Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice

Immune tolerance induction in patients with severehemophilia with inhibitors: expert panel views andrecommendations for clinical practiceGary Benson1, Gunter Auerswald2, Ivo Elezovic3, Thierry Lambert4, Rolf Ljung5, Massimo Morfini6,Eduardo Remor7, Silva Zupancic Salek8

1Northern Ireland Haemophilia Comprehensive Care Centre, Belfast, UK; 2Klinikum Bremen-Mitte, Professor Hess Children’s Hospital, Bremen,

Germany; 3Institute of Haematology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia; 4Hemophilic Care

Center, Bicetre AP-HP Hospital and Faculte de Medecine Paris XI, Paris, France; 5Department of Paediatrics and Malmo Centre for Thrombosis

and Haemostasis, Skane University Hospital, Lund University, Malmo, Sweden; 6Agency for Hemophilia – Reference Center for Inherited Bleeding

Disorders of Tuscany, Department of Emergency and Reception, Azienda Ospedaliero Universitaria Careggi, Florence, Italy; 7Department of

Psychobiology and Health, Faculty of Psychology, Universidad Autonoma de Madrid, Madrid, Spain; 8Division of Haematology, Department of

Internal Medicine, National Haemophilia and Thrombophilia Centre, University Hospital Centre Rebro, Zagreb, Croatia

Patients with congenital hemophilia require lifelong

replacement therapy with a clotting factor concentrate:

factor (F) VIII in hemophilia A and FIX in hemophilia

B (1). However, patients can develop inhibitors to these

exogenous factors, resulting in the most serious treat-

ment-related complication in hemophilia (2, 3). Once

inhibitors have developed, it is more challenging to

achieve hemostasis than in non-inhibitor patients. Fur-

thermore, the presence of inhibitors has a major impact

on patients’ physical functioning, quality of life, morbid-

ity, and mortality (4–6).

In patients with high-titer inhibitors [‡5 Bethesda units

(BU)], immune tolerance induction (ITI) aims to eradi-

cate anamnestic inhibitors and restore normal responses

to replacement therapy. The process of ITI involves reg-

ular infusion of FVIII or FIX concentrate with the goal

Abstract

For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical

response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite

30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert

opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical

decision-making. At the Sixth Zurich Haemophilia Forum, an expert panel considered recent data and con-

sensus to distill key practice points relating to ITI. The panel supported current recommendations that,

where feasible, ITI should be offered early to children and adults (ideally £5 yr of inhibitor detection) when

inhibitor titers are <10 Bethesda units (BU) and should be stopped when successful tolerance is achieved.

For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel con-

sidered that patients with a high bleeding frequency should be offered additional prophylaxis with a

bypassing agent. For patients with hemophilia B, there may be a benefit of genetic testing to indicate the

risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these

patients. For high-titer inhibitor (‡5 BU) hemophilia B patients, the panel advised that bypassing agents

could be offered on demand in addition to ITI. Within future ITI regimens, there may be a role for addi-

tional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI

therapy that offer durable and sustained effects and reduced rates of complications.

Key words immune tolerance induction; hemophilia A; hemophilia B; inhibitors; factor VIII; factor IX

Correspondence Gary Benson, Northern Ireland Haemophilia Comprehensive Care Centre, Belfast City Hospital, Belfast, UK.

Tel: 02890263737; Fax: 02890263736; e-mail: [email protected]

Accepted for publication 9 January 2012 doi:10.1111/j.1600-0609.2012.01754.x

REVIEW ARTICLE

European Journal of Haematology 88 (371–379)

ª 2012 John Wiley & Sons A/S 371

of inducing antigen-specific tolerance. Certain ITI regi-

mens may also include immunosuppressive or immun-

oregulative drugs or employ procedures such as

plasmapheresis and immunoadsorption to help reduce

and remove inhibitors (3, 7–9).

Thirty years’ experience has shown that ITI therapy

has high success rates (7, 8, 10, 11). Between 60% and

80% of patients with hemophilia A given ITI respond to

treatment, and the relapse rate is low [e.g., 15% after

15 yr in the International Immune Tolerance Registry

(IITR)] (11). The success of ITI is lower in hemophilia B

patients with inhibitors, at approximately 13–31%.

A number of recent reviews and consensus recommen-

dations have distilled the available evidence base on ITI

and describe the different regimens and their potential

benefits and drawbacks (2, 3, 7). Nevertheless, there are

several outstanding practical questions relating to the use

of ITI in the clinic, such as when to start and stop ITI

therapy, when ITI is not appropriate, which products

and doses to use, whether ITI therapy should involve

immune modulation or suppression agents, and how to

manage those patients who experience a relapse or only

achieve partial success from ITI.

These issues were discussed by a European hemophilia

expert panel at the Sixth Zurich Haemophilia Forum in

November 2010. Through a discussion of available litera-

ture and guidelines, and patient-case examples, the expert

panel identified a number of practice points pertinent to

clinical use of ITI. This article provides a summary of

the panel’s consensus and recommendations.

Overview of ITI protocols

The panel noted that to date, there have been few ran-

domized studies of ITI therapy. Most data come from

national and international registries, with some addi-

tional information from the recently terminated, random-

ized International ITI study (12).

