6 Inhibitors
1 Introduction
The development of inhibitory antibodies (inhibitors) is a serious complication of factor replacement therapy occuring in about 30% of patients with severe hemophilia A (HA) and 10-15% of patients with severe hemophilia B (HB).
Genetic and, for HA, non-genetic factors like intensity of treatment and choice of product have been identified as risk factors.
In severe HA, inhibitor development happens most likely during the first 50 FVIII exposures; in median at 11 exposure days (EDs). Regular screening is recommended, e.g. initially every 5th ED and/or after the treatment of bleeding with FVIII-concentrates.
The presence of an inhibitor is confirmed using the “Bethesda inhibitor assay” with Nijmegen modifications and classified according to the peak titer into “high”titre (>5 BU/mL) or “low titre” (<5 BU/mL).
If an inhibitor is detected, repeated measurements are recommended since some inhibitors can be transient.
In patients in HA with low-titre inhibitors, it is recommended to continue earlier prophylactic regimen and not start ITI immediately as early start with ITI can lead to the the development of high-titre inhibitors.
In hemophilia B, inhibitor development often occurs together with allergic reactions and after re-exposure to FIX there is possiblility of development of nephrotic syndrome. FIX treatment cannot be continued in these cases.
rFVIIa for the treatment of acute bleeds can be used in HA and HB inhibitor patients.
Today, aPCC is used rarely, mostly as second line treatment since it should not be combined with emicizumab and can cause allergic reactions due to containing FIX in HB.
The clinician will have to decide on a strategy for the acute treatment of bleeds, prophylactic treatment for the prevention of bleeds, and immune tolerance induction (ITI).
The development of inhibitory antibodies (inhibitors) is a serious complication of factor replacement therapy. The antibodies bind to factor VIII or IX and neutralize (inhibit) the hemostatic efficacy. The incidence of inhibitors in severe hemophilia A is about 30% [1], while patients with a moderate or mild HA develop inhibitors less frequently [2]. In HB, inhibitors are rarely seen in patients with non-severe disease, but 10-15% inhibitor rates have been reported in severe HB [3,4]. The formation of inhibitors is a complex immunological process involving both genetic and non-genetic factors [5]. For HA, non-genetic factors like the intensity of the treatment with high doses of FVIII and the type of concentrate have been reported as risk factors for inhibitor development [6,7]. In a randomized study, plasma-derived factor VIII was associated with lower incidence of inhibitor development but this finding has not been confirmed in large cohort-studies [8,9].
In severe HA, inhibitor development happens most likely during the first FVIII exposures; in median at about 11 exposure days (EDs), with most inhibitors developing before 50 ED [10]. Regular screening is recommended, e.g. every 5th ED and/or after a surgical procedure and the treatment of bleeding with FVIII.
The decision on which product type to use in previously untreated patients, should be based on safety, efficacy and availability of the product in an open dialogue with the family. Today, extended half-life (EHL) products are widely used with clinically similar inhibitor profiles [8,11].
The presence of an inhibitor is confirmed using the “Bethesda inhibitor assay” with Nijmegen modifications and classified according to the peak titer into high-titre (>5 BU/mL) or low-titre inhibitor (<5 BU/mL). The highest titre the patient ever recorded – the historical peak titre -defines if the patient has a low-responder or high-responder inhibitor. If an inhibitor is detected, repeated measurements are recommended since some inhibitors can be transient.
In patients with HA and newly detected low-titre inhibitors, it is recommended to continue earlier prophylactic regimen rather than the direct initiation of ITI since this can lead to the development of high-titre inhibitors, if the bleeding pattern allows [12]. In HB, inhibitor development often occurs together with allergic reactions and may lead to nephrotic syndrome. FIX treatment cannot be continued in these cases.
Both HA and HB inhibitor patients can present with a high bleeding frequency and the clinician will have to decide on a strategy for the acute treatment of bleeds, prophylactic treatment, and immune tolerance induction (ITI).
ITI means regular infusions of factor concentrates (factor VIII or IX) for weeks to years with or without immune-modulating drugs to achieve tolerization. While there are several studies on ITI in HA, less is known about the use of ITI in HB.
