scholarly journals Immune Tolerance Induction with Simoctocog Alfa (Nuwiq®) in Six Patients with Severe Haemophilia a and FVIII Inhibitors

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5037-5037
Author(s):  
Neha Bhatnagar ◽  
Kate Khair ◽  
Ri Liesner ◽  
Alice Wilkinson ◽  
Larisa Belyanskaya
Keyword(s):  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Poor Prognosis ◽  
Case Series ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Immune Tolerance Induction ◽  
Inhibitor Titre

Abstract Introduction and Objective: Inhibitors to coagulation factor VIII (FVIII) are the most serious complication of haemophilia A treatment. Previously untreated patients (PUPs) are at the greatest risk of inhibitors, which generally occur within the first 20 exposure days (ED) to FVIII. Immune tolerance induction (ITI) is the only clinically proven strategy for eradication of inhibitors. We present a case series of six PUPs with severe haemophilia A and inhibitors who underwent ITI with simoctocog alfa (Nuwiq®), a 4th generation human cell-line-derived recombinant FVIII approved for treatment of haemophilia A. Materials and Methods: Six male PUPs with severe haemophilia A who developed FVIII inhibitors after treatment with simoctocog alfa were started on ITI with simoctocog alfa. Primarily, we assessed the success of simoctocog alfa in patients with inhibitors. Success of ITI was determined based on undetectable inhibitor titre (< 0.6 BU/ml), FVIII recovery ≥ 66% and half-life ≥ 6 hours. Secondary objectives were to assess bleeding rate, tolerability and safety in patients with inhibitors treated with simoctocog alfa ITI. Results: The age of the patients at the start of ITI ranged from 8 to 186 months. Four of the patients were Caucasian, and two were African. All patients had a F8 mutation associated with high risk of ITI failure and two patients had an additional risk factor for ITI failure. The number of EDs prior to inhibitor development ranged from 9 to 33, and the peak inhibitor titre ranged from 0.9 to 114 BU. For ITI, five patients were treated with 100 IU/kg simoctocog alfa daily, and one with 90 IU/kg every other day. One patient achieved complete tolerisation and is now on prophylaxis at normal doses, having achieved an undetectable inhibitor titre after 9 months. This was despite an inhibitor titre ≥ 10 BU/mL at ITI start, which is considered a poor prognosis factor for ITI success. Three other patients achieved an undetectable inhibitor titre after 1, 6 and 18 months of ITI, and FVIII recovery has normalised but half-life remains short and they are on weaning doses as the half-life extends. One patient discontinued ITI with simoctocog alfa after 15 months due to an increasing inhibitor level. This patient was 15 years old at ITI start, and older age is associated with poor ITI outcome. Additionally, his haemophilia A was untreated for 15 years, during which time he developed severe arthropathy. One patient, who started ITI 3 months ago, has an ongoing inhibitor titre and continues on ITI with simoctocog alfa. Conclusions: In a case series of six patients treated with simoctocog alfa for ITI, who all had poor prognosis factors for ITI success, four patients (67%) to date have achieved an undetectable inhibitor titre. These data suggest that ITI with simoctocog alfa may be an effective treatment approach in haemophilia A patients with inhibitors. Disclosures Khair: Shire, SOBI, Pfizer, Roche, Novo Nordisk, Octapharma: Speakers Bureau; shire, SOBI, Pfizer, Roche: Research Funding. Liesner:Roche: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Sobi: Speakers Bureau. Belyanskaya:Octapharma AG: Employment.