Registry data suggest that patients with hemophilia A

given ITI achieve high success rates. For example, the

IITR study group reported a 50.9% success rate, the North

American Immune Tolerance Registry (NAITR) study

group 70%, the Spanish registry study group 68%, and the

German Immune Tolerance Registry (GITR) 79% (11, 13–

15). Hemophilia B patients with inhibitors have a relatively

low rate of ITI treatment success. Only 31% of patients

with hemophilia B and inhibitors in the NAITR had suc-

cessful ITI outcomes (13), and in the international FIX

inhibitor registry, only 13% of ITI was successful (16).

Hemophilia A

The panel reported that there are several, different, effec-

tive ITI protocols for patients with hemophilia A

(Table 1) (3, 7, 17–19). The panel recommendations on

choosing the treatments to use within an ITI regimen for

hemophilia A patients with inhibitors are described later

in this article.

Hemophilia B

Patients with hemophilia B have approximately a 10-fold

lower risk of inhibitor development than patients with

severe hemophilia A (3). The lower risk is thought to be

linked to a lower rate of both ‘severe’ gene mutations

(<20% vs. >60%) and non-sense mutations (6% vs.

30%) than is seen in patients with hemophilia A.

Another explanation suggested by the panel is that FIX

has homology to other vitamin K-dependent factors such

as FII, FVII, or FX. Baseline genetic testing after a

hemophilia B diagnosis may help identify mutations

associated with a higher risk of inhibitor development

(20, 21) and was recommended by the panel.

Current options for the management of inhibitors in

hemophilia B are limited, particularly in patients with

the anaphylactoid phenotype (2, 3). When inhibitors do

develop, the panel considered FIX to be an ITI treat-

ment option for low-titer patients (<5 BU). In patients

with a high inhibitor titer (‡5 BU), there was no consen-

sus recommendation for ITI, but it was suggested that it

Table 1 Summary of the main immune tolerance induction protocols

for patients with hemophilia A (3, 7, 17–19)

The Bonn protocol

High-dose regimen that includes a bypassing agent

FVIII �100–150 U ⁄ kg BID

pd-aPCC 50–100 U ⁄ kg BID

Reported success rate, 92–100%

Median time to success, 14 months

The Malmo protocol

High-dose FVIII plus immunomodulation (adsorption and

suppression)

Cyclophosphamide 12–15 mg ⁄ kg IV daily for 2 d, then 2–3 mg ⁄ kg

PO daily for 8–10 d

FVIII to achieve a 40–100% FVIII level, followed by FVIII infusion

every 8–12 h to achieve a 30–80% FVIII level

IVIG 2.5–5 g IV immediately after the first FVIII infusion, followed

by 0.4 g ⁄ kg daily on days 4–8


Median time to success, 1 months

The van Creveld (Dutch) protocol

Lower-dose ⁄ adaptive dosing of FVIII: neutralizing dose and

tolerizing dose

FVIII 25–50 IU ⁄ kg BID for 1–2 wk, then 25 IU ⁄ kg every other day


Median time to success, 1–12 months

BID, twice daily; F, factor; IV, intravenous; IVIG, intravenous immu-

noglobulin; pd-aPCC, plasma-derived activated prothrombin complex

concentrate.

Immune tolerance induction in hemophilia Benson et al.

372 ª 2012 John Wiley & Sons A/S

could be attempted with caution after considering the

chances of success vs. the risk of adverse events.

On-demand bypassing therapy with recombinant activated

FVII (rFVIIa; NovoSeven�; Novo Nordisk, Bagsvaerd,

Denmark) or plasma-derived activated prothrombin

complex concentrate (pd-aPCC; FEIBA�; Baxter, Deer-

field, IL, USA) can also be employed, although the panel

commented that pd-aPCC can be associated with an

anamnestic response and anaphylaxis.

Patient cases and practice points

The panel discussed five patient cases exemplifying the

complexities of and differing approaches to ITI therapy

in patients with inhibitors (Table 2). The optimal ITI

therapy – in terms of when to initiate therapy, how long

to treat, choice and dosing of ITI agents, and strategies

to deal with bleeds, complications, and poor responses to

ITI – needs to be individualized according to patient

characteristics, clinical needs, and risks.

When to start and when to stop ITI

The case examples A–D in Table 2 illustrate that ITI is

an effective option for both children and adults with

inhibitors and highlight that successful responses to ITI

may be achieved across very different timescales, depend-

ing on individual case characteristics and ITI strategies,

with treatment success taking anything from a few

months to as much as 10 yr.

The panel endorsed current consensus to consider start-

ing ITI therapy for all inhibitor patients, particularly chil-

dren, who may benefit and are willing to receive this

treatment (3, 7). Registry data show that adults can be

considered candidates for ITI therapy if they have newly

diagnosed inhibitors or inhibitors that were diagnosed

within the past 5 yr (11, 13), although this was not

reported in all registries, and International and European

guidelines recommend starting ITI therapy when the

patient’s inhibitor titer is <10 BU (2, 3, 7). Adults with

persisting low-responding inhibitors (<5 BU) can also be

considered for ITI therapy when bleeding episodes cannot

be successfully treated with replacement therapy (2).

