Benefits of prophylactic emicizumab in enhancing immune tolerance induction in a boy with hemophilia A and very high inhibitor titer

2021 ◽  
Author(s):  
Nongnuch Sirachainan ◽  
Ampaiwan Chuansumrit ◽  
Surapan Parapakpenjune ◽  
Pakawan Wongwerawattanakoon ◽  
Surapong Lertthammakiat ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
Inhibitor Titer ◽  
Very High

scholarly journals Low-Dose Immune Tolerance Induction for Hemophilia a Children with Poor-Risk High-Titer Inhibitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1122-1122
Author(s):  
Zekun Li ◽  
Zhenping Chen ◽  
Xiaoling Cheng ◽  
Xinyi Wu ◽  
Li Gang ◽  
...  
Keyword(s):  
Success Rate ◽  
Board Of Directors ◽  
Immune Tolerance ◽  
Low Dose ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Inhibitor Titer

Background: Low-dose immune tolerance induction (ITI) +/- immunosuppression as a practical ITI strategy in China showed a relatively satisfactory success rate and economic advantages in pilot study. However, the outcome still needs to be verified by larger cohort. Aim: To report the efficacy of this low-dose ITI +/- immunosuppression strategy in hemophilia A children ≥ 10 BU. Methods: This was a single center, prospective study in 53 hemophilia A subjects from Sep 2016 to Apr 2019. All subjects having ≥ 10 BU receiving ~50IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab and prednisone judging by inhibitors and ITI response. Results: Finally, 46 subjects received this strategy at a median of 3.2 (IQR, 2.3-6.5) years old, their pre-ITI inhibitor titer was median 30.0 (range, 10.1-416) BU. Analysis at median 15.1 (range 3.0-34.4) months follow-up, success (inhibitor <0.6BU) was achieved in 32 (69.6%) subjects, partial success (inhibitor <5BU but >0.6BU) in 11 (23.9%) subjects, and failure in 5 (10.9%) subjects. Between subjects administered ITI-alone and ITI- immunosuppression, no significant difference was observed in time to success (median 8.5; IQR 6.7-11.7 vs 10.2; IQR 5.1-25.1, P=0.164). The mean monthly bleeding rate on ITI was 0.49 which declined 59.3% compared with pre-ITI period. Subjects administered ITI-immunosuppression (0.54 ± 0.46) was higher than ITI-alone (0.42 ± 0.69) although with no significantly difference (P=0.089). Seven (21.9%) subjects experienced inhibitor recurrence, 4 subjects treated with ITI-alone, 3 with ITI-immunosuppression. Recurrence occurred at a median of 4.8 (range, 2.8-10.8) months after successful ITI with inhibitor titer transiently rising to median 0.7 (range, 0.7-1.5) BU. Conclusion: This low-dose ITI +/- immunosuppression therapy in subjects with pre-ITI inhibitor ≥ 10 BU showed a success rate similar to other high/intermediate-dose regimen for the whole inhibitor patients. The subjects treated with ITI-immunosuppression did not showed higher recurrence at present, while a longer time follow-up is still needed. Disclosures Poon: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; World Federation of Hemophilia: Other: Not-for-profit organization affiliation: volunteer ; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation in sponsored research; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Prevention of Inhibitor Development Using Apoptosis-Induced FVIII Producing ES Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3381-3381
Author(s):  
Shogo Kasuda ◽  
Yoshihiko Sakurai ◽  
Kohei Tatsumi ◽  
Tomohiro Takeda ◽  
Atsushi Kubo ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Es Cells ◽  
Tolerance Induction ◽  
Target Protein ◽  
Apoptotic Cells ◽  
Danger Signal ◽  
Immune Tolerance Induction ◽  
Peptide Epitopes ◽  
Inhibitor Titer