Immuntoleranzinduktion mit hoch dosiertem FVIII und intravenösen Immunglobulin-Pulsen

2010 ◽  
Vol 30 (S 01) ◽  
pp. S119-S121 ◽  
Author(s):  
C. Pinkwart ◽  
R. Haase ◽  
N. Merkel ◽  
D. Forsberg ◽  
C. Mauz-Körholz ◽  
...  
Keyword(s):  
Body Weight ◽  
Immune Tolerance ◽  
Half Life ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Initial Exposure ◽  
Immune Tolerance Induction ◽  
Fviii Inhibitor ◽  
Inhibitor Level

SummaryThe development of neutralizing allo-antibodies against factor VIII (FVIII) or FVIII inhibitors is a severe complication in the treatment of haemophilia A. About 25% of the children with severe haemophilia A develop FVIII inhibitors. Here we report on a boy with severe haemophilia A and intron 22 inversion of the FVIII gene who was diagnosed at ten months of age. After 16 exposure days to FVIII (81 days after initial exposure) he developed a FVIII inhibitor (maximum: 9.76 BU/ml). Therapy: We started immune tolerance induction (ITI) according to the Bonn protocol with high dose plasma derived FVIII concentrate (100 IU per kg body weight) twice daily. For additional inhibitor elimination treatment the patient received intravenous immunoglobulin (ivIg) at a dose of 1–2 g/kg body weight every 4 to 6 weeks. After start of treatment a rapid decline of the inhibitor level was observed, nevertheless low FVIII inhibitor levels persisted (<5 BU/ ml). Furthermore, the FVIII half-life was still accelerated. However, after every course of ivIg the inhibitor level declined and FVIII half-life was prolonged. Currently, the FVIII half-life is approaching normal values after more than seven months of ITI duration. Conclusion: Additional application of immunoglobulin is beneficial for immune tolerance induction.

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.

Natural History Of Inhibitor Recurrence Following Successful Immune Tolerance Induction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1106-1106 ◽  
Author(s):  
Ana G. Antun ◽  
Paul Monahan ◽  
Marilyn J. Manco-Johnson ◽  
Michael Callaghan ◽  
Guy Young ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Tolerance Induction ◽  
Advisory Committees ◽  
Immune Tolerance Induction ◽  
Baxter Healthcare ◽  
Inhibitor Titer

