The ongoing imperative for immune tolerance induction in inhibitor management

Innovative nonfactor therapies (NFTs) are poised to change the haemophilia treatment landscape. Emicizumab (HEMLIBRA®; Genentech, Hoboken, NJ, USA) approved for use in the United States and awaiting approval in several other countries, together with fitusiran, and concizumab, both in late stages of development (Table 1), will ultimately be used for prophylaxis in patients with and without inhibitors. All three agents are administered subcutaneously once-weekly to once-monthly,1, 2 reducing the burden of frequent intravenous factor infusions and possibly enhancing adherence to prophylactic regimens. Despite their potential, NFTs are not a panacea that obviate the need for inhibitor eradication. Regarding them as such has dangerous implications for patient care. The development of neutralizing alloantibodies following exposure to exogenously administered factor VIII (FVIII) or FIX remains the most serious treatment-related complication of haemophilia. Caused by a combination of genetic and environmental risk factors,4 inhibitors make bleeding episodes more difficult to control, thus increasing morbidity (eg, arthropathy resulting from haemarthroses,5 cognitive/neurologic deficits following intracranial haemorrhage6) and mortality.7 NFTs are envisioned as a strategy for avoiding inhibitor development by eliminating or minimizing exposure to standard factor replacement therapy. However, the preferential use of NFTs for routine prophylaxis will not prevent 100% of bleeds: the 25 patients with moderate or severe haemophilia A or B without inhibitors enrolled in the phase 1 dose-escalation trial of fitusiran experienced an “apparent reduction in,” but not zero, bleeding episodes.2 (No data are yet available for concizumab.) Furthermore, NFTs cannot be used to treat acute bleeding, and their application for surgical prophylaxis is uncertain. When bleeding occurs, FVIII or FIX concentrates will be required for hemostasis, posing a risk for inhibitor development, particularly with intensive therapy.8 NFTs are expected to be especially beneficial for patients with entrenched high-titre inhibitors who have failed immune tolerance induction (ITI) or are not candidates for or refuse ITI. For nearly 15 years, treatment options for inhibitor management have been limited to activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa). No assays are clinically available to monitor bypassing therapy, and neither agent is as predictably effective in controlling9 or preventing10, 11 bleeding as is FVIII or FIX in patients without inhibitors. Consequently, every physician with experience treating inhibitor patients has had at least one harrowing case of bleeding refractory to one intervention after another. Data from the pivotal phase 3 trial of emicizumab prophylaxis in patients with haemophilia A and inhibitors found that the drug reduced the annualized bleeding rate (ABR) by 79%, as compared with bypassing agent prophylaxis.1 Yet as is true for noninhibitor patients, the use of NFTs will not translate to a zero ABR for every inhibitor patient. Bypassing agents will be needed for breakthrough and traumatic bleeding, resulting in an unpredictable and variable response to treatment, as evidenced by fatal bleeding in an emicizumab-treated study patient after 11 doses of rFVIIa.1 (Subsequently, four deaths occurred in patients treated with emicizumab through the compassionate use or extended access programs,12 and another death was reported by the Genentech at the World Federation of Hemophilia Congress in May 2018.) Additionally, the concomitant use of bypassing agents with emicizumab may predispose to thrombosis and thrombotic microangiopathy, the latter a serious adverse event never observed with the use of aPCC or rFVIIa used alone or sequentially. The availability of emicizumab and other NFTs in the research pipeline notwithstanding, haemophilia patients will continue to be at risk for bleeding and inhibitor formation. Moreover, those who develop inhibitors will not only be vulnerable to uncontrollable haemorrhage and treatment-associated adverse events, but are currently precluded from participating in gene therapy clinical trials—the only potentially curative therapy. (Animal studies suggest gene therapy may induce tolerance in inhibitor patients,13 but these preliminary data must be confirmed in clinical trials.) For the foreseeable future, eradication must continue to be the goal for children and adults with haemophilia A and newly diagnosed inhibitors. (Inhibitor eradication is uncommonly attempted in patients with haemophilia B because of the risk for severe allergic reactions and nephrotic syndrome14). ITI is the only proven strategy for eliminating inhibitors. In patients with haemophilia A, ITI involves the regular