The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab

Abstract Introduction As a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non‐factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed. Aim The Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors. Discussion and Conclusions Despite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non‐factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low‐dose/low‐frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further.


| INTRODUC TI ON
The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) occurs in 25%-40% of patients with severe haemophilia A. [1][2][3][4][5] Persons with haemophilia A who develop high-titre inhibitors (HTI) become resistant to FVIII replacement therapy. This is associated with increased risk for bleeding and resultant morbidity (severe arthropathy and disability) and increased mortality. [6][7][8] Studies have shown that haemophilia-related long-term morbidity and mortality as well as long-term costs are diminished if inhibitors are eradicated. 9 The only proven strategy for achieving inhibitor eradication is immune tolerance induction (ITI), involving repeated administration of FVIII concentrates. [10][11][12] In 2007, DiMichele et al 12 developed a management algorithm and published consensus recommendations for ITI in persons with haemophilia A and inhibitors. Since that time, however, the treatment of haemophilia A has evolved and a number of molecules that potentially can be used in the setting of patients with inhibitors have been developed, or are in various phases of development. [13][14][15][16] With the arrival of these new molecules, the treatment environment is changing, and there are many unanswered questions about the future of inhibitor management. To provide answers to these and other questions, a group of nine experienced haemophilia treaters came together to discuss the Future of Immunotolerance Treatment (FIT) and to provide some orientation to the haemophilia community in this changing environment.

| The Fit group
The FIT group was formed in 2017 by Grifols to gain insight into how inhibitor management might change with the advent of new haemophilia therapies. Potential members were identified on the basis of their expertise in inhibitor management, their history of publishing on the subject and the fact that they represented large haemophilia centres. Identified members were invited to participate by Grifols.
No individual invited to participate declined the invitation. The group was limited to nine members as anything larger would be unmanageable. Three meetings were conducted between November 2017 and July 2018. Based on the transcripts of these meetings, a medical writer developed an initial draft manuscript. After that, the nine members took over the development of the paper with no further involvement from Grifols personnel or hired medical writers. As high-level evidence regarding the addition of emicizumab or other F I G U R E 1 FIT proposed management algorithm for current ITI proposed management algorithm for current ITI is shown in Figure 1.

| ITI success rates
The success rate of ITI has been demonstrated to range between 60% and 80% in patients with severe haemophilia A, 11,18,19 although when analysed on an intent-to-treat basis, the success rate appears to be lower. 11 When a patient is not responding to a first ITI regimen, a change in regimen (eg, dose escalation) or a change in FVIII product and/or the addition of an immunosuppressant (eg, rituximab) has been considered appropriate. Traditionally, haemophilia treaters, recognizing the importance of eradicating the inhibitor, have tried repeated attempts at ITI when inhibitor eradication is not initially achieved.

| Predictors of ITI success
Much of the awareness of predictors of ITI success arose from several large registries of ITI: an International ITI registry, 20 a German registry 21 and a North American registry. 22 Based on the findings from these registries, DiMichele et al 12  Our recommendation of starting ITI immediately is in contrast to past practice, where most clinicians would wait until the inhibitor titre had dropped to a value of <10 BU. 11,12 This trend of starting ITI as soon as possible after inhibitor development has been driven in part by a desire to avoid bleeds in patients with high pre-ITI titres 25 and in the hope of suppressing the maturation of the anti-FVIII immune response with the production of long-lived plasma cells. 26

| Product selection
It has been common practice to use the same FVIII concentrate for ITI to which the patient originally developed the inhibitor. 28 However, the FIT group does not believe that there is any corroborating evidence to support or refute this practice. In fact, several reports suggest a high rate of ITI success when a plasma-derived (pd) FVIII/VWF is used for first-time ITI in patients who develop an inhibitor with recombinant (r) FVIII. 8,27,29,30 However, given the lack of randomized studies comparing the efficacy of different FVIII product types for first-time ITI, the FIT group currently cannot recommend a specific FVIII product or product type for first-time ITI patients.

