How I treat inhibitors in haemophilia

Inhibitors in haemophilia

The use of clotting factor concentrates has transformed the lives of persons with haemophilia. Unfortunately the use of non-virally inactivated products prior to the mid-1980s resulted in most recipients being infected with hepatitis C and many also with HIV. The use of viral inactivation proved highly efficient in virtually eliminating the infective risk of plasma-derived products. Furthermore, in the last 20 years recombinant products, which do not carry the infective risk have been introduced. The most important adverse event associated with factor VIII concentrate use today is the development of FVIII alloantibodies (inhibitors).

Inhibitors are more likely to occur during the first 50 exposure days in previously untreated patients (PUPS) and develop in up to a third of the severe patients. There is debate in the literature as to whether there is a difference in the inhibitor risk in PUPS between plasma derived and recombinant concentrates [1], and a randomized clinical trial is currently investigating this. Inhibitors in previously treated patients are much rarer, occurring in approximately 2 per 1 000 patient years and recently there has been a debate as to whether B-domain deleted FVIII concentrates are associated with a higher inhibitor risk than full-length products [2,3].

Once an inhibitor develops, it results in increased mortality, morbidity and cost for the affected individual [4]. It is sometimes possible to eliminate the inhibitor using immune tolerance induction where FVIII is administered regularly and frequently. When bleeding occurs in the presence of an alloantibody, treatment with a bypassing agent is required. Sometimes it is necessary to carry out emergency or elective surgery in the presence of an inhibitor and this can be very challenging. In this manuscript the issues of ITI, treatment with bypassing agents and surgery in patients with inhibitors are reviewed.

Immune tolerance induction

Bypassing agents are less effective for treatment of bleeding and only partially effective as prophylaxis in inhibitor patients, compared with FVIII in non-inhibitor patients. For this reason, patients with persistent FVIII/IX inhibitors suffer more morbidity than non-inhibitor patients, even if their mortality has been largely normalized in recent years [4]. All patients with haemophilia A/B and persistent inhibitors should therefore be offered immune tolerance induction (ITI) to eliminate the inhibitor and to restore normal clinical responsiveness to FVIII [5].

Immune tolerance induction (ITI) should be started soon after inhibitor development, but should be delayed until the titre has fallen below 10 BU mL⁻¹. Inhibitor titre <10 at the start of ITI was the most powerful predictor of successful ITI in both the NAITI and IITI studies [6,7] and the inhibitor takes a median of 5 months to fall to this level from the time of diagnosis [8]. The NAITI showed that response to ITI did not fall off until 5 years after inhibitor diagnosis [6]. Inhibitors that fail to fall to this level over 12–24 months respond poorly to ITI. Regimens in which the start has been delayed until the inhibitor titre has fallen to <10 BU mL⁻¹ have been notably successful [9–11].

A central venous access device (CVAD) is usually inserted to facilitate ITI [8]. Some centres attempt ITI without the use of a CVAD, since infection has been reported to adversely affect the outcome of ITI. Recent results from the IITI study suggest that infection has no effect on either the proportion achieving tolerance or the time taken to become tolerant, at least in good-risk patients [8]. Implantable CVADS are significantly less likely to become infected than external lines such as Hickman or Broviac catheters [8,12,13].

Immune tolerance is usually initiated using the product used by the patient at the time of inhibitor development. Uncontrolled data have suggested low-purity pdFVIII may induce tolerance more effectively than rFVIII [14–17]. However, the reported success-rates for ITI do not appear to be influenced by the product-type used [18–20]. A randomized comparison of high-dose pdFVIII vs. rFVIII for ITI in poor-risk patients is in progress [17].

The choice of optimal ITI regimen remains problematic. The IITI and NAITI suggest that poor-risk patients (Peak titre >200 BU, Starting titre >10 BU) are best tolerized using a high-dose regimen (100–200 IU kg⁻¹ FVIII) [6,7]. These registries and the ITI study suggest that high-dose and low-dose (50 IU kg⁻¹ 3 X weekly) regimens are equally effective in inducing tolerance [6–8,21,22]. There is no evidence that 200 IU kg⁻¹ day⁻¹ are superior to 100 IU kg⁻¹ day⁻¹.

Low-dose ITI takes longer to achieve a negative Bethesda titre, however [6,8], and is associated with significantly greater intercurrent bleeding in early ITI, before the Bethesda titre becomes negative, when 85% of intercurrent bleeding on ITI takes place [8]. Many clinicians may consider that all patients requiring ITI should be started with high-dose to minimize intercurrent bleeding. Once the Bethesda titre has become negative, it may be argued that the dosing could be tailed down in stages to a low-dose regimen. The ITI study suggests that such an approach may minimize cost and may minimize intercurrent bleeding without reducing the time taken to achieve tolerance [8]. This has not been tested in a controlled trial but has been reported to be successful in small series [9]. There has been little published on the eradication of low titre inhibitors (peak titre <5 BU) but experience suggests that these are usually readily tolerized using a low-dose regimen.

