Transcript 90 µg/kg
Inhibitors in Congenital
Hemophilia
LISA N BOGGIO, MS, MD
RUSH UNIVERSITY
MEDICAL CENTER
Faculty Disclosure
CSL Behring – Advisory Board, Investigator
Novo Nordisk – Investigator
Baxter – Advisory Board, Investigator
Bayer – Investigator
Biogen-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
Right
©2009
Rush University Medical Center.
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
FIXa Interactions
A1
A3
A2
C1
C2
FVIIIa
Scandella D. Vox Sang. 1999;77 (suppl 1):17-20.
Phospholipid
interaction
FX
interaction
Residual FVIII (% of control)
Bethesda Unit
1 BU = amount of inhibitor that
inactivates half of FVIII
in incubation mixture
100
75
50
25
10
0
0.4
1
BU per mL Plasma
Kasper CK et al. Thromb Diath Haemorrh. 1975;34:869-872.
2
Genetics of FVIII Inhibitors
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
Schwaab R et al. Thromb Haemost.
1995;74:1402-1406.
Inhibitor Prevalence in Hemophilia A
Inhibitor Prevalence (%)
100
Multidomain
88%
75
50
25
Large
deletions Light chain
40%
41%
Single
domain
25%
Nonsense Intron 22/1
31%
inversions
Heavy chain
21%/17%
40%
0
Oldenburg J, Pavlova A. Haemophilia.2006;12 (suppl 6):15-22.
Non–A-Run
21%
Small
Splice site
deletions
17%
16%
C1-C2
10%
A-Run
Missense 5%
3%
Non–C1-C2 3%
Incidence of Inhibitors
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
Lusher JM et al. N Engl J Med. 1993;328:453-459.
Bray G. Ann Hematol. 1994;68(suppl 3):S29-S34.
Onset of Bleeding and Inhibitors in Patients
With Severe Hemophilia
100
80
80
60
40
Bleeding
Joint
Other
20
0
Patients (%)
% With Bleeding
100
60
40
All patients
>5 BU
<5 BU
20
0
0
1
2
3
4
Age (years)
5
Pollmann H et al. Eur J Pediatr. 1999;158(suppl 3):S166-S170.
0
50
100
150
200
250
FVIII Exposure (days)
White GC II et al. Am J Hematol. 1982;13:335-342.
Inhibitor Development
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
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.
Treatment-Related Risk Factors for Inhibitor
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
Gouw SC et al. Blood. 2007;109:4648-4654.
Risk Factors for Inhibitor Development
• 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
Viel KR et al. N Engl J Med. 2009;360:1618-1627; Ragni MV et al. Haemophilia. 2009;15:1074-1082.
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
Not currently available
Can follow factor VIII activity
Complications: inhibitor, thrombocytopenia, DIC
Study of 64 patients with acquired inhibitor
Bleeding control
Excellent 26
Good 24
Fair or poor 14
Average dose 90 U/kg q12 hours
Morrison et al. Blood 1993: 1513
Activated Prothrombin Concentrates
• 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
Sjamsoedin LJ et al. N Engl J Med. 1981;305:717-721; Hilgartner MW et al. Blood. 1983;61:36-40.
Recombinant Factor VIIa
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
Young G et al. Haemophilia. 2008;14:287-294; Kavakli K et al. Thromb Haemost. 2006;95:600-605.
Recombinant FVIIa Dosing
Package insert: dose, 90-120 µg/kg
Clinical studies indicate that an average of 2.2 doses
are needed to control a bleed at these doses
Earlier treatment results in better outcome
23% of patients respond to a single dose of rFVIIa 90
µg/kg within 3 hours
Key NS et al. Thromb Haemost. 1998;80:912-918; Lusher JM. Blood Coag Fibrinolysis. 2000;11 (suppl 1):S45-S49.
aPCC vs rFVIIa
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
Astermark J et al. Blood. 2007;109:546-551; Young G et al. Haemophilia. 2008;14:287-294.
FENOC Study
• Randomized, open-label study comparing single
dose of aPCC 75-100 U/kg vs 2 doses of rFVIIa 90120 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 = FEIBA NovoSevenComparative .Astermark J et al. Blood. 2007;109:546-551.
FENOC Study: Efficacy Outcomes
50
Frequency
40
30
20
Not effective
Poorly effective
10
0
Partially effective
Effective
2 6 12 24 36 48
aPCC
2 6 12 24 36 48
rFVIIa
Hour
Treatment
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.
