Inhibitors in Congenital Hemophilia
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Transcript of Inhibitors in Congenital Hemophilia
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