administration of FVIII over months to years to tolerize the immune system and restore normal FVIII pharmacokinetics.14 Eradication succeeds in approximately 70% of patients on high- and low-dose rFVIII regimens, according to the randomized International ITI study15 (although higher rates have been reported and will be discussed), with success ensuring hemostasis with FVIII replacement therapy, improving quality of life and decreasing lifetime healthcare costs.16 International,14 US17 and UK18 guidelines provide recommendations for ITI with regard to candidates, timing, regimen, monitoring and definitions of success (Table 2). These guidelines also discuss FVIII product choice: plasma-derived FVIII (pdFVIII) or recombinant FVIII (rFVIII). ITI is generally initiated with the FVIII concentrate used by the patient at the time of inhibitor development.14 In children treated in North America and the United Kingdom, this typically has meant starting ITI with rFVIII. However, results from the randomized, controlled, open-label Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) trial showed a lower incidence of inhibitor development in previously untreated or minimally treated patients undergoing ITI who used pdFVIII concentrates containing von Willebrand factor (VWF) compared with rFVIII.19 These findings have persuaded some clinicians to select pdFVIII/VWF for routine prophylaxis, meaning that pdFVIII/VWF may increasingly be used first-line for ITI. In vitro studies suggest that VWF-containing FVIII concentrates may be more effective in inducing immune tolerance because VWF masks potential inhibitor epitopes, thereby shielding infused FVIII from rapid degradation and prolonging antigen presentation.20 In addition, inhibitors directed against the A2 domain and light chain of FVIII are less active against VWF-bound FVIII than VWF-devoid FVIII.21 Nonetheless, the comparative ability of VWF-containing and recombinant FVIII products to induce immune tolerance in the clinical setting remains uncertain. A meta-analysis of 13 studies reported no difference in the pooled proportion of successful inhibitor eradication between patients treated exclusively with pdFVIII/VWF concentrates and those exclusively given FVIII concentrates devoid of VWF (although the proportion of poor-risk patients [Table 2] was higher in those treated with pdFVIII/VWF).22 On the other hand, experience from a single centre in Germany suggests that ITI may be more successful when the high-dose Bonn protocol (FVIII 150 IU/kg twice-daily) is used with pdFVIII/VWF concentrates (87%-91%), as compared with standard half-life rFVIII (29%-54%).23 Use of a single pdFVIII/VWF product was linked to ITI success rates of 85% among 60 children and adults treated in Germany, Italy and Spain,24 and 78% in adults treated in the United Kingdom.25 In the Observational Immune Tolerance Induction (ObsITI) Study, 22 of 35 patients (63%) with a poor prognosis for ITI success achieved inhibitor eradication.26 Finally, 13 of 25 children (52%) who had previously failed ITI with aggressive regimens using recombinant or monoclonal FVIII products experienced complete or partial success when ITI was repeated with a pdFVIII/VWF product,27 confirming that positive outcomes are indeed possible in poor-risk patients. These findings underscore the need to re-evaluate who is/is not an appropriate candidate for ITI and determine whether certain products truly yield better outcomes. To this end, a prospective, randomized, controlled, open-label study in ITI-naïve haemophilia A patients with high-responding inhibitors and a poor prognosis for successful inhibitor elimination (≥1 poor risk factor) is currently underway to resolve the debate regarding product selection (NCT01051544).28 pdFVIII/VWF is also being evaluated for rescue ITI in patients who previously failed to become tolerized with VWF-free FVIII concentrates (NCT01051076).29 In conclusion, NFTs are a highly anticipated and welcome addition to the haemophilia armamentarium. Yet, their incorporation into treatment algorithms should not lead to complacency about inhibitor development. The imperative to eradicate inhibitors has not changed, and we must continue striving to identify the best strategies for inducing immune tolerance in children and adults who develop this extremely serious complication of factor replacement therapy. Finally, whether tolerance to FVIII is maintained when haemophilia patients whose inhibitors have been successfully eradicated are transitioned from ITI to nonfactor therapy for ongoing prophylaxis is an area for future study. Louis Aledort is on the data safety monitoring boards of Octapharma and Shire and is chairman of the Kedrion advisory committee. Louis Aledort wrote the commentary with medical writing assistance provided by Michele Grygotis, an independent consultant.