No

t N

ee

din

g R

esc

ue

M

ed

ica

tio

n a

t 9h

(%

)

22/24

rFVIIa270 μg/kg

single dose

rFVIIa3 x 90 μg/kg

multiple doses

20/22

aPCC 75 U/kg

63.6

14/22

*P = 0.032

P = 0.069

F7Haem-2068: Summary

Young G et al. Haemophilia. 2008;14:287-294.

A significant reduction in the use of rescue medications occurred in the single-dose rFVIIa 270-μg/kg group compared with aPCC

A trend to significance was also noted in the multiple-dose rFVIIa arm vs aPCC

This may be biased by the study design

Prophylaxis for Patients With Inhibitors

Potential benefits Reduce incidence of bleeding

Allow for more normal quality of life Resolve target joint Prevent joint damage Improve overall functioning prior to major surgery

rFVIIa Prophylaxis Study:

Konkle BA et al. J Thromb Haemost. 2007;5:1904-1913.

Preprophylaxis Period

PostprophylaxisPeriod

Prophylaxis Period

Mea

n N

o.

of

Ble

eds

per

Mo

nth

7

6

5

4

3

2

1

0

90 µg/kg

270 µg/kg* +35%; +22%

*** ***– 45%; –59%

** ***– 27%; –50%

Bracketed data are the estimated changes (%) in no. of bleeds/month (defined as 28 days) for the 90 µg/kg and 270 µg/kg rFVIIa treatment groups during the prophylaxis or postprophylaxis period as compared with the preprophylaxis period, and during the prophylaxis period as compared with the postprophylaxis period. ***P≤0.001; **P≤0.01; *P≤0.05.

rFVIIa Prophylaxis Quality of Life

Hoots WK et al. Haemophilia. 2008;14:466-475

80

60

40

20

0% P

ati

ents

Wit

h N

o P

rob

lem

s

Mobility

Screening Preprophylaxis End of Prophylaxis

End of Postprophylaxis

EQ-5D dimensionAnxiety Self-carePain Unusual activities

aPCC Prophylaxis Case Series

Joint ROM Bleeding

Author Year N Unit/Wk Better No Δ Worse Reduction

Valentino 2009 6 700 NR NR NR 100%

Leissinger 2007 5 225 1 4 0 78%

Ohga 2007 1 150 NR NR NR 100%

DiMichele 200614

245 3 8 2 53%

Siegmund 2005 1 210 1 0 0 NR

Hilgartner 2003 7 375 2 NR 7 NR

aPCC Prophylaxis: Efficacy

DiMichele D, Négrier C. Haemophilia. 2006;12:352-362.

Ex

celle

nt/

Go

od

Eff

icac

y (

%)

Pre-/Intraoperative Postoperative0

10

20

30

40

50

60

70

80

90

100

Eradicate Inhibitor

CTX = cyclophosphamide; IVIg = intravenous immunoglobulin; EACA = epsilon aminocaproic acid.

Regimen FVIII Other

Bonn 100-150 IU/kg bid aPCC prn

Los Angeles 50 IU/kg/d Steroids

Malmö Keep FVIII >0.40 CTX, IVIg, EACA

van Creveld 25 IU/kg alternate days

Oxford On demand

Immune Tolerance Induction (ITI)

Defining Outcome With ITI

International consensus• Undetectable inhibitor titer <0.6 BU

– By Bethesda or Nijmegen assay

and • Normalized FVIII pharmacokinetics

– Plasma FVIII recovery >66% of expected and

– Half-life >6 h after 72-hour FVIII exposure-free period

Evidence-Based Approach to ITI

ITI failure• Failure to attain the definition of success

within 33 months of uninterrupted ITI• Failure to demonstrate a progressive 20%

reduction in inhibitor titer over each successive 6-month period of uninterrupted ITI, beginning 3 months after initiation to allow for expected anamnesis

Factor IX Inhibitors in Hemophilia B

DiMichele D. Br J Haematol. 2007;138:305-315.