The panel recommended that when assessing patients

for ITI, clinicians consider aspects of the patient’s condi-

tion and history that may impact on treatment success

and choice of ITI regimen. In children, for example, the

most consistent predictors of successful ITI therapy from

registry data are a pre-ITI inhibitor titer of <10 BU and

a peak historical inhibitor titer of <200 BU (7, 8, 11),

but there are no clear cutoffs.

The panel noted that in patients who do not appear to

achieve a successful outcome, it is difficult to know when

to stop ITI therapy or when to consider that ITI has

become a form of intense prophylaxis.

In keeping with current clinical guidance, the panel

concurred that ITI therapy should be stopped when

patients achieve successful tolerance (Table 3).

Situations when ITI may not be beneficial

The majority of cases of hemophilia with inhibitors

develop in patients before the age of 20 yr when there is

a strong case for trying ITI to restore responsiveness to

factor concentrates. In adulthood, inhibitors typically

occur in three circumstances: in newly diagnosed

patients, in patients who did not receive ITI in child-

hood, and in patients who fail or relapse following ITI.

The panel noted that in cases in which more than 5 yr

have lapsed since the diagnosis of inhibitors, there may

be a risk of poor outcome following ITI (3). While ITI

may have clinical and cost-benefits in patients with

Table 2 Five patient cases exemplifying differing approaches to ITI

and different ITI regimens that may be given to patients with

inhibitors

Patient A

Adult managed 40 yr with hemophilia A, intron 22 inversion

First joint bleed at 5 yr of age and developed inhibitors at the age

of 7. Historical peak inhibitor, 50 BU

No attempts were made to tolerize the patient

Started ITI, at the age of 40, with FVIII 50 IU ⁄ kg given every 48 h

for 5 months, after which the inhibitor titer fell to 1.14 BU ⁄ mL

Currently has an inhibitor titer <0.5 BU

Patient B

Teenager, aged 15 yr, with hemophilia A and inhibitors (peak titer,

6.0 BU)

Treated for 9 yr and 7 months with FVIII 40 IU ⁄ kg alone, given 3·per week (Monday, Wednesday, Friday), with no immune

modulation, in order to reduce inhibitor titers

On ITI. Breakthrough bleeds requiring bypassing agent: 2 ⁄ yr

Patient C

Six-yr-old child with hemophilia A, intron 22 inversion, and inhibitors

(peak titer, 6.0 BU)

Received FVIII 100 IU ⁄ kg daily for 5 yr and 4 months to reduce

inhibitor titer. Standard success outcome achieved, for example,

half-life >6 h, >66% recovery, and inhibitor <0.5 BU

Patient D (brother of Patient C)

Four-yr-old child with hemophilia A, intron 22 inversion, and

inhibitors (peak titer, 17.6 BU)

Given ITI of FVIII 100 IU ⁄ kg daily for 3 yr and 5 months

Inhibitor persistently 5 BU

Patient E

Patient with hemophilia B and inhibitors

ITI regimen involved premedication with antihistamines, and ITI of

high-dose FIX (2 · 125 IU ⁄ kg daily) for 75 d with dexamethasone

and IVIG pulses every 3–4 wk

Regimen was effective in reducing inhibitors within 8 wk, and the

dose of FIX was down-titrated slowly

Patient continued to receive IVIG every 3–4 wk for 1 yr

BU, Bethesda units; F, factor; ITI, immune tolerance induction; IVIG,

intravenous immunoglobulin.

Benson et al. Immune tolerance induction in hemophilia


frequent bleeds that are not satisfactorily controlled by

bypassing agents, the use of ITI in adults who have

failed ITI or have had inhibitors for more than 5 yr may

not be warranted.

Choosing the treatments to use within an ITIregimen

The recent recommendations on ITI identify that there

are no definitive data to support the superiority of one

ITI regimen over another (3). The panel debated this

issue further and offered the following top-line perspec-

tive of the available evidence on different treatment

options for use within ITI.

Factor concentrates: which one and what dose?

When selecting factor concentrates, clinicians can choose

either plasma-derived (pd) or recombinant factor concen-

trate. In the management of hemophilia A, there is a

need to elect to treat with either high- or low-dose FVIII

according to patient needs and risks.

The panel concurred with treatment guidelines which

recommend that ITI therapy should be conducted with

the same concentrate as the one against which antibodies

were developed (2, 3). This should ensure successful tol-

erance induction and reduce the risk of further inhibitor

development to new molecules. Importantly, a recent

study reported that recombinant factor concentrates,

unlike pd products, are not associated with the risk of

transmission of a bloodborne pathogen: non-enveloped

viral DNA was detected in 26% of the pd products

tested, but in none of recombinant products tested (22).

In hemophilia A, the panel also suggested that testing

for inhibitor epitope specificity and ⁄or in vitro cross-reac-

tivity toward different FVIII products may help predict

the individual response to ITI, supporting the choice for

a specific type of FVIII concentrate.

It was noted by the expert panel that evidence from

registries is helpful but may not fully inform factor

choice in the clinic. For example, registry data suggest

ITI success rates of between 25% and 50% with high-

dose antihemophilic factor (Recombinant; Recombinate;

Baxter) and 88% with high-dose human coagulation

FVIII ⁄von Willebrand factor (VWF) complex (Hae-

mate� P; CSL Behring, King of Prussia, PA , USA),

but there are no controlled trial data to delineate

between these agents (10, 23, 24).