While inhibitory antibodies in HA at a low titre could be overcome by saturating levels of the deficient factor, acute severe bleedings in patients with high titer inhibitors need to be treated with “bypassing agents”. These agents will not be affected by the factor VIII or IX inactivating antibodies but induce hemostasis. There are two bypassing agents currently available in Nordic countries: recombinant coagulation factor VIIa (rFVIIa)- which is first line therapy in patients with HA on emicizumab and HB - and plasma-derived activated prothrombin complex concentrate (aPCC), which should not be routinely be used in combination with emicizumab or HB patients since it contains FIX. These agents are also used in inhibitor patients for surgical procedures. For prophylaxis, emicizumab administered subcutaneously is now available, and has been effectively used for patients with HA.
Until some years ago, the main treatment option for inhibitor patients was the eradication of the inhibitor by immune tolerance induction (ITI) therapy. However, since emicizumab has become available, and effectively reduces the bleeding tendency also in inhibitor patients, the use of ITI has become more individualized due to the need for venous access, costs and uncertainties of keeping tolerance. However, ITI should be discussed with the patient and the family, since it is by now the only way of eradicating the immune response and making the patient eligible for all future treatment options. However, opinions on this matter are diverse and have to be discussed regularly within the heamophilia community [13].
2 Prevention of bleeds
2.1 Recommendations for HA
Inhibitory antibodies at a low titer can be overcome by saturating levels of FVIII by continuing regular prophylaxis, but regular measurements for recovery and inhibitor titre are recommended.
Emicizumab subcutaneously (3 mg/kg weekly for 4 weeks followed by 1.5 mg/kg weekly or 3 mg/kg every 2nd week with the aim to use whole vials and possibility to adjust the interval) should be considered as a first-line prophylactic option in patients with HA and inhibitors where FVIII prophylaxis is not sufficient and can be used both during ITI and in the case of ITI failures.
Emicizumab should not routinely be combined with aPCC and always at doses below 100 U/kg and day due to the risk of thrombotic microangiopathy (TMA) and thromboembolic events.
The second-line option for prophylaxis in HA is rFVIIa (90 to 270 µg/kg) once daily intravenously.
A hemostatic improvement should be assessed as a decrease of the number of significant bleeds with ≥ 50%.
2.2 Recommendations for HB
First-line option for prophylaxis in hemophilia B is rFVIIa (90 to 270 µg/kg) once daily intravenously.
Second-line option is aPCC (dosing above). aPCC contains FIX and cannot be given to patients with allergic reactions to FIX or nephrotic syndrome.
Re-balancing therapies as concizumab or fitusiran or Serpin PC are part of ongoing studies for inhibitor patients with HA or HB and no recommendation can be given at this state. However, compassionate use of these therapies could be discussed as prophylactic regimen in HB patients with inhibitors and severe bleeding phenotype.
For both, HA and HB, patients with low-responding inhibitors, prophylaxis with the deficient factor can be used to prevent against bleeds as well as potentially induce, tolerance. However, the bleeding pattern, recovery and inhibitor titre has to be followed closely. Also, in HB the risk for allergic reactions and nephrotic syndrome is apparent: in a recent Nordic study, 92% of patients developed allergic reactions and 25% a nephrotic syndrome [14]; FIX cannot be used in these patients.
While some inhibitors are transient or persistent at a low titre, most inhibitors in HA – in about 2/3 of cases - rise and become a high-titre inhibitor [5].
For the prevention of bleeds, emicizumab with subcutaneous administration can be used in patients with HA and inhibitors at all ages, and it offers good bleed protection in HA patients with inhibitors. Emicizumab, is a humanized antibody that bridges activated FIX and FX, mimicking FVIII function. Several studies on emicizumab in various patient groups (HAVEN studies) have been performed. In the HAVEN study on HA patients with inhibitors, a total of 169 HA patients with inhibitors, 12 years of age or older, were enrolled in the pivotal study. Patients were given 3 mg/kg once-weekly for 4 weeks followed by 1.5 mg/kg weekly thereafter. Patients with emicizumab prophylaxis (s.c) had 87% lower bleeding rate (treated bleeds) than patients with no prophylaxis (p<0.001). The ABR was 2.9 events in prophylaxis group versus 23.3 events in participants with no prophylaxis. Also, compared to previous prophylaxis with bypassing agents, the bleeding rate was significantly lower [15]. TMA and thromboembolic events were reported among 5 participants after treatment with aPCC with average doses of more than 100 U/kg daily for more than one day. Therefore, aPCC is not recommended as first-line option for the treatment of bleeds during emicizumab. If aPCC would be necessary, the dose should be as low as possible.