| Dose and regimen
There are two main approaches when starting patients on ITI: (a) begin ITI with a non-tailored prespecified regimen regardless of the patient's initial prognostic status or (b) select the starting regimen that is tailored to the patient's prognostic status. The FIT group recommends the second approach and, as shown in Figure 1

| ITI monitoring and decision points to adjust ITI
Being on ITI is a state of constant flux, with inhibitor titres rising or falling depending on the patient's response to ITI. Given this, it is important that inhibitor titre testing and monitoring including F I G U R E 2 Hypothetical new approach for the management of inhibitor patients in the era of non-factor therapies. *To expose patients to the potential risks of immunosuppressive therapy in the age of good alternatives such as emicizumab would not be appropriate and, hence, we deliberately did not include it as a treatment

Monthly monitoring on inhibitor titer, joint status and bleeding phenotype
Start as soon as inhibitor is detected *To expose patients to the potential risks of immunosuppressive therapy in the age of good alternatives such as emicizumab would not be appropriate and, hence, we deliberately did not inclu de it as a treatment option.

Decision point at 9 mo
If emicizumab is not added then recommend the same regimens as in Figure 1 Escalation

| Central venous access devices (CVADs)
The need for a CVAD generally depends on the ITI dosing regimen and on the patient's age. As CVADs are associated with wellknown complications (local and systemic infections, mechanical device failure and thrombosis), peripheral venous access generally should be used whenever possible. 33 However, the experience of FIT group members is that it is almost impossible to undertake high-dose/high-frequency ITI regimens in young children without a CVAD.

| Success definition
The FIT group agrees that the response to ITI should be defined gen-

| When to discontinue ITI
The maximum time limit for ITI has not been established. Some studies have suggested that 33 months might represent a maximal time to undertake ITI as after 33 months few additional patients are likely to achieve ITI success. 34

| PART B: FIT G ROUP REFLEC TI ON S AND RECOMMENDATI ON S FOR ITI IN THE ER A OF NON -FAC TOR THER APIE S
Newer, non-factor therapies that can be used in patients with inhibitors have been developed and are likely to impact greatly on the practice of ITI in the future. Emicizumab, the first of these non-factor therapies to be licensed for inhibitor patients, is a bispecific antibody that binds to both factor IXa and factor X and in doing so supports conformational changes that allows factor IXa to activate FX in the absence of FVIII. 35 The efficacy of emicizumab in preventing bleeds has been demonstrated to be much higher than that of traditional bypassing agents. 13 On the basis of this, emicizumab was approved Should emicizumab be given concurrently with ITI to prevent bleeds?
Given that now with emicizumab low-dose ITI regimens may no longer be handicapped by higher bleeding rates in comparison with high-dose ITI regimens (which are associated with much higher cost and burden) will ITI regimens change?
Will government and insurance payers support the cost of concomitant emicizumab with ITI?
Will there be any role for prophylaxis with traditional bypassing agents (rFVIIa and FEIBA)?
If patients undergo ITI (particularly patients receiving concomitant emicizumab) and achieve success, will they continue on emicizumab?
If patients remain on emicizumab post inhibitor eradication, must they continue on some regular exposure to FVIII to maintain tolerance to FVIII? patients with and without inhibitors has raised myriad questions ( Table 1).
The FIT group's vision about a hypothetical new approach to the management of inhibitor patients in the era of non-factor therapies is shown by the new algorithm in Figure 2. The FIT group's reflections considered only clinical implications of emicizumab in the management of inhibitor patients, but the group acknowledges that there also will be cost implications that should be considered on a country-by-country basis.