As demonstrated in the hemophilia A cases (A–D) in

Table 2, the success of treatment does not always relate

to the choice of FVIII dose. Treatment with high-dose

FVIII was eventually successful in eradicating inhibitors

in two pediatric cases, yet low-dose FVIII was effective

in the adult patient (case A) within 5 months. However,

in case B, a teenage patient, 9 yr of low-dose ITI would

appear to have been a protracted course of ITI, and an

alternative strategy might have allowed the patient to

respond more quickly to therapy.

In addition, the panel reported that high-dose FVIII

does not necessarily lead to more rapid or more effective

outcomes. Registries have provided inconsistent findings

with regard to the success rates for high-dose FVIII

(>200 IU ⁄kg) relative to low dose (<200 IU ⁄kg). In the

Italian ITI registry, relatively high daily doses (100–

200 IU ⁄kg) were used in children, based on the rationale

that the cost of concentrates would be four times greater

in adults. Some registry findings suggest that the early

use of high-dose therapy leads to better rates of inhibitor

eradication, while other registries, such as the NAITR,

report an inverse relationship between factor dose and

outcomes in hemophilia A (13). Adding to the uncertain-

ties over whether to choose low or high doses of factors,

patients (n = 133) in the International ITI study

achieved tolerance earlier and experienced less bleeding

in the high-dose FVIII arm (200 IU ⁄kg daily) than in the

low-dose arm (50 IU ⁄kg, three times weekly), although

Table 3 Accepted definitions of success, partial success, failure, and relapse during and after ITI in patients with hemophilia A with inhibitors,

based on (2, 3, 38)

Success Partial success Failure Relapse

Inhibitor titer <0.6 BU ⁄ mL on ‡2

consecutive monthly

measurements

FVIII recovery ‡66% of expected

values

FVIII half-life ‡6 h after 72-h FVIII

washout, and no anamnestic

response upon subsequent

FVIII exposure

Reduction in inhibitor titer to

£5 BU ⁄ mL

FVIII recovery <66% of predicted

FVIII half-life <6 h after 72-h FVIII

washout associated with clinical

response to FVIII therapy, and no

increase in inhibitor titer >5 BU

over 6 months of on-demand

treatment or 12 months of

prophylaxis

Failure to attain defined success or

partial success within 33 months

of uninterrupted ITI

Failure to demonstrate ongoing inhibitor

titer reduction ‡20% during each interim,

non-overlapping 6-months period of

uninterrupted ITI, beginning 3 months

after initiation to allow for expected

anamnesis (reasonable duration of

unsuccessful ITI: minimum 9 months,

maximum 33 months)

Inhibitor recurrence within

12 months of successful ITI

BU, Bethesda units; F, factor; ITI, immune tolerance induction.



there was no difference between arms in overall ITI suc-

cess rates (12).

The opinion of the panel was thus that the choice of

factor dose for ITI should be based on balancing individ-

ual patient needs against risks.

Does the patient need additional treatments?

Bleeding control during ITI. Bleeding episodes in inhibi-

tor patients are often managed with bypassing agents,

such as rFVIIa or pd-aPCC. The panel suggested that

additional prophylaxis with pd-aPCC may also be benefi-

cial as additional therapy during ITI for patients with a

high bleeding frequency.

The panel noted potential limitations of bypassing

treatment including the high costs of therapy and the

need for frequent injections. In addition, they high-

lighted that pd-aPCC can be associated with an anam-

nestic response and anaphylaxis, and its long infusion

time may be an issue when treating school-age children

at home.

Immune modulation. From their discussions, the panel

concluded that, despite the inclusion of cyclophospha-

mide within the Malmo protocol (Table 1), there is no

clear evidence supporting inclusion of immune-modulat-

ing or immune-suppressing agents, such as rituximab or

mycophenolate, within ITI regimens (25–28). However,

they noted that data from a consecutive cohort of 15

hemophilia A patients with inhibitors treated with ritux-

imab in the United Kingdom highlight some potential

benefits when this agent is used together with FVIII (29).

In clinical practice, the panel recommended that clini-

cians balance the risk of bleeding against the risk of

infection, both of which can be life-threatening in inhibi-

tor patients.

Hemophilia B: additional agents. The hemophilia B

patient case described in Table 2 (Patient E) required

premedication with antihistamines and use of corticoster-

oids to reduce the potential for allergic responses to

FIX, in addition to intravenous immunoglobulin (IVIG)

pulses every 3–4 wk for 1 yr after successful ITI. This

case highlights the importance of tailoring regimens and

titrating treatment to match the patient’s clinical need

and likely reaction to therapies used within ITI regimens.

Recent consensus recommendations note that many cases

of ITI in hemophilia B with inhibitors fail because of

allergic reactions (3).

The panel suggested that in hemophilia B inhibitor

patients with life- or limb-threatening bleeding, in addi-

tion to FIX for ITI, clinicians should consider use of

bypassing agents, plasmapheresis, or immunoadsorption.

They also suggested that there may be a role for corti-

costeroids and IVIG therapy for the optimal manage-

ment of these patients (2, 3, 30).