Bypassing agents have earlier been used to prevent bleeds in patients with inhibitors, especially in HA, but since there is excellent prophylactic therapy with emicizumab available for HA patients, bypassing agents for preventing bleeds will mostly not be the choice of therapy anymore. However, bypassing agents – mainly rFVII due to possible allergic reactions with aPCC - are still an option for patients with HB and inhibitors and bleeds [16,17]. A reduction in bleeds up to approximately 60% has been reported for rFVIIa in daily doses of 90 to 270 µg/kg and up to around 70% with aPCC in the dose of 50 to 85 U/kg 3 times weekly or every other day compared to on-demand treatment.
Re-balancing therapies as concizumab [18] – which got approval recently in Canada -, fitusiran [19,20] or Serpin PC [21] are part of ongoing studies and seem to have a potential role especially in HB patients with persistent inhibitors and bleeds. No recommendation can be given at this state, but compassionate use could be discussed from patient case to patient case.
3 Treatment of acute bleeds in inhibitor patients
3.1 Recommendations
Tranexamic acid should always be considered, both in minor bleeds alone or in combination with emicizumab or bypassing agents.
In HA with low inhibitor titer and a minor bleed, FVIII could be used as the first option to saturate the inhibitor and reach a hemostatic factor level.
In HB with low inhibitor titer and minor bleed, FIX could be used if no allergic reactions or signs of nephrotic syndrome are apparent and a clinical response can be achieved. Patients with short half-lifes may not respond to this treatment.
In HA/HB with low inhibitor titer and a major severe bleed, FVIII/IX might initially be infused, but in that case frequently monitored - at least daily - and rFVIIa provided if and when the half-life becomes too short, the inhibitor titer rises or the patient does not show clinicala response. If FVIII/IX cannot be monitored, rFVIIa should be considered as a first-line option.
In HA with high inhibitor titer and a major bleed, rFVIIa 90-120 µg/kg every 2-3 h is indicated for treatment.
Children may need higher doses up to 270 µg/kg of rFVIIa as an initial dose followed by lower doses depending on the hemostatic effect.
Due to the hemostatic effect of emicizumab, the number of doses of FVIII/rFVIIa can most often be reduced in HA patients using emicizumab. The first dose of rVIIa is however recommended to be 90 µg/kg.
In HA, rFVIIa is preferred over aPCC due to increased risk of thrombotic complications when used in combination with emicizumab.
In HB, rFVIIa is preferred over aPCC due to possible allergic reactions.
aPCC dosing in non-emicizumab patients could be started with 50-100 IU/kg every 6-12 h but the daily dose of aPCC should not exceed 200 IU/kg.
For patients with emicizumab and need for aPCC a maximum of 50 IU/kg are recommended and the dose of 100 IU/kg/day should not be exceeded.
If bleeds are resistant to monotherapy with each bypassing agent , a sequential use in the order of aPCC (50 IU/kg) and rFVIIa (90 µg/kg) with an interval of ≥ 2 hrs or a combined use of aPCC (20-30 IU/kg) and rFVIIa (30-60 µg/kg) may be considered but the risk of thrombosis should always be considered. Experience on the use of sequential therapy with aPCC and rFVIIa under emicizumab is very limited.
For both HA and HB, tranexamic acid should be offered in case of a bleed. Since most patients with HA and persistent inhibitors receive emicizumab, breakthrough bleeds occur less often in this patient group. If breakthrough bleeds require additional hemostatic drug intervention besides tranexamic acid, rFVIIa should be used as first-line option. For patients on emicizumab, the initial dose of rFVIIa should not exceed 90 µg/kg and if neede, repeated doses of 45 upp to 90 µg/kg at an interval of 2 to 4 hours may be considered.