Abstract [Background] Hemophilia A is an X-linked bleeding disorder resulting from abnormality in the coagulation factor VIII (FVIII) gene. Development of inhibitors remains a significant problem for a treatment of hemophilia A. Approximately 25–30% of sever type hemophilia A patients develop inhibitor antibodies that reduce or completely negate the benefits of replacement therapy. Furthermore, a major issue that all gene therapy trials for hemophilia are facing is the risk of forming inhibitory antibodies to the transgene product. Although immune tolerance induction (ITI) is the effective method to decrease inhibitor concentration, it costs too expensively and there are some patients who do not show any response to ITI. Thus, it is desired to establish a novel immune tolerance induction method. Recent immunological studies have pointed out that “danger signal” is required to initiate immune reactions and immune tolerance is induced in the absence of danger signal. Apoptotic cell death is considered to be associated with immune tolerance because processing of intracellular antigen occurs without danger signal. Recently, Miyake et al. reported that intravenous injection of apoptotic cells expressing a fragment of myelin oligodendrocyte glycoprotein (MOG) on cell membrane reduced MOG-specific T cell response and prevented the development of experimental autoimmune encephalomyelitis (EAE) [J Clin Invest2007;117:2268–78.]. Based on these principles and findings, we investigated the novel immune tolerance approach with pretreatment of apoptotic embryonic stem (ES) cells secreting FVIII. [Methods] All animal experiments were performed in accordance with institutional and national regulations and approved by the Nara Medical University Animal Care Committee. We have already established mouse ES cells secreting human FVIII by integrating human FVIII gene [Kasuda et al, J Thromb Haemost 2008]. As a pretreatment, hypo-osmotic stress-induced apoptotic ES cells were injected intraperitoneally into the FVIII-KO mouse. After the various periods, administration of hFVIII concentrates (4 IU/body) was repeated every week. Then, titration of inhibitor was measured chronologically with Bethesda methods. [Results] In the non-pretreatment group (n=15), the inhibitor titer was 0.03 ± 0.00 BU/ml at 1 week after first administration of hFVIII concentrates. Then, the inhibitor titer rose to 0.18 ± 0.03 BU/ml and 3.03 ± 0.12 BU/ml with every following hFVIII administration. On the other hand, in the pretreatment group #1 (hFVIII administration was begun 1 week after pretreatment, n=9), inhibitor titer showed the significantly low levels (0.54 ± 0.27 BU/ml) even after thrice administration of hFVIII (p<0.05). Furthermore, in another pretreatment group #2 (hFVIII administration was begun 2 weeks after pretreatment, n=3), inhibitor titer showed much lower levels (0.09 ± 0.03 BU/ml) after thrice administration (p<0.01). [Discussion] We showed the possibility of reduction of inhibitor titer with pretreatment of apoptotic hFVIII secreting ES cells. The efficacy for the reduction of inhibitor titer depended on the period between pretreatment with apoptotic cells and first hFVIII administration, suggesting that a specified period is required to induce immune tolerance. Unlike the method using a peptide fragment of target protein (MOG) in the previous report by Miyake et al., our method features the utilization of a whole target protein (FVIII), by which tolerance to multiple epitopes of the protein would be induced. Identification of the precise peptide epitopes of a target protein would not be necessary since selection and presentation are executed by the host’s own antigen presenting cells. We aspire for the complete suppression of inhibitor formation with an ingenious administration of apoptotic ES cells. We believe that this approach has potential for future clinical therapy.

scholarly journals Immune Tolerance Induction (ITI) with a Plasma-Derived Factor VIII for Patients with Hemophilia a and Inhibitors: A Retrospective Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4923-4923
Author(s):  
Miguel A. Escobar ◽  
Linda Shaffer ◽  
Mark Holguin ◽  
Timothy McCavit ◽  
Sandeep K. Rajan ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Off Label ◽  
Inhibitor Titer ◽  
Antihemophilic Factor ◽  
Partial Success

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer <0.6 Bethesda Units [BU] at 33 months of ITI, FVIII recovery ≥66% and half-life ≥6 hours), "partial success" (a reduction in inhibitor titer to <5 BU mL with FVIII recovery <66% and/or FVIII half-life <6 hours associated with clinical response to FVIII therapy not followed by a treatment-limiting anamnestic rise in inhibitors to >5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

Durability of ITI Utilizing Rfviiifc

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3793-3793
Author(s):  
Margaret V. Ragni ◽  
Lynn M. Malec ◽  
Janna M. Journeycake
Keyword(s):  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Viii Inhibitor ◽  
Inhibitor Titer