The burden of ITI therapy: complications andtheir management

Hemophilia A

The panel agreed that ITI therapy can exact a potentially

high clinical burden and carries a considerably increased

risk of infection in those patients using central venous

access devices (3). The randomized International ITI

study provides valuable data on the safety of ITI in

severe hemophilia A. Preliminary findings from 45

patients in the ITI study reported 102 serious adverse

events, 85% of which were judged by the Data Safety

Monitoring Committee to be unrelated to the

study ⁄product. All required hospitalization, for reasons

including 29 bleeding episodes (14 patients) and 44 cathe-

ter infections in 13 patients with central venous access

catheters (31).

In patients undergoing ITI who develop infections

through venous access sites, the panel concurred with

recommendations for standard medical management of

port infection, change and removal of infected ports, and

use of alternative infusion routes via fistula (3). In addi-

tion, bleeds occurring during or as a result of ITI should

be treated on demand (or potentially prophylactically)

with a bypassing agent (32). It was noted that since the

International ITI study, there has been wider use of

bypassing agents as an alternative means of managing

patients with hemophilia and inhibitors.

Hemophilia B

The panel cautioned that in the management of hemo-

philia B with inhibitors, the use of ITI regimens, includ-

ing high-dose FIX as used in the Bonn ITI protocol,

may be accompanied by life-threatening side effects, such

as bleeding, anaphylaxis, and nephrotic syndrome (21).

As cyclophosphamide use has been associated with a risk

of reduced fertility (33), the use of this drug in patients

with hemophilia B presents another potential ITI-related

treatment disadvantage. It was observed by the panel

that the study of agents such as rituximab within ITI

regimens is in its infancy, yet such novel approaches to

inhibitor reduction in hemophilia B may hold some

promise of remission (26).

Psychological burden of ITI

The presence of inhibitors may adversely affect health-

related quality of life (6, 34). However, despite observa-

tional data suggesting that ITI can increase the risk of

complications and burden on patients, the panel advised

that the available literature provides no empirical data

on the impact of ITI on psychological health or well-

being.



The diagnosis of inhibitors can induce feelings of sad-

ness, helplessness, or anger in patients and parents (35,

36), and thus the need for ITI might increase distress. To

counter such concerns, the panel recommended that clini-

cians help patients and their families to find strategies to

cope with an inhibitor diagnosis and need for ITI ther-

apy. This should include provision of a full explanation

of what to expect from ITI therapy, so patients ⁄ families

can take more responsibility for their role in the success

of ITI.

Management of patients with relapse or partialsuccess

Hemophilia A

As described earlier, successful responses to ITI may be

achieved over very different time spans – ranging from a

few months to several years – depending on patient char-

acteristics and circumstances. When patients experience

an increase in their inhibitor level, decisions regarding

changing treatment dose or product can be challenging.

Figure 1 summarizes the panel’s view, based on pub-

lished recommendations (2, 3), on when to stop and

when to reconsider a failing or partially successful ITI

strategy. Current consensus recommendations offer defi-

nitions of partial success, failure, and relapse (Table 3),

which can be used in clinical practice to help guide treat-

ment decision-making (37, 38).

In patients with incomplete or no response to first-line

ITI regimens, the panel concurred with international

consensus recommendations that suggest a number of

strategies in an attempt to achieve a positive ITI out-

come (3) (Fig. 1):l Continue the current ITI regimen or maximize ITI

doses (3, 39).l Switch to a VWF-containing FVIII product (40–47).l In patients with high-risk inhibitors, consider adding

rituximab or another immune-modulating drug, such as

mycophenolate, to the current regimen (28, 48–50).

The panel agreed that the management of patients

who fail ITI despite all attempts continues to pose dilem-

mas. Currently, it is unclear whether FVIII ⁄VWF is a

suitable option in patients who fail initial ITI therapy (2,

3). In this respect, retrospective data on the use of a sin-

gle VWF-containing pd-FVIII product concentrate in

rescue ITI reported that 52% of patients attained partial

or complete success (41). Two prospective ITI studies are

now assessing FVIII ⁄VWF as either rescue therapy in

ITI-experienced patients (RESISTexp) or as first-line ther-

apy in ITI-naive patients (RESISTnaive) (51).

Until there are more data to guide treatment decisions,

the panel advised that it is important to appreciate that

some patients may not be suitable candidates for salvage

ITI, including those who have shown poor compliance,

patients for whom availability and cost of factor concen-

trates is a barrier, adult patients with long-standing

inhibitors, and perhaps also patients who have previously

failed salvage ITI therapy. According to the panel, rather

than salvage ITI, prophylaxis with a bypassing agent

could be considered for these patients.

Figure 1 When to stop and start immune tolerance induction in patients with hemophilia A with inhibitors, based on (2, 3).



Hemophilia B

There are a number of options for patients with hemo-

philia B who fail ITI. If a patient has a low inhibitor

titer (<5 BU), ITI with FIX may be suitable. In patients

with higher inhibitor titers, on-demand rFVIIa (90–

160 lg ⁄kg every 2–3 h) was the preferred choice of the

panel because it lacks anamnestic risk. Other options for

patients failing ITI include pd-aPCC 50–100 IU ⁄kg max-

imal twice daily or secondary prophylaxis with rFVIIa

up to 270 lg ⁄kg (or pd-aPCC 50–100 IU ⁄kg once daily).