If aPCC and emicizumab together will be required as second line treatment and/or in resistant severe bleeds, the initial dose of aPCC should not exceed 50 U/kg and total daily dose should not exceed 100 IU/kg due to risk for thrombosis and TMA [15,22]. For HB patients, aPCC can be used with caution due to possible allergic reactions.
Studies before the era of emicizumab of rFVIIa and aPCC have shown to be effective in majority of cases [23]. Several studies have shown that rFVIIa can be administered at a dose of 270 µg/kg on a single occasion, especially in children, instead of three doses of 90 µg/kg, without reducing the efficacy or exposing the patient to complication risk [24], in patients not receiving emicizumab.
The mechanisms of action differ between aPCC and rFVIIa. Therefore, a sequential or combined use of them has been studied and suggested to improve efficacy in bleedings hard to control [25]. However, the risk of thromboembolic complications – especially in patients with HA treated with emicizumab or patient with other thrombogenic factors like central venous lines - needs to be taken into account and these agents should be used very cautiously, when used in parallel, and only in resistant cases.
4 Immune tolerance induction (ITI) therapy
4.1 Recommendations for HA
In patients with mild/moderate HA, the possibility of spontaneous remission (≈ 20%) should be taken into consideration and a watch and wait strategy might be advisable before treatment.
Children and adults with confirmed low-responding inhibitor treated with factor VIII prophylaxis should continue on regular factor VIII treatment to induce tolerance with repeated measurements of inhibitor titres and assessment of recovery. In persistant inhibitors or patients with bleeds, emicizumab could be offered.
Children and adults with high-responding inhibitor are recommended to use emicizumab for bleeding control during ITI.
ITI should be discussed with the patient and the family, since it is by now the only way of eradicating the immune response and making the patient eligible for all future treatment options. However, since emicizumab offers efficient bleeding control in inhibitor patients with HA, the requirement of ITI should be discussed individually since venous access, costs and issues about keeping the tolerance are obstacles in ITI.
ITI can be started immediately independent on the inhibitor titre.
For patients on emicizumab, low-dose ITI with FVIII SHL or EHL such as 50 IU/kg 3 times weekly is recommended as a starting ITI regime.
For patients not on emicizumab, a high factor dose regimen seems to reduce the time to reach a negative inhibitor titer, and since bleeds mainly occur during this period, a daily dose of 100-200 IU/kg/d should be used.
No consistent data indicate the beneficial use of one type of product over the others. In case of ITI failure, the addition of immunosuppression should be considered.
Switch of ITI protocol or discontinuation of ITI should be considered when no further significant decline or improvement in clinical phenotype has occurred for 4-6 months.
In patients with hemophilia A and persistent high-responding inhibitors failing ITI protocols, the approach to further ITI therapy should be discussed.
After successful tolerance, the dosing should be tapered to regular prophylactic treatment. For patients using emicizumab, currently no data is available on the frequency and dosing of FVIII after tolerization of the patient.
4.2 Recommendations for HB
The principal goal in all patients with inhibitors – both children and adults - should be to eradicate the inhibitor and to tolerize the patient.
Children and adults with confirmed low-responding inhibitors without allergic reactions to FIX could continue on regular factor IX therapy to induce tolerance.
Besides inhibitor measurements, also FIX recovery is important to indicate the most optimal therapeutic strategy. HB patients can have a low inhibitor titre but very short half-lifes.
For patients with persistent high-titer inhibitors without allergic symptoms, a dose of 100-200 IU/kg/d could be used.
Immunosuppression should be considered as first-line treatment in all HB patients with allergy to FIX and in high-titre patients, e.g. rituximab or “Beutel-protocol”, especially in patients with allergy to FIX.
In patients with hemophilia B and persistent inhibitors failing ITI protocols with and without immunosuppression or allergy to FIX, ITI may be stopped and compassionate use of re-balancing therapies could be discussed.
After successful tolerance, the dosing should be tapered to regular prophylactic treatment.
4.3 ITI in mild/moderate hemophilia A
In HA, up to 25% of new inhibitors occur in patients with mild or moderate disease altering the bleeding phenotype from mild/moderate to severe even after 50 ED [2,26]. Inhibitors most commonly arise following an intensive episode of replacement therapy for surgery or major trauma and appear to be associated with s high-risk factor VIII gene mutations [27]. Importantly, some inhibitors might be transient and disappear spontaneously.