| Tolerization is still the goal
With the availability of emicizumab, and, in the future, other nonfactor therapies, the first decision that a clinician will grapple with if a patient develops a HTI is whether ITI should still be attempted (with or without concomitant emicizumab/non-factor therapy) or should we not bother with ITI and instead place the patient immediately on emicizumab alone.
There is no evidence and no expectation that emicizumab given alone will result in eradication of inhibitors although it is possible that some inhibitors will resolve without ITI (addressed earlier).
However, for any inhibitor titre >10 BU, if patients/clinicians were to choose not to undertake ITI, such patients would (we believe) have an inhibitor for the rest of their lives.
Although emicizumab, and in the future other non-factor therapies, may ultimately be shown to be excellent long-term prophylactic agents for patients with haemophilia A with and without inhibitors, they do not appear (for now) to be able to prevent all bleeds. Consequently, bleeds are still likely to occur and will require additional episodic treatment: FVIII (if patient is inhibitor-negative or has a LTI) or bypassing agents (if patient has a HTI). The recently reported experience of Mahlangu et al where FVIII was given to patients without inhibitors on emicizumab (215 events) without any thrombotic complications suggests that treating bleeds with FVIII in patients on emicizumab in whom the inhibitor has been eradicated is likely to be both safer and more convenient than treating bleeds with current bypassing agents (rFVIIa or FEIBA) in patients on emicizumab in whom the inhibitor persists. 36 The same would apply to patients undergoing surgery. Therefore, recognizing the value of not having an inhibitor, the FIT group believes that all patients with inhibitors should still be offered at least one attempt at ITI. Ultimately, it is the decision of the patient/family, and given the considerable demands of ITI, emicizumab alone without an attempt at ITI is an alternative.

| Concomitant use of emicizumab and ITI
Although the efficacy and safety of emicizumab given together with Eradication of inhibitors is still a desirable goal and ITI is the only approach that currently offers this potential.
Patients with inhibitors should be offered at least one attempt at ITI.
Although inhibitor eradication is still a laudable goal, for those patients who for various reasons must delay or are unable to undertake ITI, emicizumab alone is now an option.
The likelihood of successful ITI is mainly on the basis of historical pre-ITI peak titre and peak titre during ITI. ITI dose/regimen may be chosen according to patients' risk group.
Monitoring should be done frequently (suggest monthly), and ITI dose/frequency can be adjusted depending on how the patient is doing (based on changes in inhibitor titre and bleeding phenotype).
For patients who are not appearing to be successful with ITI, adjustments to the ITI regimen can be undertaken. This includes switching FVIII products or intensifying the regimen. With the availability of emicizumab, the FIT group would in general not be supportive of adding immunosuppressive therapy.  non-factor therapies, and recognizing the demanding and costly nature of ITI, we believe that clinicians, patients/families and/or payers will likely limit ITI to only one attempt. Therefore, every attempt should be made to ensure success with the first course of ITI.

| CON CLUS I ON S AND RECOMMENDATIONS
Since the first report of ITI in the 1970s, the haemophilia community has adopted ITI as standard of care when patients with severe haemophilia A develop HTIs. ITI has for the past almost 50 years remained relatively unchanged. Now, non-factor therapies beginning with emicizumab raise many questions. There is a need to provide haemophilia treaters with guidance in this changing therapeutic environment. The FIT group's key conclusions are summarized in conducted prospective studies to evaluate the impact of adding emicizumab, and in the future, other non-factor therapies, into the management of patients with inhibitors.

ACK N OWLED G EM ENTS
The authors thank Life Science Praxis, Barcelona, Spain, and William Fiedelman, MD, for assistance during preparation of this manuscript.
Dr. Fiedelman reviewed the transcripts of the three FIT group meetings and contributed to development of the initial draft manuscript.
He was paid by Life Science Praxis (a company contracted by Grifols to provide editorial assistance). After that, FIT members took over the ongoing development of the manuscript and all revisions following reviewers' comments.

D I SCLOS U R E S
The FIT group was supported by an unrestricted grant from Grifols, S.A., Barcelona, Spain. All authors participated in the planning conferences leading to this manuscript and received partial or full reimbursement for expenses but otherwise did not receive any honoraria for their participation in any FIT group activities.