Currently, prophylactic use of rFVIIa is approved for

use in hemophilia patients with inhibitors in Argentina,

Australia, New Zealand, and Russia.

Conclusions

The management of hemophilia with inhibitors is chal-

lenging for physicians and patients. Various forms of ITI

offer the means to reduce inhibitor titers and restore

responses to factor concentrates; however, the optimal

regimen and strategy for ITI needs to be decided on a

case-by-case basis. When ITI is delayed to allow the

inhibitor titer to decline, management of bleeds with

rFVIIa is preferred (3).

To help physicians in decision-making, the panel

agreed that further randomized, controlled clinical trials

of ITI therapy are needed. In the meantime, ITI registry

data and clinical experience have provided valuable

insights on how to address some of the challenges facing

physicians.

The expert panel reached the following conclusions

regarding ITI therapy in patients with hemophilia A,

based on their review of the literature and clinical experi-

ences:l ITI therapy should be started when the patient’s

inhibitor titer is <10 BU.l Long-standing inhibitors (>5 yr since detection) are

difficult to treat; thus, therapy should begin as soon

as possible after diagnosis.l Based on ITI study results, and following consider-

ation of patient characteristics, optimal ITI treatment

for high-titer patients could include rFVIII at high

doses, if available.l In patients with a high bleeding frequency, prophy-

laxis with pd-aPCC or rFVIIa may be beneficial.l ITI therapy should be stopped when successful toler-

ance is achieved, and patients should be switched to

prophylaxis.l ITI therapy complications tend to be serious and

associated with infusion risks, particularly infection

caused by the use of central venous access devices.l In patients who do not achieve complete success with

ITI therapy, an alteration of treatment regimen is

advised, such as optimizing the ITI dose, switching to

a VWF-containing FVIII, or, in high-titer patients,

using an immune-modulating drug.l Further work is needed to find an alternative to ITI

therapy with a longer effect and perhaps an alterna-

tive route to intravenous administration.

The panel reached the following conclusions for ITI

therapy in patients with hemophilia B:l Patients should receive baseline genetic testing to

identify large mutations that may be associated with

a higher risk of inhibitor development.l Patients with low-titer inhibitors (<5 BU) should

receive ITI.l There are no consensus recommendations for ITI in

patients with high inhibitor titers (‡5 BU), but ITI

could be attempted with caution. rFVIIa or pd-aPCC

can be given on demand in addition to ITI for the

management of bleeds.l For patients who fail ITI, options include high-dose

(270 lg ⁄kg), on-demand rFVIIa in children (or pd-

aPCC).

Acknowledgements

Gary Benson, Ivo Elezovic, Thierry Lambert, and Silva

Zupancic Salek declare no conflicts of interest for this

manuscript. Gunter Auerswald has received honoraria

and research support, has been a P.I. for Baxter, Bayer,

CSL Behring, and Novo Nordisk, has been a consultant

for Pfizer and Novo Nordisk, and has participated in

Scientific Advisory Boards for Baxter and Novo

Nordisk. Rolf Ljung has during the last 5 yr received

consultatory or speaker’s fees from Bayer, Baxter, Novo

Nordisk, and Octapharma. Massimo Morfini has

received a fee for speaking and for consulting from Novo

Nordisk, CSL Behring, Pfizer, Baxter, and Bayer. Edu-

ardo Remor has received a fee for speaking from Novo

Nordisk Region Europe A ⁄S. He has no interests that

might be perceived as posing a conflict or bias. Financial

support for the Sixth Zurich Haemophilia Forum was

provided by Novo Nordisk Region Europe A ⁄S, who

also financially supported medical writing assistance by

Anne Stirland and Winnie McFadzean of PAREXEL in

compliance with international guidelines for good publi-

cation practice.

References

1. Keeling D, Tait C, Makris M. Guideline on the selection

and use of therapeutic products to treat haemophilia and

other hereditary bleeding disorders. A United Kingdom

Haemophilia Center Doctors’ Organisation (UKHCDO)

guideline approved by the British Committee for Stan-

dards in Haematology. Haemophilia 2008;14:671–84.



2. Astermark J, Morado M, Rocino A, et al. Current Euro-

pean practice in immune tolerance induction therapy in

patients with haemophilia and inhibitors. Haemophilia

2006;12:363–71.

3. DiMichele DM, Hoots WK, Pipe SW, Rivard GE, Santa-

gostino E. International workshop on immune tolerance

induction: consensus recommendations. Haemophilia

2007;13(Suppl 1):1–22.

4. Brown TM, Lee WC, Joshi AV, Pashos CL. Health-

related quality of life and productivity impact in haemo-

philia patients with inhibitors. Haemophilia 2009;15:911–7.

5. Darby SC, Keeling DM, Spooner RJ, Wan Kan S, Gian-

grande PL, Collins PW, Hill FG, Hay CR, UK Haemo-

philia Centre Doctors’ Organisation. The incidence of

factor VIII and factor IX inhibitors in the hemophilia

population of the UK and their effect on subsequent mor-

tality, 1977-99. J Thromb Haemost 2004;2:1047–54.

6. Morfini M, Haya S, Tagariello G, Pollmann H, Quintana

M, Siegmund B, Stieltjes N, Dolan G, Tusell J. European

study on orthopaedic status of haemophilia patients with

inhibitors. Haemophilia 2007;13:606–12.