Progress on ITI is usually monitored firstly by measuring the inhibitor titre monthly and then, when the Bethesda titre is consistently negative, measuring the FVIII recovery monthly, without a washout. Once this has normalized (>66%), the half-life is usually measured after a 3-day washout every 3 months until normal [8]. A truncated half-life is probably adequate for this purpose and the ITI data are being re-analysed to determine whether the approach of Bjorkman to half-life estimation [23], which minimizes sample requirement may be appropriate. When all three of these parameters are normal, the patient is considered tolerant [8].

Most patients achieve tolerance within 6–12 months but a minority may take 1–3 years or more. ITI can be abandoned in such patients after 6–9 months and rescue therapy introduced if there is no evidence of a significant decline in inhibitor titre. ITI is also often stopped for logistic reasons, because of failure of venous access and/or repeated CVAD infection. Long interruptions in ITI are to be avoided because they are significantly associated with a poor outcome [24]. Patients whose inhibitor titres rise >500 BU are unlikely to succeed. Similarly patients whose titres fail to decline or continue to rise over a 6 month period are unlikely to be successfully tolerized and consideration should be given to either changing the regimen or stopping ITI.

It is a matter of individual judgement when to consider that the patient has failed ITI or should be changed to a different regimen. Options for rescue therapy in unresponsive patients are limited and there is insufficient data to recommend any specific strategy. The alternatives include the use of a higher dose regimen, changing to pdFVIII with a high VWF content, adding immunosuppression such as Rituximab or both.

Patients with mild haemophilia A who develop an inhibitor respond less well to immune tolerance than those with severe haemophilia [25] though these patients had a median age of 32 and inhibitors presenting earlier in life may be more likely to respond.

Immune tolerance induction, ITI for haemophilia B must be carefully considered because of the relatively poor overall success rate (25%) and the risk of anaphylaxis and potentially irreversible nephrotic syndrome [5,6]. Regimens analogous to haemophilia A have been used including low- and high-dose FIX and a modified Malmo regimen [26]. The NAITR reported 31% success with a median dose of 100 U⁻¹ kg⁻¹ day⁻¹ and 6/7 patients were successfully tolerized using the Malmo regimen [26]. There is anecdotal evidence to suggest greater efficacy for regimens including an immunosuppressive element in patients with haemophilia. Patients with an allergic phenotype and a family history of inhibitors have a poorer outcome.

Treatment and prevention of acute bleeds

Immune tolerance induction ITI is the treatment of choice of patients with inhibitors, because it allows replacement therapy with clotting factor concentrates. However, this approach is only successful in about two thirds of inhibitor patients. Treatment of acute bleeding in patients with inhibitors is one of the most challenging in haemophilia management and it absorbs a huge amount of economic resources [27]. The difficulty associated with treatment is related to the high number of variables to be taken into account: site and severity of haemorrhage, inhibitor level, product efficacy and safety, patient age and cost [28].

In low-responders or those with low inhibitor levels, high doses of factor concentrate can overcome the inhibitor and allow the attainment of haemostatic factor levels [29]. In patients with higher inhibitor levels a FVIII bypassing agent is necessary to manage bleeding events [30].

The two main bypassing agents used in this setting are activated prothrombin complex concentrate (APCC; FEIBA; Baxter BioScience, USA) and recombinant activated FVII (rFVIIa; NovoSeven; Novo Nordisk, Denmark). These agents were shown to have a similar efficacy when used to treat mild or moderate joint bleeds [31]. The doses used in a randomized cross-over study were one APCC infusion of 85 U kg⁻¹ or 2 rFVIIa infusions of 105 μg kg⁻¹ 3 h apart. This dosing was deemed effective at 6 h in about 80% of cases without requiring additional infusions. A controlled study has shown the equivalence of a single rFVIIa dose of 270 μg kg⁻¹ with 3 rFVIIa doses of 90 μg kg⁻¹ at 3 h intervals [32]. Unfortunately, reliable laboratory monitoring is not available for inhibitor bypassing therapy, and efficacy must be deemed only on the basis of changes in symptoms and signs. The thrombin generation test (TGT) that evaluates the overall coagulating capacity may be useful to monitor treatment efficacy and to predict outcome and dosing to use [33,34], but standardization is still unavailable.

