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