manuel carcao md, msc paediatric hematologist associate professor hospital for sick children...

Manuel Carcao MD, MScPaediatric Hematologist

Associate Professor Hospital for Sick Children

University of TorontoToronto, Canada

Prevention of Inhibitors in Hemophilia

How to reduce

inhibitors

Wish to thank the Organizers, the Lebanese Society of Haematology, the

WFH and Bayer for bringing me to Lebanon

Haemophilia at the start of 20th century

A terrible disease with no treatment

Tremendous Progress in Hemophilia Care during the 20th Century

Discovery of Cryoprecipitate

National and International Hemophilia Organizations

Recombinant factors

Hemophilia treatment centers

Virally inactivated safe factor concentrates

“Prophylaxis superior to ondemand therapy”

Discovery of the FVIII and FIX genes

Immune Tolerance Induction

Home Care

Where are we now in Haemophilia Care

• We have safe factor concentrates

But expensive and hence much of the world has little access to these products

Inhibitors continue to occur with no reduction in their incidence

Inhibitors•Antibodies formed against factor concentrates

•Inactivate / neutralize / inhibit the activity of factor

•→ Patients become refractory to conventional factor replacement → need expensive and less effective alternative bypassing agents

Light chainHeavy chain

EconomicClinical

Inhibitor development is a huge problem

Clinical More difficult to treat

bleeds ↑ susceptibility to

Life-threatening bleeds e.g. ICH

Worse joint disease Worse quality of life

Inhibitor development is a huge problem

Economic

Inhibitor development is a huge problem

Bypassing agents$$$

Immune tolerance therapy (to eradicate

inhibitors)$$$$$

Why Do Inhibitors Develop? Boy with Severe Haemophilia A

“Produces no FVIII”

Immune system does not see endogenous FVIII

No immune central

tolerance

Why Do Inhibitors Develop?

Receives exogenous FVIII

Boy with Severe Haemophilia A“Produces no FVIII”

Why Do Inhibitors Develop?

FVIII

Receives exogenous FVIII

Boy with Severe Haemophilia A“Produces no FVIII”

Inhibitors develop early in life (usually)

Median ≈11 Exposure Days; age 1.5 yrs

20-40% in severe

haemophilia A

NON-GENETICPOTENTIALLY MODIFIABLE

GENETIC NON-MODIFIABLE

Multifactorial Risk Factors for Inhibitor Development

GENETIC NON-MODIFIABLE

• Type of Hemophilia: A >>>B• Hemophilia Severity:

Severe (20-40%) > Moderate (5-10%) >Mild (1-5%)• Mutation: Null (25-50%); non-null (<10%)• Ethnicity: 2X higher in African ancestry• Family History of an inhibitor: risk by 2-3X• Inherited polymorphisms for immune-modulating

genes

NON-GENETIC POTENTIALLY MODIFIABLE

• Choice of Factor concentrate: • Unclear if a risk factor

• Intense exposure to factor early on in life: • ↑ risk (2-3X)

• Early start of Prophylaxis: • ↓ risk by 40-60%

1) Ben 2) Nathan

A Case of 2 brothers with

severe hemophilia A

Born 200713 mo of age: Diagnosed

I-22 inversion (SHA)

13 mo 21 mo: On demand (6

Exposures to rFVIII for soft

tissue bleeds)

21 mo of age: Tongue bleed

(5 Consecutive days)

2 wks later: Inhibitor (9 BU)

1) Ben

Intense exposure

Born 200713 mo of age: Diagnosed

I-22 inversion (SHA)

13 mo 21 mo: On demand (6

Exposures to rFVIII for soft

tissue bleeds)

21 mo of age: Tongue bleed

(5 Consecutive days)

2 wks later: Inhibitor (9 BU)

1) Ben

Intense exposure

Bypassing therapy&

ITT X 1.5 yrs&

Port

Born 2009

Diagnosed at birth

Age 8 mo: no exposures

Parents asked - “Is there

anything that we can do to try

to reduce Nathan’s chances of

developing an inhibitor?”

2) Nathan

Interventions to reduce inhibitors

Which factor to use?

How can we expose him in the

least immunogenic way?