Abstract Introduction The formation of Factor VIII (FVIII) inhibitory antibodies is a major complication of hemophilia A. Currently immune tolerance induction (ITI) is successful in up to 70% of patients. Outside of the International Immune Tolerance Registry, where 6 of 128 patients had a recurrent inhibitor between 1 and 6 years, little is known about the probability of inhibitor recurrence following successful ITI. Objective To determine the probability of inhibitor recurrence and the influence of adherence to post-ITI prophylaxis on inhibitor recurrence following successful ITI. Methods All persons with hemophilia A (FVIII level < 50%) who completed ITI (defined as inhibitor titer <0.6 BU/ml) between 1/1/1998 and 8/15/2010 at 12 U.S. Hemophilia Treatment Centers were identified. Demographic and clinical characteristics were obtained through review of subject medical records and included age at start of ITI, race, ethnicity, hemophilia severity, peak inhibitor titer prior to the start of ITI and ITI regimen. For those subjects where tolerance was confirmed with measurement of FVIII half-life > 6 hours and/or FVIII recovery > 66% in addition to inhibitor titer < 0.6 BU/ml, information was also collected on post-ITI prophylaxis regimen, adherence to post-ITI prophylaxis, and the presence of a recurrent inhibitor titer (≥ 0.6 BU/ml) or last inhibitor titer prior to 8/15/2011. Adherence during the 6 months prior to inhibitor recurrence or last inhibitor titer was determined by review of pharmacy and infusion logs compared with prescribed treatment regimen. Follow-up time started when the subject was considered tolerized (normalized half-life or recovery if half-life not performed) and ended at the time of inhibitor recurrence or the last recorded inhibitor titer. Estimates of the probability of remaining inhibitor-free at 1, 3 and 5 years were calculated with the Kaplan-Meier method. The association between adherence (completing >80% of prescribed infusions vs. < 80% of prescribed infusions) and inhibitor recurrence was assessed using the chi-square test. Results Eighty-three male subjects were enrolled. The median age at start of ITI was 3.3 years (range: 0.08 - 39). The majority of the subjects were white (73%) and non-Hispanic (73.5%). Seventy-one (85.6%) had severe hemophilia. The median peak inhibitor titer was 8.5 BU/ml (range: 0.6 - 950). Four subjects (5%) had a prior unsuccessful course of ITI. FVIII alone was used in 85% of subjects. Sixty-seven (80.7%) met criteria for tolerance and 64 had follow-up data available, with a median follow up time of 3.4 years (range: 0.08-12.4). Forty-four subjects (68.7%) remained tolerant without a recurrent inhibitor titer after a median 4.7 years (range: 0.25-12.4) of follow-up. Twenty subjects (31.3%) had at least one inhibitor titer ≥ 0.6 BU/ml after a median of 1.6 years (range 0.08-5.7). The probability of recurrent inhibitor at 1 year is 0.15 (95% CI: [0.05, 0.20]); at 3 years is 0.30 (95% CI: [0.2, 0.4]) and 5 years is 0.35 (95% CI: [0.2, 0.5]) (Figure 1). Four subjects discontinued post-ITI prophylaxis anywhere from 6 months to greater than 6 years after tolerance was achieved, of whom 2 (50%) developed a recurrent inhibitor. Of those that remained on post-ITI prophylaxis, 41 subjects (64.1%) were adherent (took >80% of prescribed infusions) to their post-ITI prophylaxis regimen, of whom 13 (31.7%) developed a recurrent inhibitor. Twenty-three (35.9%) who were non-adherent (took <80% of the prescribed infusions) of which 7 (30.4%) subjects developed a recurrent inhibitor; no statistically significant association was found between adherence and inhibitor-free status (p=0.92). Conclusion ITI is currently the most effective treatment to eradicate FVIII inhibitors, however 5 years after completion, 30-35% of patients will have at least one inhibitor titer ≥ 0.6 BU/ml. A recurrent inhibitor is unlikely after 5 years. Adherence to post-ITI prophylaxis does not appear to be a major driver of inhibitor recurrence. It is imperative to elucidate the factors that influence the durability of successful ITI to improve quality of life and cost of treatment in these patients. Disclosures: Monahan: Baxter: Consultancy, Honoraria, Research Funding, travel support, travel support Other; Bayer: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Prolor Biotech: Research Funding; Asklepios: Consultancy, Research Funding, travel support Other. Manco-Johnson:Eisai: Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carpenter:Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding. Kruse-Jarres:Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy; Baxter Healthcare: Consultancy. Ragni:Novo Nordisk: Research Funding; Merck: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Tacere Benitec: Consultancy; Smith Kline Glaxo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Kempton:Novo Nordisk: Research Funding; Baxter Healthcare: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Outcome of Immune Tolerance Induction Using an Extended Half-Life Clotting Factor Concentrate — Recombinant Factor VIII Fc (Eloctate™) — a Report from India

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2494-2494
Author(s):  
Aby Abraham ◽  
Shashikant Apte ◽  
Chandrakala Shamukhaiah ◽  
Fouzia N. ◽  
Kannan Subramaniam ◽  
...  
Keyword(s):  
Median Duration ◽  
Immune Tolerance ◽  
Half Life ◽  
Tolerance Induction ◽  
The Other ◽  
Clotting Factor ◽  
Immune Tolerance Induction ◽  
Inhibitor Titre ◽  
History Of ◽  
Inhibitor Titer