The limited data available in patients with non-severe hemophilia A suggests that when eradication treatment is indicated, strategies that modulate the immune system, such as the use of rituximab may have greater benefit than ITI with FVIII concentrates only [28]. Therefore, the clinician will have to decide if a watch-and wait strategy, immunosuppression and/or ITI should be started [29].
4.4 ITI in severe hemophilia A
Also in severe HA, the inhibitor could be transient in around 20% of cases and a watch-and-wait-strategy should be used with a re-measurement of the inhibitor before intitiating ITI. Also, in children and adults with confirmed low-responding inhibitor treated with factor VIII prophylaxis should continue on regular factor VIII treatment since early initiation of ITI could induce high-titre inhibitors [12]. Repeated measurements of inhibitor titres and assessment of recovery and bleding pattern are important in this patient group. In low-titre patients with bleeds, emicizumab could be offered with parallel FVIII exposure. Emicizumab should be offered to high-titre inhibitor patients.
In patients with persistant inhibitors, especially high-titre inhibitors, emicizumab is recommended since it offers bleeding control but ITI treatment should also be discussed, since it is by now the only way of eradicating the immune response and making the patient eligible for all future treatment options. The benefits of ITI with the tolerization of the patient to FVIII has to be weighed against the need for venous access, costs and issues about keeping the tolerance are obstacles in ITI.
The principle consists of repeated exposures for the deficient factor with or without the concomitant use of immunosuppressive agents by at least three exposures per week of FVIII intravenously. Most studies show tolerance to be induced in 60-80% of the cases with HA [30] with several different regimens. One of the first protocols used was the “Bonn-protocol” using 200IU FVIII daily, published by Brackmann et al. in 1977 [31]. In the International Immune Tolerance study, patients were randomized into high (200 IU/kg/d) and low dose (50 IU/kg 3 times/week) FVIII regimens. No difference in success rate between the treatment arms was seen, but the time to achieve a negative titer, i.e. the phase with most frequent bleedings, was significantly shorter with the high dose regimen [32]. A higher efficacy rate of von Willebrand-containing FVIII products to induce tolerance compared with more highly purified products has been suggested, but it has not been possible to confirm these findings [33]. Newer studies on EHL products show similar success rates to SHL [34]. ITI can be started without the inhibitor to drop below 10 BU.
Today, emicizumab treatment for prevention of bleeds is started in most high-titre inhibitor patients and those with persistent inhibitor and bleeds. The choice of ITI regimen has therefore changed, with studies still ongoing. A low-dose regimen with about 50 IU/kg three times weekly is recommended under emicizumab since high-dose regimens have shown a risk for thrombotic events in recent studies and success rate seems to be similar compared to high-dose regimens.
After successful tolerance, the dosing should be tapered to regular prophylactic treatment. For patients using emicizumab, currently no data is available on the frequency and dosing of FVIII after tolerization of the patient with different strategies at the moment [13].
A switch of ITI protocol or discontinuation of ITI should be considered when no further significant decline or improvement in clinical phenotype has occurred for 4-6 months.
4.5 ITI in hemophilia B
For HB, ITI treatment may be jeopardized by the occurrence of an allergic or anaphylactoid reaction or nephrotic syndrome. The use of ITI in these patients therefore needs careful monitoring and should initially be provided in the hospital setting. Children and adults with confirmed low-responding inhibitors without allergic reactions to FIX could continue on regular factor IX therapy to induce tolerance.
In all other cases, immunosuppressive drugs should be considered as first line therapy, such as the use of steroids, rituximab, cyclophosphamide, cyclosporine, mycophenolate mofetil and/or other agents, e.g. the “Beutel-protocol” or treatment with immunosuppressive drugs and extracorpral adsorption as in the “Malmö-protocol” [35,36]. The FIX inhibitor should not only be judged by BU but also recovery since there can be mismatches. The success rate in HB might be lower in patients with HB compared to HA, but can be achieved even after several attempts [14] . After successful tolerance, the dosing should be tapered to regular prophylactic treatment.
In patients with hemophilia B and persistent inhibitors failing ITI protocols with and without immunosuppression or allergy to FIX, ITI may be stopped and compassionate use of re-balancing therapies could be discussed.