Interventions to reduce inhibitors

Which factor to use?

Is there a factor that has less inhibitors?

Plasma derived

(PD) FVIII

Recombinant (r) FVIII

Type of Factor

Plasma derived

(PD) FVIII

Recombinant (r) FVIII

Type of Factor

Some studies suggest lower incidence of

inhibitors

Plasma derived

(PD) FVIII

Recombinant (r) FVIII

Type of Factor

Some studies suggest lower incidence of

inhibitors

But confounding variables

Differences in how Inhibitor surveillance

Different populations - different inhibitor risks

Reporting bias – studies showing low inhibitor

incidence more likely to be reported

Iorio et al. JTH, 2010

• Systematic literature review of inhibitor development in Hemophilia A

Pd-FVIII(1,167 pts)

rFVIII(927 pts)

24 studiesincluded

Iorio et al. JTH, 2010

• Systematic literature review of inhibitor development in Hemophilia A

Inhibitor development

Pd-FVIII(1,167 pts)

rFVIII(927 pts)

P value

HTI and LTI in severe pts

16% (10-23%)

34% (29-40%) <0.001

HTI (≥ 5 BU)in severe pts

9% (4-19%)

18% (14-23%) 0.009

24 studiesincluded

Iorio et al. JTH, 2010

• Systematic literature review of inhibitor development in Hemophilia A

Inhibitors Pd-FVIII(1,167 pts)

rFVIII(927 pts)

P value

All in severe pts

16% (10-23%)

34% (29-40%) <0.001

≥ 5 BU in severe pts

9% (4-19%)

18% (14-23%) 0.009

24 studiesincluded

Most of the difference explained by •Testing frequency

“more recent studies (usually with rFVIII) have tested more frequently and consequently find more inhibitors”

•Follow-up time “if patients are followed for a longer time more inhibitors will be found”

“factor type was not a statistically significant determinant of inhibitor development”

Iorio et al. JTH, 2010

• Systematic literature review of inhibitor development in Hemophilia A

Inhibitors Pd-FVIII(1,167 pts)

rFVIII(927 pts)

P value

All in severe pts

16% (10-23%)

34% (29-40%) <0.001

≥ 5 BU in severe pts

9% (4-19%)

18% (14-23%) 0.009

24 studiesincludedMost of the variability explained by

•Testing frequency “more recent studies have tested more and find more inhibitors”

•Follow-up time

When taken into account factor type not statistical significance

“..not possible to prove or disprove the hypothesis that

there is a higher risk of inhibitor development associated with the

use of recombinant vs. Plasma derived FVIII”

• Systematic literature review of inhibitor developmentSippet Study(Survey of Inhibitor development in plasma-product exposed toddlers)

Is ongoing

(150 of 300 patients already enrolled)

Randomized head to head comparison

Interventions to reduce inhibitors

How can we expose him in the

least immunogenic way

Early prophylaxis &avoidance of intense

exposure

Can introduction of early prophylaxis reduce risk of

inhibitor?

1. Is there an explanation as to why early start of prophylaxis may reduce inhibitor incidence?

2. Is there any evidence that it does?

DangerFVIII Risk

InflammationSevere bleed (ICH)

Surgery

1. Possible explanation “The Danger Signal Theory”

Signal 1 Signal 2

Baseline genetic risk

• Cytokine production• Activation of Antigen Presenting Cells• Activation of T lymphocytes• Antibody prod. by B lymphocytes

Matzinger P. The danger model: a renewed sense of self. Science 2002; 296:301-5.