Abstract The development of inhibitors is the most serious adverse effect of replacement theray with clotting factor concentrates (CFC) in hemophilia. Its eradication is also difficult, usually requiring months of frequent exposure to high doses of the CFC - immune tolerance induction (ITI). There is limited data on use of extended half-life (EHL) CFC for ITI. A limited program of ITI was made possible in India with some of the rFVIIIFc (Eloctate™) provided through the humanitarian aid program of the World Federation of Hemophilia. This report summarizes the interim outcome of ITI in these patients treated at three centers participating in this program. ITI with rFVIIIFc was offered to patients with hemophilia A and significant inhibitors. The CFC dose used ranged from 50 IU/kg, 3x/week, to 200 IU/kg per day, depending on the weight, convenience and early response as well as availability of rFVIIIFc. All patients completing at least 10 weeks of ITI are included in this analysis. Bethesda assay was done every 2-4 weeks. Successful ITI was defined as a negative Bethesda assay with a FVIII recovery of >60%. Patients received either FEIBA or rVIIa for breakthrough bleeds. Thirty eight patients were included in this analysis. The median age at initiation of ITI was 15 years (range:2 -39). Nine (24%) patients had a family history of inhibitors. The median age at which inhibitors developed was 11 years (range:0.6 -38). Nine (24%) patients had history of surgery prior to onset of inhibitor. Ten patients (26%) had exposure to only plasma derived factors. All patients were on episodic CFC replacement therapy except two (5%) who were receiving low-dose prophylaxis prior to inhibitor development. The median exposures to FVIII was 20 (range:2-80) and duration of inhibitors prior to ITI was 2 years (range:0.1 - 20). The median highest inhibitor titre recorded prior to ITI was 19 BU (range:4-1177). Only 3 patients had their maximum inhibitor titer below 5BU. The median inhibitor titre at the time of starting ITI was 10.4 BU (range: 0.6-1177). The median peak inhibitor titer after starting ITI was 40.4 BU (range:3.5-13933). Out of the 38, 17 (45%) patients achieved a negative inhibitor status after ITI for a median duration of 23 weeks (range: 10-64). Among the 17 patients who had successful ITI, the median duration of ITI required to achieve negative inhibitor status was 20 weeks (range:10-60). Among the other 21 patients who had persistence of inhibitors, 4 were included in other clinical trials, 3 discontinued due to personal reasons while the other 14 are continuing ITI based on availability of appropriate EHL CFC. Among these patients with persistence of inhibitors, the last inhibitor titer was 6.4 BU (range:0.9-9240) after a median of 26 weeks of ITI (range:11-64). The median number of breakthrough bleeds during ITI was 1 (range:0-12), being 1 (range:0-6) among responders and 1 (range:0-12) among those with persistence of inhibitors. A comparison of the group which responded within this duration of ITI and those who did not respond is shown in the table. Older age and the peak inhibitor titer prior to ITI were the two significant variables which affected early outcome of ITI. These data show that EHL rFVIIIFc can be effective in ITI with nearly 45% of patients achieving a negative inhibitor titer within 1 year and with responses starting as early as 1 month and nearly half of them within 4 months. There was also a relatively low median annualized bleed rate during ITI. More patients need to be treated with different doses of rFVIIIFc to assess its potential in ITI and to determine the optimal protocols but the initial data is promising. Disclosures No relevant conflicts of interest to declare.

Immune tolerance induction with antihaemophilia factor (human) in poor prognosis patients with haemophilia A

Haemophilia ◽  
2021 ◽  
Author(s):  
Miguel Escobar ◽  
Linda Shaffer ◽  
Mark Holguin ◽  
Timothy McCavit ◽  
Novinyo S. Amega ◽  
...  
Keyword(s):  
Immune Tolerance ◽  
Poor Prognosis ◽  
Tolerance Induction ◽  
Haemophilia A ◽  
Immune Tolerance Induction

scholarly journals The Atlanta Protocol: Immune Tolerance Induction in Pediatric Patients with Hemophilia a and Inhibitors on Emicizumab

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 634-634 ◽  
Author(s):  
Glaivy M. Batsuli ◽  
Karen L. Zimowski ◽  
Kelly Tickle ◽  
Shannon L. Meeks ◽  
Robert F. Sidonio
Keyword(s):  
Clinical Evaluation ◽  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Pediatric Patients ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Advisory Board ◽  
Third Generation ◽  
Immune Tolerance Induction