42

Occur in 3% of patients Approximately 80% are high-responding Frequent occurrence of allergic/anaphylactic

reactions prior to or simultaneously with the onset of inhibitors

Antibodies to FIX protein IgG4 and IgG1 subclasses

Hemophilia B: Genetics

Belvini D et al. Haematologica. 2005;90:635-642.

43

• Type of mutations: missense (69.5%), nonsense (14.4%), small deletions (6.4%), splice site (5.9%), large deletions (2.5%), promoter mutations (1.3%)

• Correlation with disease severity– Deletions, nonsense mutations: severe hemophilia B (HB)– Missense mutations: mild HB (88%), moderate HB (90%),

severe HB (59%)

• Mutation type and risk for inhibitor development– Inhibitors in 4.7% with severe HB– Large deletions, nonsense mutations, frameshift

ISTH-SSC International FIX Inhibitor Registry

ISTH-SSC = International Society on Thrombosis and Haemostasis Scientific and Standardization Committee.

Chitlur M et al. Haemophilia. 2009;15:1027-1031.

44

Focus on patients with FIX inhibitor-related complications (severe allergic or anaphylactic reactions)

Median age at inhibitor detection: 19.5 months (9-156)

Median exposure days to FIX replacement therapy: 11 days (2-180)

Mean peak inhibitor titer: 30 BU (1-1156)

Success Rate of ITI Regimens for FVIII Inhibitors

International and North American ITI Studies; reported at Bonn, August 1997.

International

North American Combined

Success 114 (69%) 93 (72%) 207 (70%)

Failure 51 (31%) 37 (28%) 88 (30%)

Prognostic Factors for ITI Host Factors

IL = interleukin; TNFa = tumor necrosis factor-alpha. DiMichele D. J Thromb Haemost. 2007;5(suppl1):143-150.

• No single host-related variable has been shown to be specific and sufficient for predicting anti-FVIII antibody development– Hemophilia severity– FVIII gene mutation (null mutations)– Ethnicity– Family history – IL-10 (odds ratio, 4.4) and TNFa polymorphism

F8 Gene Mutations and ITI Outcome

Rocino A et al. Haematologica. 2006;91:558-561.

Successful ITI 12/17 (70%) of patients with intron 22 inversion 5/7 (75%) of patients with other null mutations

Null mutations did not affect chance of achieving successful ITI

Coppola A et al. J Thromb Haemost. 2009;7:1809-1815.

ITI Success and F8 Mutation

Coppola A et al. J Thromb Haemost. 2009;7:1809-1815.

Low risk

High risk

20

40

60

80

100

Cu

mu

lati

ve IT

I Su

cc

ess

Ra

te (

%)

0

0 5 10 15 20Time (months)

403025 35

Prognostic Factors for ITI

DiMichele D. J Thromb Haemost. 2007;5(suppl 1):143-150.

Pre-ITI titerHistorical peak titerDose of FVIII concentrateFVIII product typeImmune modulationSupportive careBypass therapy bleeding prophylaxis

Influence of Inhibitor Titer

DiMichele D. J Thromb Haemost. 2007;5(suppl 1):143-150.

International ITI Study: Results

Hay and DiMichele. Blood. 2012; 119: 1335

Time to Tolerance

Hay and DiMichele. Blood. 2012; 119: 1533

Intent to Treat Group

Responding Group

ITI Milestones By Treatment Arm

Hay and DiMichele. Blood. 2012; 119: 1533

n LD n HD p

Phase 1: start of ITI to negative titer

29 9.2 (4.9-17.0)

31 4.6 (2.8-13.8)

.017

Phase 2: negative titer to first normal recovery

27 13.6 (8.7-19.0)

23 6.9 (3.5-12.0)

.001

Phase 3: normal recovery to tolerance

24 15.5 (10.8-22.0)

22 10.6 (6.3-20.5)

.096

Work Still Needs To Be Done

Role of gene haplotypes in inhibitor development

Rates of inhibitor development in PUPs with plasma-derived factor (SIPPET)

Inhibitor rates with long-acting factors