DangerFVIII

No Danger Signal

FVIII

Risk

Risk

Prophylaxis

InflammationSevere bleed (ICH)

Surgery

1. Possible explanation “The Danger Signal Theory”

Signal 1

Signal 1

Signal 2

Baseline genetic risk

2. EVIDENCE: early introduction of prophylaxis inhibitor risk1. Morado 2005 Spain

2. Santagostino 2005 Italy

3. Gouw 2007 Multi-Europe + Canada

4. Gouw 2007 Netherlands

5. Ragni 2009 USA

6. Kurnik 2010 Germany

7. MacLean 2011 UK

1. Morado 2005 Spain

2. Santagostino 2005 Italy

3. Gouw 2007 Multi-Europe + Canada

4. Gouw 2007 Netherlands

5. Ragni 2009 USA

6. Kurnik 2010 Germany

7. MacLean 2011 UK

Largest

Interventional

2. EVIDENCE: early introduction of prophylaxis inhibitor risk

#3) Gouw et al (CANAL study) (2007)

Retrospective cohort study

366 consecutive severe hemophilia A patients

born 1990-2000

14 centers (13 Europe + 1 Canada)

87 developed inhibitors (24%)Median age at INH. development: 15 mo (14 ED)

Gouw SC et al. Blood. 2007;109(11):4648-4654.

A large study

#3) Gouw et al (CANAL study) (2007)

Main Findings

1) Intense exposure risk of inhibitor

(≥ 5 CED) at 1st exposure= 3.3 X(≥ 5 CED) during 1st 50 ED= 2.0 X

2) Early start of prophylaxis

risk of inhibitor by 60%

Gouw SC et al. Blood. 2007;109(11):4648-4654.

#7) Kurnik et al. (2010) (Bremen & Munich)

New Early Start (Low dose) Prophylaxis

Traditional (High dose) Prophylaxis

Prophylaxis regimen

Start very early25 U/kg 1/wk

No Ports

40–50 U/kg; 3/wkstart at or after 1st joint/severe bleed

# of patients 26 consecutive 30 consecutive

Kurnik K et al. Haemophilia 2010; 16:256-62.

Interventional PILOT Study to explore whether early start of prophylaxis would reduce inhibitor development

Median age at

New Early Start (Low dose) Prophylaxis

Traditional (High dose) Prophylaxis

Start of prophylaxis 10.7 mo 19 mo

EDs before prophylaxis 1 30

Inhibitor incidence

1 / 26 (3.8%) [0 HTI]

Kurnik K et al. Haemophilia 2010; 16:256-62.

Findings#7) Kurnik et al. (2010) (Bremen & Munich)

Median age at

New Early Start (Low dose) Prophylaxis

Traditional (High dose) Prophylaxis

Start of prophylaxis 10.7 mo 19 mo

EDs before prophylaxis 1 30

Inhibitor incidence

1 / 26 (3.8%) [0 HTI]

14 / 30 (47%) [ 8 HTI]

Kurnik K et al. Haemophilia 2010; 16:256-62.

Findings#7) Kurnik et al. (2010) (Bremen & Munich)

Early start of prophylaxis protects against inhibitor development

It permits children to be exposed to FVIII without any danger signals for

inhibitor development

Conclusions from these studies

• At 8 months of age• Parents asked is there

anything that we can do to reduce Nathan’s chances of developing an inhibitor

What happened to Nathan?

• 8 mo: Started on Early Low dose “Prophylaxis” with PD FVIII 25 U/kg every 2 wks - peripheral IV

• 18 mo: to 1 / wk prophylaxis

• 25 mo: to 2 / wk prophylaxis

• Now 34 mo: Has had > 75 ED No Inhibitor

What happened to Nathan?

• Why did he not get an inhibitor?

–Choice of Factor?

–Early Prophylaxis?

–Luck?

We will never know from one case alone!

What happened to Nathan?

Summary1.Inhibitor Development is a major

problem

2.Reducing inhibitors is critical

3.Non genetic inhibitor risk factors are important and may be modifiable

4.We must try to reduce inhibitor development

Thank-you for your attention

Thank-you for the kind invitation to come to Beirut

Do I believe that exposing children with severe hemophilia A at very young ages to factor in the least

immunogenic way will result in less inhibitors?