Abstract Introduction: The formation of neutralizing anti-factor VIII (fVIII) antibodies, called inhibitors, is a challenging complication in hemophilia A care. While novel non-factor therapies significantly reduce bleeding symptoms in patients with hemophilia A and inhibitors, the absence of fVIII tolerance remains unchanged. Additionally, there are concerns regarding the hemostatic efficacy and safety of bypassing agents necessary for the management of breakthrough bleeds in patients with inhibitors on these novel therapies. Immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII. Here we report on the response to ITI in pediatric patients following initiation of the bispecific humanized monoclonal antibody Emicizumab. Methods: Patients between the ages of 1 - 11 years old with hemophilia A and an active inhibitor (≥0.6 Bethesda Units (BU)/mL) treated at the Emory Pediatric Hemophilia Treatment Center were included in this analysis. In general, ITI was initiated after four weekly loading doses of Emicizumab with standard or extended half-life recombinant (rfVIII) or plasma-derived (pdfVIII) fVIII at 100 units/kg three times per week. Factor choice was determined by the fVIII product used for the ITI attempt prior to initiation of Emicizumab or a standard half-life third generation rfVIII product if no prior ITI attempts. FVIII pharmacokinetics during ITI including the estimated fVIII half-life, fVIII incremental recovery of expected, and inhibitor titers were measured with chromogenic-based assays using bovine reagents. Bleeding symptoms and treatment regimens for bleeds/procedures were also monitored. Results: Eight patients are currently receiving ITI according to this Atlanta Protocol. Details regarding this cohort are outlined in Table 1. Three of the 8 patients required central venous access for ITI fVIII infusions. These eight patients have historical peak inhibitor titers, defined as the highest inhibitor titer prior to this ITI regimen, ranging from 2.0 - 198 BU/mL. Four patients have just recently started ITI. The other 4 patients (patients 1, 2, 4, and 5) have been treated with Emicizumab and ITI for a median duration of 15 weeks (range 13-18 weeks). Two of the 4 patients are on ITI with a standard half-life third generation rfVIII product, 1 is on a standard half-life third generation B domain deleted (BDD) rfVIII product, and 1 is on an extended half-life (EHL) rfVIII-Fc fusion product. Their last measured inhibitor titers after initiation of ITI range from 0.3 - 3.7 chromogenic BU (CBU). All inhibitor titers declined with the start of ITI, and none of the 4 patients experienced an amnestic response (Figure 1). The fVIII incremental recovery improved in 3 of the 4 patients from a median of 30% of expected (range 17-69%) prior to Emicizumab with ITI to 85% of expected (range 67-85%) at the last clinical evaluation. The 1 patient remaining has an fVIII incremental recovery <10% of expected at the last clinical evaluation. Only one patient has required treatment with a single dose of recombinant activated factor VII (rfVIIa) for a right knee hemarthrosis during ITI without complication. There were 3 additional mild bleeding symptoms in 2 patients that did not require intervention including 1 trauma-induced forehead hematoma that self-resolved and 2 episodes self-resolving epistaxis lasting <5 minutes. Two of the 4 patients reported no bleeding symptoms. There were no episodes of thrombosis or thrombotic microangiopathy. Conclusions: This is the first report detailing the Atlanta Protocol for ITI in hemophilia A patients with inhibitors receiving Emicizumab prophylaxis. Although early, these results suggest that ITI can be safely administered in these patients and is able to achieve continued improvement in clinical indicators of tolerance. Disclosures Batsuli: Bayer: Other: Advisory Board; Genentech: Other: Advisory Board; Octapharma: Other: Advisory Board. Zimowski:National Hemophilia Association/Shire: Other: Funding for clinical fellowship in Hemostasis/Thrombosis. Meeks:Bioverativ: Other: Advisory Board; Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board; Catalyst Biosciences: Other: Advisory Board; Genentech: Other: Advisory Board; HEMA Biologics: Other: Advisory Board; Shire: Other: Advisory Board; Pfizer: Research Funding. Sidonio:Genentech: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Biomarin: Other: Advisory Board; Novo Nordisk: Other: Advisory Board; Octapharma: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Kedrion: Research Funding.

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