Unsatisfactory response to therapy should result in an early change in treatment, by increasing the dose and/or the frequency, or in type of bypassing agent, rather than continuing with the same product and dosing with unfavourable results [31].

Unresponsive bleed to intensive treatment with one or both bypassing agents used singly have been shown to respond to their combination infused simultaneously [35] or at short intervals from each other [36]. In fact, a synergistic effect has been reported in vitro [37] and in vivo [38].

A European survey [39] collected 11 sequential bypassing therapy courses in nine haemophilia patients, aged 9–73 years (median 24) with unresponsive bleeds to single therapy with one or both bypassing agents, including five major surgeries. Bypassing agents were administrated by alternating one APCC dose (20–80 U kg⁻¹ every 8–12 h) to 1–3 rFVIIa doses (90–270 μg kg⁻¹ every 3–12 h). Bleeding control was achieved in 12–24 h in all patients and treatment was discontinued after 1–15 days. No clinical adverse events were observed, but a significant D-dimer increase was seen in three of five assessed patients. Bypassing agent combination carries a high risk of disseminated intravascular coagulation or thromboembolism and it should be only used as salvage therapy and only for the shortest period of time.

Given the morbidity associated with frequent and difficult-to-manage bleeding and the substantial quantities of bypassing agent required [40], the use of bypassing agents prophylactically has been suggested to reduce the bleeding frequency and to improve quality of life, especially of those who are ineligible for immune tolerance induction or have failed it, with a relatively high bleeding frequency. Both bypassing agents have shown to be capable to reduce bleeding rate in most patients [41–43], and to maintain or increase joint range of motion [44]. Two prospective trials have recently been carried out, one with rFVIIa [45] and one with FEIBA [46]. Patients with at least 12 bleeding events in the previous 3 months were randomly assigned to receive rFVIIa daily at standard (90 μg kg⁻¹) and high dosage (270 μg kg⁻¹). During 3-month prophylaxis with the standard and the high dosages the bleeding frequency decrease of 45% and 59%, respectively, and target joint bleeding of 61% and 43%, compared to the previous 3 months. In the randomized, cross-over FEIBA study, prophylaxis was administered three times a week to patients with at least six bleeds in the previous 6 months: it was able to decrease overall bleeding rate of 62% and target joint bleeding of 72%. Both studies showed that prophylaxis with bypassing agents was safe, well tolerated and able to improve the quality of life. The daily rFVIIa administration is necessitated by the shorter half-life of rFVIIa compared to FEIBA, and might diminish the appeal of rFVIIa as a prophylactic modality. The costs of prophylaxis can represent a major barrier to its acceptance. Patients on prophylaxis with FEIBA were reported to cost 2.4 times more than during on-demand treatment.

Surgery in inhibitor patients

Since the first successful elective surgical knee synovectomy performed in a haemophilia patient with inhibitors [47] indications expanded progressively from invasive procedures restricted to life and/or limb-threatening to elective surgeries.

Twelve articles including five case studies, five case series and two clinical trials covering a total of 80 orthopaedic procedures performed with rFVIIa were reviewed in 2008 [48]. The initial dose was variable but was mostly 90 μg kg⁻¹. Bleeding complications were noted in a minority of procedures and were mostly felt to be related to an inadequate amount of rFVIIa. Based on these observations a higher initial bolus dose of 120 μg kg⁻¹ followed by a similar or a 90 μg kg⁻¹ dose every 2 h gradually extended has been proposed. An even higher dosing regimen has been proposed [49], with a preoperative bolus of 120–180 μg kg⁻¹, followed by doses of 90 μg kg⁻¹ at 2 h intervals for the next 48 h, thereafter the intervals being increased to 3, 4 then 6 h on days 3, 5 and 8, respectively, and continued until discharge. For those preferring continuous infusion, a 50 μg kg⁻¹ h⁻¹ dosing was suggested [48] based on a prospective study [50]. Some authors prefer bolus dosing because they believe that the burst of thrombin generation achieved is important for haemostasis [51].

There are less data available for surgeries performed with FEIBA compared to rFVIIa. The publications from single institutions, national or international cohorts reported mainly minor surgeries and a limited number of major procedures [52–56]. Usually a first dose of 50–100 U kg⁻¹ per dose is given 1 h before the surgery and is repeated every 6–12 h for a maximum daily dose of 200 U kg⁻¹ and tapered until discharge. The ongoing SURgical Interventions with FEIBA (SURF) open-label, prospective, non-interventional, post-authorization safety surveillance study has already recorded 13 major surgeries of a total of 35 procedures and will further increase this experience [57].