YES

Multiple PD FVIII

Single PD FVIII

Single rFVIII

Inhibitor Risk in PUPs: High titer (≥5 BU) only

Wight J, Paisley S. Haemophilia 2003;9:318-35

Multiple PD FVIII

Single PD FVIII

Single rFVIII

Inhibitor Risk in PUPs: High titer (≥5 BU) only

Wight J, Paisley S. Haemophilia 2003;9:318-35

No difference

• Often very small studies with few patients

(some as low as n= 19 pts)

• Mostly retrospective

• Reporting bias – studies showing low

incidence more likely to be reported

Single PD FVIII studies

Larger StudiesGoudemand J. et al. Blood

2006;107:46-51

148 patients followed in FranceType of factor Pts % Inhibitor % HTI

rFVIII (Recombinate & Kogenate) 62 32% 15%FVIII-LFB (VWF containing-pdFVIII) 86 10% 5%

P value - adjusted for race, family history & age at 1st

exposure0.049 NS

Other recent large studies

Chalmers et al. Haemophilia 2007

348 PUPS with severe hemophilia A

Gouw et al. (CANAL) Blood 2007

366 PUPS with severe hemophilia A

Other recent large studies

Chalmers et al. Haemophilia 2007

348 PUPS with severe hemophilia A

Gouw et al. (CANAL) Blood 2007

366 PUPS with severe hemophilia A

No statistically increased

risk of inhibitors with rFVIII

vs. Pd FVIII

(after adjusting for other

risk factors)

Type of Factor

Recombinant (r) FVIII

Plasma derived (PD) FVIII

40 separate slides – must reduce by 10

Written by David Lillicrap June 11, 2010

• After studying FVIII Ab generation for the past several years in many hemophilic mice, the lessons we have learnt are - most severe hemophiliacs will not have central tolerance for FVIII - ie. they don't make FVIII and thus won't delete FVIII-specific T cells or generate Tregs in the thymus. Because of this, you need to provide these patients with FVIII so that they can generate peripheral tolerance to the protein. This requires controlled "non-inflammatory" presentation of FVIII by APCs to FVIII-specific CD4+ cells that will either die by apoptosis, become anergic (functionally useless) or become FVIII-specific Tregs. It's the generation, expansion and maintenance of this latter T cell population that likely keeps us from generating FVIII inhibitors. You are much more likely to achieve this in a controlled low dose prophylaxis setting than at the time of a surgical intervention where coexistent high doses of FVIII and inflammation may favor immunogenicity and FVIII-specific T effector cell generation.

#1) Morado et al (2005)10 year retrospective review

50 PUPS with Severe Hemophilia A- 19 treated on-demand - 31 treated on prophylaxis

Main findings

15/19 PUPS treated on demand inhibitorsMean age at inhibitor = 21 mo

0/31 PUPS placed on Prophylaxis inhibitors Mean age at start of prophylaxis = 34 mo

Morado M et al. Haemophilia. 2005;11(2):79-83.

#1) Morado et al (2005)10 year retrospective review

50 PUPS with Severe Hemophilia A- 19 treated on-demand - 31 treated on prophylaxis

Main findings

15/19 PUPS treated on demand inhibitorsMean age at inhibitor = 21 mo

0/31 PUPS placed on Prophylaxis inhibitors Mean age at start of prophylaxis = 34 mo

Morado M et al. Haemophilia. 2005;11(2):79-83.

Problem with study:

By time pts were started on prophylaxis those who were destined to develop inhibitors had already developed them.

Analysis flawed!

#3) Gouw et al (CANAL study) (2007)

Main Findings of the Canal Study

Intense therapy at 1st exposure = 3.3 fold risk

Intense therapy during first 50 ED = 2 fold risk

Early start of prophylaxis (min. 1/wk)

risk of inhibitor by 60%

Gouw SC et al. Blood. 2007;109(11):4648-4654.

Analysis:

Cox Regression (Kaplan Meier type) analysis done

To adjust for time varying issues of when prophylaxis is commenced in relation to exposure days

Much larger study with better analysis!

Inhibitor Risk in PUPs: All Inhibitors

Wight J, Paisley S. Haemophilia 2003;9:318-35

Multiple PD FVIII

Single PD FVIII

Single rFVIII

#2) Santagostino E et al. (2005)

Case-control study

108 PUPS with severe hemophilia A60 inhibitor POS. patients (Cases)48 inhibitor NEG. patients (Controls)

Main FindingsCases: Only 7/60 (12%) had been placed on prophylaxis

Controls: Most [34/48 (71%)] had been placed on prophylaxis

Santagostino E et al. Br J Haematol. 2005;130(3):422-427

#2) Santagostino E et al. (2005)

Main problem

Median age at inhibitor detection: 23 mo

Median age at start of prophylaxis: 35 mo

Santagostino E et al. Br J Haematol. 2005;130(3):422-427

Similar problems to Morado study By time pts were started on prophylaxis those who were destined to develop inhibitors had already developed them.