Introduction: The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy in patients with severe hemophilia A who develop inhibitors. The long-acting recombinant factor VIII Fc fusion protein, rFVIIIFc (Eloctate™), which is safe and effective in the prevention and treatment of bleeding events, may promote tolerance to FVIII as shown in preclinical animal models and an inhibitor prone child, as Fc suppresses immunoregulatory Tcells to proteins to which Fc is attached. We therefore previously hypothesized rFVIIIFc would provide effective ITI, specifically shortening and simplifying ITI, and have previously described successful inhibitor eradication in three patients. Long-term follow-up data after successful ITI in patients with severe hemophilia remains limited. In the International Immune Tolerance Induction study, at 1-year follow-up, 6 of 66 subjects who had achieved tolerance demonstrated evidence of relapse at a median of 9.5 months. Of these 6 subjects, 1 had a measurable inhibitor titer and 5 had reduced FVIII recovery. We aim to provide follow-up data on our cohort of patients who had successful inhibitor eradication utilizing rFVIIIFc for ITI. Methods: Immune tolerance induction was initiated in three patients with severe hemophilia A and anti-VIII >5 B.U., in two as initial ITI (Pt. 1, 3), and one as salvage (Pt. 2) after failing to achieve ITI with standard rFVIII due to poor compliance. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to <0.6 B.U. Tolerance was a priori defined as achieving anti-FVIII <0.6 B.U., FVIII recovery of at least 60%, and half-life (t½) >6 hours. Once a t½ >6 hours was documented, incremental reduction to rFVIIIFc occurred. Patients continued to be followed by their local HTC as per standard of care. Results: ITI was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc every other day or three times weekly per MD discretion. The time to initial anti-FVIII <0.6 B.U. was 4-12 weeks. Patient 1 and 2 were able to achieve tolerance, with a FVIII recovery of at least 60%, and half-life (t½) >6 hours, at weeks 18 and 17, respectively, after initiation of ITI. Patient 3 has improved but is not yet fully tolerized, as evidenced by 57% recovery and a t½ of approximately 7 hours. Anti-VIII inhibitor titers remain negative at 15, 16 and 15 months, from the initiation of ITI in patients 1, 2, and 3 respectively. Patients 1 and 2 have been able to decrease their post ITI prophylaxis dosing regimen to 80 IU/kg and 65 IU/kg three times a week while maintaining a FVIII trough of >1%. No patients were maintained on bypassing prophylaxis during ITI and no patients have experienced hemarthroses or other major bleeding event since the initiation of ITI. Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. At a mean duration of follow up of 15.3 months, all patients achieved an anti-VIII inhibitor titer of 0 B.U. Repeat pharmacokinetics studies will be available at planned subsequent follow-up visit. To date, these data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in three children with inhibitors, and has provided durable and continuing immune tolerance to FVIII. Whether rFVIIIFc ITI will be successful and durable in a larger cohort of children with severe hemophilia A will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the Hemophilia Inhibitor Response to Eloctate (HIRE) Study, has begun recruitment. Disclosures Ragni: SPARK: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Malec:Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding; Biogen: Consultancy. Journeycake:CSL: Consultancy; Biogen: Consultancy; Baxalta/Shire: Consultancy.

scholarly journals IgG subclasses of anti-FVIII antibodies during immune tolerance induction in patients with hemophilia A

2008 ◽  
Vol 142 (4) ◽  
pp. 644-652 ◽  
Author(s):  
Pauline M. W. van Helden ◽  
H. Marijke van den Berg ◽  
Samantha C. Gouw ◽  
Paul H. P. Kaijen ◽  
Marleen G. Zuurveld ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Igg Subclasses ◽  
Immune Tolerance Induction

scholarly journals Anti-A2 and anti-A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A

2015 ◽  
Vol 13 (4) ◽  
pp. 540-547 ◽  
Author(s):  
P. Lapalud ◽  
C. Rothschild ◽  
E. Mathieu-Dupas ◽  
J. Balicchi ◽  
Y. Gruel ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Immune Tolerance Induction ◽  
A1 Domain

The long-term course of factor VIII inhibitors in patients with congenital haemophilia A without immune tolerance induction

2011 ◽  
Vol 105 (01) ◽  
pp. 59-65 ◽  
Author(s):  
Camila Caram ◽  
Roberta Grazielle de Souza ◽  
Júlio Carepa de Sousa ◽  
Tatiana Araújo Pereira ◽  
Ana Maria do Amaral Cerqueira ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Factor Viii ◽  
Immune Tolerance ◽  
Tolerance Induction ◽  
Clotting Factor ◽  
Haemophilia A ◽  
Immune Tolerance Induction ◽  
Inhibitor Titre ◽  
Very High

