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Chapter 136 Inhibitors in Hemophilias 2031

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inhibitors but, considering their prothrombotic potential, should be required urgent orthopedic surgery. Unique among the ITI regi-
administered cautiously when APCCs are used in large doses. Anti- mens, the Malmö protocol, to lower the inhibitor level, uses immune-
fibrinolytic inhibitors are considered to be safe for use in conjunction modulatory therapies in conjunction with large doses of clotting
with FVIIa. 103 factor concentrate. 137,138
As experience with ITI regimens increased, it became evident that
low-dose FVIII protocols could also induce tolerance. Such regimens
Newly Proposed Tools start with a dose of 25 IU/kg every other day, a 16- to 24-fold lower
dose than those used in high-dose ITI protocols. 139,140
Among the alternative treatments recently developed there is a Because of different ITI treatment protocols and outcomes, a ret-
recombinant porcine FVIII preparation (rpFVIII); a preliminary rospective International Immune Tolerance Registry was established
study demonstrated its efficacy in acquired hemophilia with severe in 1989. The registry eventually collected 314 inhibitor patients
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bleeds. The clinical rationale for this preparation is based on the (>90% high titer) who underwent mostly high-dose ITI treatment
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fact that porcine FVIII has a limited cross-reactivity with inhibitors regimens. The success rate was shown to range from 50% to 60%
to human FVIII. A similar concentrate from plasma had been used over time. Predictors of successful ITI included a low maximum
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for years in the UK and proved efficacious and safe but in the long inhibitor titer (85% success with ≤20 BU titer); low immediate
run anamneses to porcine FVIII were shown to occur. Whether a pre-ITI BU (59% failure rate for >20 BU); higher FVIII dosages
similar situation will occur with rpFVIII is difficult to say, as there (86% success with ≥200 IU/kg/day); age of patient at initiation of
are no data available on the molecular structure of the preparation ITI (60% failure for age >20 years); and shorter time interval between
and the clinical experience is too short. The very short half-life of inhibitor detection and ITI initiation (>70% success for <5-year
rFVIIa prompted the industry to develop new products with a pro- interval). 142,143 Although other registries yielded similar findings, 144–146
longed activity, but their development was halted because of the uncertainty remained as to the optimal daily dose of FVIII, the use of
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occurrence of antibodies to FVIIa. Further, a phase I trial of a new concomitant immunosuppressive/immune-modulating agents, and
formulation of rFVII for subcutaneous injection was performed that the type of clotting factor replacement therapy (plasma-derived versus
showed a prolonged half-life (5.6 vs. 2.7 hours for the intravenous recombinant concentrates). Another major issue was the definition
administration and a good safety profile). 131 of success: stringent criteria (disappearance of the inhibitor, normal
A novel therapeutic approach has recently been reported based on FVIII recovery and half-life) were not always accepted and therefore
the use of a conformational replica of FVIII, Emicizumab. This had an impact on the retrospective outcome evaluations. Although
humanized, bispecific antibody binds both FIX and FX forming a never formally proven, some believe that low- and/or intermediate-
thrombin-generation complex. This complex, in vitro and in vivo, purity factor concentrates containing vWF may be more efficacious
elicits thrombin formation independent of the FVIII levels and, most than recombinant FVIII for successful ITI. 147–150
importantly, the presence of an inhibitor to FVIII. A recent clinical A number of treatment-related elements that may influence ITI
trial showed a strong reduction of spontaneous bleeding in patients outcomes cannot be addressed by registries. These include the number
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with hemophilia A with or without inhibitors. Other advantages of acute bleeds during ITI, use of CVADs, onset of infections during
of this drug are its bioavailability by the subcutaneous route and the ITI, and the use of plasma-derived PCCs or FVIIa to treat bleeds.
long-lasting efficacy; further, aPTT remained short during the study Most of these questions were addressed in a randomized prospective
period. This approach could represent a novel, alternative therapy for multinational ITI trial that compared high- to low-dose ITI regimens,
inhibitor patients. with the decision to use recombinant or a vWF-containing FVIII
replacement product left to the discretion of the treating physi-
cian. 151,152 The results published to date have confirmed that ITI can
Immune Tolerance Therapy eradicate inhibitors in almost 70% of cases, even when very stringent
outcome definitions are applied. Recombinant FVIII preparations
ITI means the frequent, regular, long-term administration of a con- were used in 90% of the enrolled individuals, making it very unlikely
centrate with the goal of inducing tolerance to FVIII or FIX . Today, that plasma-derived vWF-containing concentrates could yield results
ITI is considered the ultimate therapy for a patient with hemophilia superior to the recombinant preparations. The success rates gained
complicated by an inhibitor. Immunologic mechanisms that underlie with high-dose (200 IU/kg daily) or low-dose (50 IU/kg three times
ITI-induced tolerance include peripheral T-cell anergy, inhibition of a week) ITI regimens were similar; however, successful ITI was
B-cell memory, the formation of antiidiotypic antibodies or activity achieved 50% earlier with the high-dose regimen. The low-dose
of suppressor T-cells. regimen was associated with an increased frequency of breakthrough
The goal of the procedure is to eradicate the alloantibodies. Suc- bleeding events during ITI. This safety signal led to premature dis-
cessful ITI enables reinitiating on-demand or prophylactic replace- continuation of the study.
ment therapies for bleeding. A high proportion of patients with a CVAD (41/99, 41%) devel-
Taking into account that about 25% of inhibitors are persistently oped access device infection, but this complication did not affect the
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low titer and/or transient, ITI should be exclusively proposed to those likelihood of success and therefore should not reduce the ITI use
patients who are high responders (anamneses >10 BU), and clearly as an indication; however, this untoward side effect pinpoints the
symptomatic. need for trained and professional device nursing when long-term
The first successful implementation of ITI was accomplished in treatments are needed. Further prospective studies are warranted to
1974 when a child with a high-titer inhibitor (>500 BU) required determine the optimal and most cost-effective dosing regimens for
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emergency reversal of a life-threatening bleed. 133,134 Very large ITI. At any rate, a recent large retrospective study reporting on ITI
doses of FVIII concentrate and APCC were administered and the in patients with freshly diagnosed inhibitors, stressed the importance
hemorrhage was eventually controlled. A serendipitous finding was of starting the procedure as soon as possible, no matter the inhibitor
that the inhibitor titer decreased to almost 40 BU. This was the titer or other risk factors.
first documentation that high-dose FVIII administration could In mild and moderate hemophilia A, inhibitors are less common
decrease inhibitor titers and provided proof of principle for the than in severely affected patients but the change in the bleeding
Bonn protocol, which originally used high doses of FVIII (100 IU/ phenotype may pose significant challenges. ITI role in this clinical
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kg) twice daily. 133,134 Bypass agents are administered as needed, to context is less clear as shown by a UKHCDO study from 1998
treat acute bleeds that occur during ITI. This regimen is continued and a more recent one published in 2012. 155
until the inhibitor disappears, which can take up to a maximum of A number of high-risk and/or ITI-relapsed patients have been
3 years. 134,135 treated with Rituximab, an anti-CD20 monoclonal antibody, with or
The Malmö ITI protocol was developed to induce a more rapid without FVIII concentrate. Success rates have ranged from 33% to
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elimination of an inhibitor in a patient with severe hemophilia B who 57%, although only a few patients exhibited long-lasting