F7Haem-2068: Study Design
First bleed
T0 T+3h T+6h
Second bleed
T0 T+3h T+6h
rFVIIa
270 μg/kg
rFVIIa
90 μg/kg
rFVIIa
90 μg/kg
rFVIIa
90 μg/kg
27 patients
with
hemophilia
+ inhibitors
Third bleed
T0 T+3h T+6h
aPCC
75 U/kg
Placebo
Placebo
rFVIIa
270 μg/kg
aPCC
75 U/kg
rFVIIa
90 μg/kg
rFVIIa
90 μg/kg
Placebo
rFVIIa
90 μg/kg
Placebo
rFVIIa
270 μg/kg
rFVIIa
90 μg/kg
Placebo
Placebo
The rFVIIa doses were blinded and placebo-controlled.
Young G et al. Haemophilia. 2008;14:287-294.
rFVIIa
90 μg/kg
rFVIIa
90 μg/kg
aPCC
75 U/kg
Patients Not Needing Rescue
Medication at 9h (%)
F7Haem-2068: Hemostasis Achieved
*P = 0.032
P = 0.069
100
80
91.7
22/24
90.9
20/22
63.6
60
14/22
40
20
0
rFVIIa
270 μg/kg
single dose
rFVIIa
aPCC
3 x 90 μg/kg 75 U/kg
multiple doses
Key et al, 92%; Kavakli et al, 90.5%; Young G et al. Haemophilia. 2008;14:287-294.
F7Haem-2068: Summary
A significant reduction in the use of rescue
medications occurred in the single-dose rFVIIa 270μg/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
Young G et al. Haemophilia. 2008;14:287-294.
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
Mean No. of Bleeds per Month
rFVIIa Prophylaxis Study:
**
***
– 27%; –50%
7
***
***
– 45%; –59%
6
*
+35%; +22%
90 µg/kg
270 µg/kg
5
4
3
2
1
0
Preprophylaxis Prophylaxis Postprophylaxis
Period
Period
Period
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.
Konkle BA et al. J Thromb Haemost. 2007;5:1904-1913.
% Patients With No Problems
rFVIIa Prophylaxis Quality of Life
80
60
40
EQ-5D dimension
Anxiety
Self-care
Pain
Unusual activities
Mobility
20
0
Screening Preprophylaxis
Hoots WK et al. Haemophilia. 2008;14:466-475
End of
End of
Prophylaxis Postprophylaxis
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
2006
1
4
245
3
8
2
53%
Siegmund
2005
1
210
1
0
0
NR
Hilgartner
2003
7
375
2
NR
7
NR
aPCC Prophylaxis: Efficacy
Excellent/Good Efficacy (%)
100
90
80
70
60
50
40
30
20
10
0
Pre-/Intraoperative
DiMichele D, Négrier C. Haemophilia. 2006;12:352-362.
Postoperative
Eradicate Inhibitor
Immune Tolerance Induction (ITI)
Regimen
Bonn
Los Angeles
Malmö
van Creveld
Oxford
FVIII
Other
100-150 IU/kg bid
aPCC prn
50 IU/kg/d
Steroids
Keep FVIII >0.40
CTX, IVIg, EACA
25 IU/kg alternate days
On demand
CTX = cyclophosphamide; IVIg = intravenous immunoglobulin; EACA = epsilon aminocaproic acid.
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
42
Factor IX Inhibitors in Hemophilia B
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
DiMichele D. Br J Haematol. 2007;138:305-315.
43
Hemophilia B: Genetics
• 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
Belvini D et al. Haematologica. 2005;90:635-642.
44
ISTH-SSC International FIX Inhibitor Registry
Focus on patients with FIX inhibitor-related
complications (severe allergic or anaphylactic
reactions)
Median age at inhibitor detection: 19.5 months (9156)
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
North
American
Combined
Success
114 (69%)
93 (72%)
207 (70%)
Failure
51 (31%)
37 (28%)
88 (30%)
International and North American ITI Studies; reported at Bonn, August 1997.
Prognostic Factors for ITI Host Factors
• 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
IL = interleukin; TNFa = tumor necrosis factor-alpha.
DiMichele D. J Thromb Haemost. 2007;5(suppl1):143-150.
F8 Gene Mutations and ITI Outcome
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
Rocino A et al. Haematologica. 2006;91:558-561.
Coppola A et al. J Thromb Haemost. 2009;7:1809-1815.
Cumulative ITI Success Rate (%)
ITI Success and F8 Mutation
100
80
Low risk
60
High risk
40
20
0
0
5
10
15
20
25
Time (months)
Coppola A et al. J Thromb Haemost. 2009;7:1809-1815.
30
35
40
Prognostic Factors for ITI
Pre-ITI titer
Historical peak titer
Dose of FVIII concentrate
FVIII product type
Immune modulation
Supportive care
Bypass therapy bleeding prophylaxis
DiMichele D. J Thromb Haemost. 2007;5(suppl 1):143-150.
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
Responding
Group
Intent to Treat
Group
Hay and DiMichele. Blood. 2012; 119: 1533
ITI Milestones By Treatment Arm
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
Hay and DiMichele. Blood. 2012; 119: 1533
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