SummaryThe development of alloantibodies that inhibit or neutralise the function of factor VIII is considered the most serious complication of the treatment of congenital haemophilia A. In order to describe their course without immune tolerance induction (ITI), we documented data on all performed inhibitor tests with dates as well as on clotting factor infusions of all consecutive patients who were treated in our centre between 1993 and 2006. Patients were tested every 7.1 months (95% confidence interval [CI], 6.6–7.8). A ‘sustained negative inhibitor status’ was defined as consistent non-positive inhibitor measurements for two years or longer. A total of 60/486 (12%) patients tested had a positive inhibitor titre in two or more occasions. Most of the patients (56%) with a maximum inhibitor titre of < 5 Bethesda unit (BU)/ml (named “low titre inhibitor”) developed a sustained negative inhibitor status. Among patients with high (5–9.9 BU/ml) and very high (≥ 10 BU/ ml) inhibitor titres, the proportions were 50% and 3%, respectively. Our findings suggest that ITI might not be needed for all patients with non-transient inhibitors, especially when their maximum inhibitor titre is below 10 BU/ml. Further studies in countries where ITI is not available are needed to examine predictors of the natural sustained negative inhibitor status.

Successful Treatment of Inhibitor Formation in Adult Congenital Hemophilia A with Rituximab.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4074-4074 ◽  
Author(s):  
Chirag J. Amin ◽  
Alice D. Ma
Keyword(s):  
Factor Viii ◽  
Knee Replacement ◽  
Immune Tolerance ◽  
Bolus Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
Recombinant Factor Viii ◽  
Promising Alternative ◽  
Immune Tolerance Induction

Abstract Inhibitor development in congenital hemophiliacs can be clinically catastrophic. Immune tolerance induction therapy has previously been the standard of care in eradicating inhibitors; however due to a multitude of factors, this may not be applicable in certain patients. The role of Rituximab is receiving more attention in this subset of patients. In this abstract, we report that treatment with Rituximab led to successful eradication of high-titer inhibitors in 3 patients with mild to moderate hemophilia A who developed inhibitors after receiving intensive treatment with recombinant Factor VIII (FVIII). Patient Characteristics: Three patients, aged 50–70, with baseline FVIII levels of 2–9%, developed inhibitors after recombinant Factor VIII infusion. Patient A was treated with continuous infusion FVIII for a post-surgical hemarthrosis for approximately 7 days. Patient B received bolus dose FVIII for a GI bleed for at least 10 days, and Patient C received bolus dose FVIII for knee replacement for 10 days. Factor VIII inhibitors were detected in these patients after one month. None of these patients had been treated with immune tolerance previously or had known inhibitors. Each patient received Rituximab 375mg/m2 every week for 4 weeks total. During and after treatment, FVIII levels and Bethesda inhibitor titers (BU) were monitored. Results: All three patients had eradication of their inhibitors (Figure 1) and return of their FVIII levels to baseline by six months post-treatment. Notably, patient C’s inhibitor peak was 117 BUs, 7 months prior to Rituximab treatment. Patient C’s initial response to Rituximab has been previously reported at ASH in abstract form. We now report that 4 years later, this patient has had a recurrence of his inhibitor after monoclonal FVIII for a contralateral knee replacement but with a peak titer of only 2 (Table 1). Inhibitor Trends after Rituximab Treatment Inhibitor Trends after Rituximab Treatment Bethesda Inhibitor Titer (BU) per Month (*) after Receiving Rituximab 0* 1 3 6 36 48 51 NA=Not applicable as data has not matured yet Patient A (BU) 5 0.7 0 0 NA NA NA Patient B (BU) 17 7 2 0 NA NA NA Patient C (BU) 40 4 0 0 0 2 0.5 Conclusion: Inhibitors in patients with mild-moderate hemophilia differ from those with severe FVIII deficiency, behaving more like the autoantibodies seen in patients with spontaneous FVIII inhibitors. In support of this idea, we successfully treated high titer inhibitors which developed in 3 patients with baseline FVIII levels of 2–9%. All three patients had prompt resolution of their inhibitor titers during the course of therapy, with return of their baseline FVIII levels. Historically, patients with mild-moderate hemophilia treated at the Harold R. Roberts Comprehensive Hemophilia Center at the University of North Carolina were treated either with immune tolerance induction or by bypass agents alone, with inhibitor eradication taking months to years (data not shown). While performance of larger prospective trials would be ideal, the small number of patients with this condition limits the ability to perform these trials. Our findings, in combination with other case series from other institutions, reveal a promising alternative for prompt and reliable treatment in mild-moderate hemophiliacs with inhibitors.

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