Sub-analysis helped but did not completely resolve statistical issues

#2) Santagostino E et al. (2005)

Main problem

Median age at inhibitor detection: 23 mo

Median age at start of prophylaxis: 35 mo

Santagostino E et al. Br J Haematol. 2005;130(3):422-427

Similar problems to Morado study By time pts were started on prophylaxis those who were destined to develop inhibitors had already developed them.

Sub-analysis helped but did not completely resolve the analytical issues

Conclusion: Pts who started prophylaxis had an 80% lower incidence of inhibitors

#4) Gouw et al (2007) [4 PUP studies]Retrospective cohort study of 4 rFVIII registration studies involving 236 PUPS (FVIII <2%)

67 (28%) developed inhibitors (median 10 ED; 16 mo)

Main findingsIntense exposure risk of inhibitor

(≥ 5 CED) at 1st exposure= 2.1 X(≥ 5 CED) during 1st 50 ED= 1.6 X

Unable to comment on effect of prophylaxis as few pts on prophylaxis

Gouw SC et al. JTH 2007; 5: 1383-90.

#5) Ragni et al (2009)Case–control study (single center – USA) 77 PUPS (severe hemophilia A)

20 Inhibitor POS.57 age-matched Inhibitor NEG. controls

Main finding

Patients who developed inhibitors had received (prior to inhibitor development) much greater intensity exposure (p < 0.005)

Ragni M et al. Haemophilia 2009; 15: 1074-82.

#5) Ragni et al (2009)

“Given the potential benefits of prophylaxis

in reducing inhibitor formation … it is

critical to direct efforts at early prevention

through early institution of prophylaxis”

Ragni M et al. Haemophilia 2009; 15: 1074-82.

#6) Maclean et al (2011)

Retrospective case control study from 13 UK haemophilia centers of 156 PUPS born (1982-2007)

78 inhibitor POS.78 inhibitor NEG. [age & center matched controls]

All Followed for at least 50 ED

Maclean P et al. Haemophilia 2011; 17:282-7.

Main Findings1) High intensity treatment during 1st 50 ED

inhibitor risk

≥ 5 CED: 2.7 fold (CI: 1.4–5.4)

≥ 10 CED: 5.5 fold (CI: 1.5–20) (e.g. ICH )

2) To few patients started prophylaxis to find a statistically significant effect of prophylaxis

Maclean P et al. Haemophilia 2011; 17:282-7.

#6) Maclean et al (2011)

Why Do Inhibitors Develop?

Severe hemophilia(20-30%)

Mild / Mod Hemophilia (3-10%)

No endogenous factorSome endogenous factor

(conformationally altered)

Entire Exogenous factor

= foreign protein

Small part of exogenous factor

= foreign protein

A Population map of the world

The world is changing

YES YES

YES YESWoof

YES YESWoof

Thanks for your attention!

Clinical Evidence for decreased inhibitors with Pd-FVIII

(% developing inhibitors)

Goudemand et al, Blood 2006: PUPS with

SHA (France)

Chalmers et al, Haemophilia 2007:

PUPS with SHA (UK)

rFVIII 32% (26 / 86 pts) 27% (46 / 172 pts)

Pd VWF-FVIII 10% (6 / 62 pts) 14% (18 / 132 pts)

Both retrospective studies

Clinical Evidence for decreased inhibitors with Pd-FVIII

(% developing inhibitors)

Goudemand et al, Blood 2006: PUPS with

SHA (France)

Chalmers et al, Haemophilia 2007:

PUPS with SHA (UK)

rFVIII 32% (26 / 86 pts) 27% (46 / 172 pts)

Pd VWF-FVIII 10% (6 / 62 pts) 14% (18 / 132 pts)