7. Coppola A, Di Minno MN, Santagostino E. Optimizing

management of immune tolerance induction in patients

with severe haemophilia A and inhibitors: towards evi-

dence-based approaches. Br J Haematol 2010;150:515–28.

8. Dimichele D. The North American Immune Tolerance

Registry: contributions to the thirty-year experience with

immune tolerance therapy. Haemophilia 2009;15:320–8.

9. Freiburghaus C, Berntorp E, Ekman M, Gunnarsson M,

Kjellberg BM, Nilsson IM. Immunoadsorption for

removal of inhibitors: update on treatments in Malmo-

Lund between 1980 and 1995. Haemophilia 1998;4:16–20.

10. Brackmann HH, Oldenburg J, Schwaab R. Immune toler-

ance for the treatment of factor VIII inhibitors – twenty

years’ ‘bonn protocol’. Vox Sang 1996;70(Suppl 1):30–5.

11. Mariani G, Kroner B, Immune Tolerance Study Group

(ITSG). Immune tolerance in hemophilia with factor VIII

inhibitors: predictors of success. Haematologica

2001;86:1186–93.

12. Hay CRM, Goldberg I, Foulkes M, DiMichele DM, on

behalf of the International Immune Tolerance Study

Group. International prospective randomised immune

intolerance (ITI) study: interim analysis of therapeutic effi-

cacy and safety. Haemophilia 2010;16:403–7.

13. DiMichele DM, Kroner BL. The North American

Immune Tolerance Registry: practices, outcomes, outcome

predictors. Thromb Haemost 2002;87:52–7.

14. Haya S, Lopez MF, Aznar JA, Batlle J, Spanish Immune

Tolerance Group. Immune tolerance treatment in haemo-

philia patients with inhibitors: the Spanish Registry.

Haemophilia 2001;7:154–9.

15. Lenk H, ITT Study Group. The German Registry of

immune tolerance treatment in hemophilia – 1999 update.

Haematologica 2000;85(Suppl 10):45–7.

16. Chitlur M, Warrier I, Rajpurkar M, Lusher JM. Inhibi-

tors in factor IX deficiency a report of the ISTH-SSC

international FIX inhibitor registry (1997–2006). Haemo-

philia 2009;15:1027–31.

17. Freiburghaus C, Berntorp E, Ekman M, Gunnarsson M,

Kjellberg B, Nilsson IM. Tolerance induction using the

Malmo treatment model 1982–1995. Haemophilia

1999;5:32–9.

18. Mauser-Bunschoten EP, Roosendaal G, van den Berg

HM. Low-dose immune tolerance therapy: the van creveld

model. Vox Sang 1996;70(Suppl 1):66–7.

19. Oldenburg J, Schwaab R, Brackmann HH. Induction of

immune tolerance in haemophilia A inhibitor patients by

the ‘Bonn Protocol’: predictive parameter for therapy

duration and outcome. Vox Sang 1999;77(Suppl 1):49–54.

20. Green PM, Montandon AJ, Ljung R, Bentley DR, Nils-

son IM, Kling S, Giannelli F. Haemophilia B mutations

in a complete Swedish population sample: a test of new

strategy for the genetic counselling of diseases with high

mutational heterogeneity. Br J Haematol 1991;78:390–7.

21. Warrier I, Ewenstein BM, Koerper MA, et al. Factor IX

inhibitors and anaphylaxis in hemophilia B. J Pediatr

Hematol Oncol 1997;19:23–7.

22. Modrow S, Wenzel JJ, Schimanski S, Schwarzbeck J,

Rothe U, Oldenburg J, Jilg W, Eis-Hubinger AM. Preva-

lence of nucleic acid sequences specific for human parvovi-

ruses, hepatitis A and hepatitis E viruses in coagulation

factor concentrates. Vox Sang 2011;100:351–8.

23. Gruppo RA, Valdez LP, Stout RD. Induction of immune

tolerance in patients with hemophilia A and inhibitors.

Am J Pediatr Hematol Oncol 1992;14:82–7.

24. Rothschild C, Laurian Y, Satre EP, et al. French

previously untreated patients with severe hemophilia A

after exposure to recombinant factor VIII : incidence of

inhibitor and evaluation of immune tolerance. Thromb

Haemost 1998;80:779–83.

25. Aleem A, Saidu A, Abdulkarim H, Al-Diab AR, Al-Sagh-

eer A, Qayum A, Al-Momen AK. Rituximab as a single

agent in the management of adult patients with haemo-

philia A and inhibitors: marked reduction in inhibitor

level and clinical improvement in bleeding but failure to

eradicate the inhibitor. Haemophilia 2009;15:210–6.

26. Alexander S, Hopewell S, Hunter S, Chouksey A.

Rituximab and desensitization for a patient with severe

factor IX deficiency, inhibitors, and history of anaphy-

laxis. J Pediatr Hematol Oncol 2008;30:93–5.

27. Chuansumrit A, Husapadol S, Wongwerawattanakoon P,

Hongeng S, Sirachainan N, Pakakasama S. Rituximab as

an adjuvant therapy to immune tolerance in a haemo-

philia A boy with high inhibitor titre. Haemophilia

2007;13:108–10.