Globally, rFVIIa or APCC secured haemostasis safely in different types of elective or emergency minor and major surgeries, in adult and paediatric patients with inhibitors. Comparison of efficacy is difficult due to the variety of treatments, the different definitions for minor or major surgery and the diverse modalities for evaluation of success. For surgery, no comparative studies between the two products have been carried out. The absence of objective evidence of differences in the relative responsiveness and safety, has led to a recommendation of both agents equally [5]. However, in 2008, a MEDLINE search indicated that 82% of major procedures were covered with rFVIIa and 71% of the minor procedures were performed with APCC [58].

Despite a twofold to fivefold increase in the cost concentrate to cover surgery with bypassing agents compared to non-inhibitor patients [53,59,60], outcomes were not always favourable. Indeed, discordant responsiveness to both agents has been described, including some patients treated with high doses, pointing out the inter-individual variability of efficacy [58,61]. Bleeding complications remained more frequent in inhibitor (2/7, 28%) than in non-inhibitor patients (2/109, 2%; P < 0.05) in a retrospective study of outcome of 116 primary total knee replacements (TKR). Inhibitor was also a risk factor for infection as inhibitor was present in 3/9 patients with TKR infection (33%) and 4/83 patients without TKR infection (5%; P < 0.05) [62].

Insufficient correction of haemostasis may indeed increase angiogenesis and induce delayed wound healing [63]. In a mouse model of haemophilia B, cutaneous wounds required 7 days of haemostatic treatment to normalize wound closure [64]. Not only adequate initial haemostasis is required to limit the risk of bleeding but prolonged treatment may be warranted. Unfortunately this is not always feasible, especially for less affluent countries where the majority of surgeries are still performed for emergencies and where elective surgeries are often discouraged [60]. In addition to cost saving considerations [49,65], shortage or transient availability of products are not rare and may also force clinicians to switch products [60]. A rapid decrease in dose or intervals of haemostatic coverage may account for a higher rate of complications including bleeding, infections and poor functional outcomes. In case of post-surgical bleeding episodes, a change in dosing or product should be rapidly implemented similarly to unresponsive severe bleeding episodes [28]. The experimental sequential or combined therapy of bypassing agents should be reserved to salvage treatment [39].

The use of antifibrinolytics and thromboprophylaxis are still debated. Local means such as topical thrombin or fibrin glue may improve haemostasis and should be considered [60]. Success depends not only on haemostatic treatments but also on pre/post-operative assessment and rehabilitation [66]. The use of thrombin generation assays or thomboelastography to guide the choice of product and adjust the dose of the bypassing agent for the surgery [67,68] may increase in the future if standardization problems improve.

Regarding safety, adverse reactions related to rFVIIa or APCC are rare but some disseminated intravascular coagulation and thrombosis have been described [50,52,56,69]. In patients with mild/moderate haemophilia A and history of inhibitor requiring surgery, the risk of anamnesis with APCC or potential re-challenge with FVIII should be taken into consideration. The profile of inhibitor specificity may change in parallel to a new anamnesis and subsequently modify the clinical phenotype into severe haemophilia. Alternatives including rFVIIa, or desmopressin, if appropriate, should be considered in these patients [70].

The increasing experience of efficacy and safety with bypassing agents secured emergency surgeries and helped patients and carers in experienced centres to consider elective procedures more often as a viable option. Indeed, recommendations to lower the threshold for offering validated surgical procedures in experienced centres have been suggested provided that the benefit/risk ratio was carefully assessed [69].

Conclusion

Inhibitors remain the most challenging issue facing haemophilia treaters today. They are seen in up to a third of severe patients with haemophilia when first treated and an attempt to eradicate them where the health resources allow it should always be made. Effective treatment of bleeds is available with two bypassing agents, which appear to be of similar efficacy and safety but neither is as good as FVIII concentrate in patients without inhibitors. Surgery in inhibitor patients should not be undertaken lightly and should only be carried out in centres with the necessary expertise.

Disclosures

Dr Makris has attended advisory boards for Baxter and NovoNordisk. He is the project lead of EUHASS which has received funding from Baxter and NovoNordisk. The ITI Study was supported by unrestricted grants from Bayer, Baxter, CSL Behring, Wyeth/Pfizer and the Japanese Green Cross. Dr Hay has no pharmaceutical shareholdings but has acted on advisory panels or speaker bureas and as an investigator in clinical trials for Baxter, Bayer, Novo Nordisk, CSL Behring, Inspiration, and Pfizer.Dr. Gringeri has served on Baxter advisory boards and receiving speaker’s fees and travel fees from Baxter, CSL Behring, Grifols, Kedrion, Octapharma.Dr d’OIRON received fees or honoraria from BAXTER , NOVONORDISK, BAYER, PFIZER, SOBI and CSL Behring for attending advisory boards, consultancy or speaking at symposia.