Both retrospective studies

No randomized head to

head comparison

(Sippet study)

Overall incidence of Inhibitor development (PUP studies)

1998 1997 1998 1998 2001Gruppo Lusher Rothschild Lusher Courter

Product Rec Kog Rec Kog Refacto

# of pts 72 64 52 97 92

Incidence 31% 28% 29% 28% 35%

Rec = Recombinate Kog = KogenateNo statistical difference in inhibitor incidence

Specific FVIII products

•A few PD FVIII products reported to be associated with high incidence of inhibitors–Belgium –NetherlandsModifications in the manufacturing +/or viral inactivating process led to Neo-antigen development

•A few PD FVIII reported to be associated with a low incidence of inhibitors

Product (Study Period); Author (Country), date of publication

# of pts

% Inhibitor

% with HTI

Octanate (00-06); Klukowska (Poland), 06 24 8% 8%

Emoclot (87-03); Gringeri (Italy), 06 71 10% 7%FVIII-LFB (88-01); Goudemand (France), 05 86 10% 6%

OctaVI (89-99); Glomstein (Norway), unpub. 19 11% n.a.

Fandhi (97-99); Rokicka-Milewska (Poland), 00 19 5% n.a.

8Y (85-04); Brown (UK), unpub. 74 4% 3%

OVERALL 269 8% 6%

Information courtesy of Dr A. Gringeri, Sept 06

European studies on Inhibitor development in SHA PUPs treated with pdFVIII

Product (Study Period); Author (Country), date of publication

# of pts

% Inhibitor

% with HTI

Octanate (00-06); Klukowska (Poland), 06 24 8% 8%

Emoclot (87-03); Gringeri (Italy), 06 71 10% 7%FVIII-LFB (88-01); Goudemand (France), 05 86 10% 6%

OctaVI (89-99); Glomstein (Norway), unpub. 19 11% n.a.

Fandhi (97-99); Rokicka-Milewska (Poland), 00 19 5% n.a.

8Y (85-04); Brown (UK), unpub. 74 4% 3%

OVERALL 269 8% 6%

Information courtesy of Dr A. Gringeri, Sept 06

Reporting bias

European studies on Inhibitor development in SHA PUPs treated with pdFVIII

Product (Study Period); Author (Country), date of publication

# of pts

% Inhibitor

% with HTI

Octanate (00-06); Klukowska (Poland), 06 24 8% 8%

Emoclot (87-03); Gringeri (Italy), 06 71 10% 7%FVIII-LFB (88-01); Goudemand (France), 05 86 10% 6%

OctaVI (89-99); Glomstein (Norway), unpub. 19 11% n.a.

Fandhi (97-99); Rokicka-Milewska (Poland), 00 19 5% n.a.

8Y (85-04); Brown (UK), unpub. 74 4% 3%

OVERALL 269 8% 6%

European studies on Inhibitor development in SHA PUPs treated with pdFVIII

Information courtesy of Dr A. Gringeri, Sept 06

Overall conclusions regarding Type of and Inhibitor risk

1. No consensus as to whether rFVIII is more immunogenic than pd FVIII

2. Some pd FVIII may be less immunogenic - Some much more immunogenic

3. No difference in inhibitor risk between rFVIII products

4. There is bias in reporting

Recent experiences of pdFVIII vs. rFVIII

• Shirahata et al (2011; Hemophilia)• Japan experience of inhibitor development in

153 pts (PUPS) with severe hemophilia A• Inhibitor incidence

pdFVIII rFVIII29.7% 25%

No difference

Recent experiences of pdFVIII vs. rFVIII

• Strauss et al (2011; Hemophilia)• Israeli experience of inhibitor development in

292 pts (PUPS) with severe hemophilia A• Inhibitor incidence

pdFVIII rFVIIIAll inhibitors 8.8% (22/249) 32.5% (14/43)

HTI 8.8% (22/249) 28% (12/43)

Not clear that all severe All severe

ICH is a risk factor for inhibitors

• Strauss et al (2011; Hemophilia)• Israeli experience of inhibitor

development in 292 pts (PUPS) with severe hemophilia A

• 9/11 patients who suffered an ICH developed an inhibitor