28. Carcao M, St LJ, Poon MC, Grunebaum E, Lacroix S,

Stain AM, Blanchette VS, Rivard GE. Rituximab for

congenital haemophiliacs with inhibitors: a Canadian

experience. Haemophilia 2006;12:7–18.

29. Collins PW, Mathias M, Hanley J, Keeling D, Keenan R,

Laffan M, Perry D, Liesner R, UK Haemophilia Centre

Doctors’ Organisation. Rituximab and immune tolerance



in severe hemophilia A: a consecutive national cohort.

J Thromb Haemost 2009;7:787–94.

30. Beutel K, Hauch H, Rischewski J, Kordes U, Schneppen-

heim J, Schneppenheim R. ITI with high-dose FIX and

combined immunosuppressive therapy in a patient with

severe haemophilia B and inhibitor. Hamostaseologie

2009;29:155–7.

31. DiMichele DM, Hay CR. The international immune toler-

ance study: a multicenter prospective randomized trial in

progress. J Thromb Haemost 2006;4:2271–3.

32. Carcao M, Lambert T. Prophylaxis in haemophilia with

inhibitors: update from international experience. Haemo-

philia 2010;16(Suppl 2):16–23.

33. Meistrich ML. Male gonadal toxicity. Pediatr Blood

Cancer 2009;53:261–6.

34. Remor E, Arranz P, Miller R. Psychosocial impact of

inhibitors on haemophilia patient’s quality of life. In:

Rodriguez-Merchan EC, Lee C, eds. Inhibitors in Patients

with Haemophilia. Oxford: Blackwell Science, 2002:187–92.

35. Gargallo B. Hemophilia treatment. Immune tolerance: the

parent’s perspective. Haematologica 2000;85:81–2.

36. Keilback C. The challenge of inhibitors – one family’s

story. All About Hemophilia: A Guide for Families, 2nd

edn, Chapter 15. Montreal: Canadian Hemophilia Society,

2010:11–3.

37. DiMichele D. Immune tolerance therapy for factor VIII

inhibitors: moving from empiricism to an evidence-based

approach. J Thromb Haemost 2007;5(Suppl 1):143–50.

38. DiMichele DM. Inhibitor treatment in haemophilias A

and B: inhibitor diagnosis. Haemophilia 2006;12(Suppl

6):37–41.

39. Mariani G, Siragusa S, Kroner BL. Immune tolerance

induction in hemophilia A: a review. Semin Thromb

Hemost 2003;29:69–76.

40. Auerswald G, Spranger T, Brackmann HH. The role of

plasma-derived factor VIII ⁄ von Willebrand factor

concentrates in the treatment of hemophilia A patients.

Haematologica 2003;88:EREP05.

41. Kurth M, Puetz J, Kouides P, et al. The use of a single

von Willebrand factor-containing, plasma-derived FVIII

product in hemophilia A immune tolerance induction: the

US experience. J Thromb Haemost 2011;9:2229–34.

42. Berntorp E. Immune tolerance induction: recombinant vs.

human-derived product. Haemophilia 2001;7:109–13.

43. Dasgupta S, Repese Y, Bayry J, et al. VWF protects

FVIII from endocytosis by dendritic cells and subsequent

presentation to immune effectors. Blood 2007;109:610–2.

44. Ettingshausen CE, Kreuz W. Role of von Willebrand

factor in immune tolerance induction. Blood Coagul

Fibrinolysis 2005;16(Suppl 1):S27–31.

45. Kreuz W, Ettingshausen CE, Auerswald G, Saguer IM,

Becker S, Funk M, Heller C, Klarmann D, Klingebiel T,

GTH PUP Study Group. Epidemiology of inhibitors and

current treatment strategies. Haematologica

2003;88:EREP04.

46. Orsini F, Rotschild C, Beurrier P, Faradji A, Goudemand

J, Polack B. Immune tolerance induction with highly puri-

fied plasma-derived factor VIII containing von Willebrand

factor in hemophilia A patients with high-responding

inhibitors. Haematologica 2005;90:1288–90.

47. Yee TT, Williams MD, Hill FG, Lee CA, Pasi KJ.

Absence of inhibitors in previously untreated patients with

severe haemophilia A after exposure to a single intermedi-

ate purity factor VIII product. Thromb Haemost

1997;78:1027–9.

48. Franchini M, Mengoli C, Lippi G, Targher G, Montag-

nana M, Salvagno GL, Zaffanello M, Cruciani M.

Immune tolerance with rituximab in congenital haemo-

philia with inhibitors: a systematic literature review based

on individual patients’ analysis. Haemophilia 2008;14:903–

12.

49. Mateo J, Badell I, Forner R, Borrell M, Tizzano E,

Fontcuberta J. Successful suppression using Rituximab of

a factor VIII inhibitor in a boy with severe congenital

haemophilia: an example of a significant decrease of treat-

ment costs. Thromb Haemost 2006;95:386–7.

50. Mathias M, Khair K, Hann I, Liesner R. Rituximab in

the treatment of alloimmune factor VIII and IX antibod-

ies in two children with severe haemophilia. Br J Haema-

tol 2004;125:366–8.

51. Gringeri A. VWF ⁄FVIII concentrates in high-risk

immunotolerance: the RESIST study. Haemophilia 2007;

13(Suppl 5):73–7.



Documents

Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice