Low-responding Inhibitors Research Articles

Inhibitors in hemophilia: association with surgery plans and outcomes in a retrospective cohort study

BackgroundThe development of antibodies (inhibitors) to clotting factors compromises the management of hemophilia A and B, resulting in resistance to clotting factor replacement and, in many cases, the need for bypassing agents to achieve hemostasis. ObjectivesTo evaluate the association between the presence of inhibitors and achievement of perioperative hemostasis, development of complications, and presurgical plan deviations. MethodsWe conducted a retrospective study using data from the Indiana Hemophilia and Thrombosis Center surgical database (1998-2019). Associations between perioperative outcomes and inhibitor status were assessed while controlling for patient and procedural characteristics. ResultsA total of 1492 surgeries were performed in 539 persons with hemophilia, with 72 procedures performed in 20 patients with inhibitors (15 with hemophilia A; 5 with hemophilia B). High-responding inhibitors (>5 BU/mL) were present in 27 procedures, low-responding inhibitors (≤5 BU/mL) were present in in 13 procedures, and 32 procedures were performed in patients with historically persistent inhibitors. Adjusting for age, diagnosis, surgery setting, hemostatic agent, data collection period, and surgery type (major/minor), inhibitors were associated with a higher risk of inadequate perioperative hemostasis (33.4% vs 8.6%; adjusted relative risk [adjRR], 3.78; 95% CI, 1.89-7.56; P < .001). Reported complications include hemorrhage, fever, pain, thrombosis, and infections. Complications were not statistically different based on inhibitor status (31.7% vs 14.6%; adjRR, 1.25; 95% CI, 0.63-2.49; P = .526). Presurgical plan deviations (eg, hemostatic medication dose adjustments, procedure rescheduling, and changes in the length of postoperative hospitalization) occurred more frequently in surgeries involving inhibitors (70.8 vs 39.5%; adjRR, 1.47; 95% CI, 1.12-1.93; P = .005). ConclusionInhibitors are associated with higher risks of adverse perioperative outcomes. Strategies to address inhibitor development should be prioritized to avoid undesirable perioperative outcomes.

Observational Study of Recombinant Factor-VIII-Fc, Eloctate, in Hemophilia Patients with and without Inhibitors

Background: Inhibitor formation is a serious complication of hemophilia A, occurring in up to 30% with severe disease. It is associated with a T-cell response to infused factor VIII which neutralizes and renders it ineffective. Bypass therapy (rVIIa, FEIBA) is less effective, resulting in high morbidity and mortality. While immune tolerance (ITI) with high-dose FVIII neutralizes the inhibitor, it is costly, invasive, and unsuccessful in 30%. Basic studies suggest rFVIIIFc, Eloctate, is less immunogenic than standard recombinant FVIII, rFVIII, as the Fc portion contains regulatory T cells that promote tolerance. In the hemophilia mouse model, rFVIIIFc reduces inhibitor frequency, lowers titer, and shortens ITI, but little is known of its impact on inhibitor patients, as they were excluded from clinical trials.Methods: We, therefore, reviewed outpatient medical records on 60 patients with hemophilia A with and without inhibitors, cared for at the Hemophilia Center of Western Pennsylvania between January 1, 2006 and June 1, 2017, who were treated with rFVIIIFc and on whom anti-FVIII inhibitor assay results were available. This study was approved by the University of Pittsburgh IRB as an expedited study, PRO17020097. Means, medians, and standard deviations or frequencies (percentages) were determined for clinical variables, including age, race, proportion developing inhibitors, peak titer, proportion achieving tolerance, and time to tolerance on ITI. Comparisons between patients with high-titer, low-titer, and no inhibitors were by student's t test for continuous data, or chi-square or Fisher's exact test for discrete data. A p-value of < 0.05 was considered statistically significant.Results: The 60 patients whose charts were reviewed for this study included 18 (30.0%) with hemophilia A with an inhibitor (HA-I), of whom 9 had high-responding inhibitors (≥5 BU) and 9 had low-responding inhibitors (<5 BU); and 42 (70.0%) with hemophilia A without an inhibitor (HA). HA-I were similar to HA in age, with 44.4% vs. 50.0% ≥ 18 years of age, respectively, p>0.5, and in disease severity, 83.3% vs. 64.2% < 0.01 IU/dL, p=0.105, but a greater proportion were black, 16.7% vs. 4.8%, p=0.007, and had an intron 22 inversion mutation, 37.5% and 19.2%, p=0.001 (Table). The majority of both groups were previously treated patients (PTPs), 17 of 18 HA-I (94.4%) vs. 41 of 42 HA (97.6%). Following initiation of rFVIIIFc, none of 42 HA, 0/42 (0%) developed inhibitors, while, by contrast, inhibitors were detected in 6 of 18 (33.3%) HA-I, p=0.002. The 6 patients developing inhibitors after rFVIIIFc included 5 PTPs and 1 PUP: the single PUP was from an inhibitor-prone kindred with an exon 14 nonsense variant (75% inhibitor risk) (Haemophilia, 2016), and developed a low-responding inhibitor, 1.4 BU, after 10 exposures to rFVIIIFc, which resolved to <0.6 BU within 1 month while continuing rFVIIIFc. The 5 PTPs developing inhibitors on rFVIIIFc included 4 of 9 (44.4%) previous high-responding inhibitors (≥5 BU) and 1 of 8 (12.5%) previous low-responding inhibitors (<5 BU). All 4 past high-responders had previously failed or had never undergone immune tolerance induction (ITI); while the single past low-responder had longstanding fluctuating low-level inhibitor titers. Following initiation of rFVIIIFc, the 4 PTPs with past high-responding inhibitors developed inhibitors, median anti-FVIII = 40 BU (0-87.7), which resolved, in all 4, to anti-VIII <0.6 BU after a median 2.2 months (1-13) while continuing rFVIIIFc; the 1 PTP with a past low-responding inhibitor and chronic fluctuating low-level inhibitor, developed a low-responding inhibitor 0.6 BU (0-0.6 BU), which resolved to <0.6 BU while continuing rFVIIIFc, but continues to fluctuate between 0 and 0.6 BU.Discussion: These findings indicate that PTPs without inhibitors or with tolerized inhibitors do not develop inhibitors after switching to rFVIIIFc. By contrast, most PTPs with high-responding inhibitors who failed or never underwent ITI, develop inhibitor recurrence after switching to rFVIIIFc, but these are rapidly tolerized while continuing rFVIIIFc. In PTPs with low-responding inhibitors, rFVIIIFc may reduce but does not eliminate fluctuating low-level titers. Finally, in PUPs at risk for inhibitor formation, rFVIIIFc may induce low-responding low-titer inhibitors which are rapidly tolerized while continuing rFVIIIFc. [Display omitted] DisclosuresRagni:SPARK: Research Funding; NovoNordisk: Honoraria; Alnylam: Consultancy, Honoraria, Research Funding; Sangamo: Research Funding; Genentech/Roche: Research Funding; Bioverativ: Consultancy, Honoraria, Research Funding; MOGAM: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Biomarin: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding. Malec:Bioverativ: Consultancy, Research Funding.

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study.

Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test. A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0-7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens. In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

The Japanese Immune Tolerance Induction (J-ITI) study in haemophilia patients with inhibitor: Outcomes and successful predictors of ITI treatment.

Immune tolerance induction (ITI) was the primary therapeutic approach to eradicate inhibitors in haemophilia patients. Several large ITI registries had been reported, but successful predictors of ITI outcome are still debated. No reports are available on large ITI studies in non-caucasian countries. We designed a retrospective cohort study of ITI in Japanese haemophilia patients with inhibitor. Retrospective data were collected from 155 haemophilia (H)A (140 severe-type) and 7 HB (7 severe-type) patients treated at 45 institutions. ITI outcome was centrally reviewed. We defined "success" as undetectable inhibitor after 2 consecutive measurements. The ITI success rate was 71.2% for HA and 83.3% for HB. Cumulated success rates for HA achieving 50% and 75% were 0.7 and 2years after treatment, respectively. Significant successful predictors in HA were low-responding inhibitors compared to high-responding inhibitors, shorter time to the start of ITI, and lower historical and treatment peak titres of inhibitor. Dose regimen (high dose; ≥90 IU/kg every day, low dose; ≤75 IU/kg, 3d/wk) and the type of therapeutic product did not affect outcomes. The success rate of salvage ITI using von Willebrand factor-containing factor VIII was 50% (n=6/12), and patient age at the start of salvage ITI was a significant predictor. The inhibitor recurred in 6 HA cases (3.9%). The results provided potentially important information for improving future success rates for ITI in inhibitor patients.

Inhibitors in Hemophilia: Treatment Challenges and Novel Options.

Hemophilia A (HA) and hemophilia B (HB) are rare congenital severe bleeding disorders, that may be controlled by proper administration of adequate prophylaxis with factor VIII (FVIII), and factor IX (FIX) concentrates, respectively, to prevent joint damage due to recurrent bleeding. However, approximately 30% of patients develop inhibitory antibodies that render factor replacement therapy ineffective. Due to the high variability of patients' bleeding tendency, there is a need to "individually tailor treatment" for this unique group of patients. While replacement therapy with FVIII or FIX can be used for treating HA or HB patients with low responding inhibitors, hemophilia patients with high-responding inhibitors are treated with bypassing agents. Unfortunately, the Bethesda assay applied for inhibitor measurement in most laboratories does not fully predict either bleeding tendency or therapy response. Immune tolerance induction (ITI) may eradicate most inhibitors, yet treatment is challenging during bleeding episodes. The role of bypassing agents and their various treatment strategies still deserves attention. Recently, new nonreplacement therapies have emerged for patients with hemophilia including patients with inhibitors. Adequate monitoring of bypassing therapy and of the new nonreplacement therapies in inhibitor patients is extremely challenging, thus global hemostatic assays are increasingly used to assess clot formation. This review aims to summarize the current treatment and monitoring challenges for inhibitor patients; in this perspective, we will discuss our institutional approach for optimal decision-making and individual therapy tailoring.

Surgeryand Invasive Procedure With Bypassing Agents In Hemophilic Patients With Inhibitors: A Single Center Experience

Inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX) are one of the most important complications of managing patients with hemophilia A and B. For hemophiliacs with inhibitors, recent advances in the use of bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven®) and Factor VIII Inhibitor Bypassing Activity (FEIBA®) have enabled them to aggressively manage their diseases in emergency or elective surgery. This report shows an updated evaluation of the safety and effectiveness of bypassing agents in the treatment of peri-operative bleeding in this patient population. We reviewed the cases of patients with hemophilia and inhibitors underwent surgery or other invasive procedures between May 2008 and July 2013 using bypassing agents or high dose FVIII concentrates at a single center. Thirty two procedures (23 orthopedic surgeries and 9 other surgeries and procedures) were conducted in 16 hemophilia patients with inhibitors. The median age of the patients was 30.5 years old (range, 7-52). Most patients (14/16, 87.5%) are hemophilia A and 2 patients (12.5%) were hemophilia B. The median titer of inhibitors at procedures was 15 BU (range, 0.7-1900). Patients with low responding inhibitors were 2 cases, and high dose factor VIII concentrates were used. Most patients had high responding inhibitors and one of two bypassing agents was used. Twenty one cases were covered using FEIBA®, nine with rFVIIa initially. The median duration of hospitalization was 14 days (range, 1-58). In most cases, bleeding stopped or controlled well. But, in 5 cases, patients’ bleeding was controlled by sequential bypassing therapy. 4 cases were performed at emergency conditions, and those are segmental resection of small bowel, craniectomy with intracerebral hematoma removal, exploratory thoracotomy, and angiography with embolization. Efficacy of bypassing agents at various surgeries and procedures, based on final patient outcome, was 93.8% (30/32). Two deaths occurred at emergency condition as a result of hypovolemic shock secondary to intracranial hemorrhage or retroperitoneal bleeding. Good control of hemostasis can be achieved with bypassing agents in hemophilia patients with inhibitors undergoing invasive procedures. If surgery or procedure would perform at emergency condition, more active and aggressive management should be needed. The use of bypassing agents in peri-operative period can allow invasive procedure and surgery to be safe and successful in hemophilic patients with inhibitors. Disclosures: No relevant conflicts of interest to declare.

A review of immune tolerance induction with Haemate® P in haemophilia A

Immune tolerance induction (ITI) has been shown to successfully eliminate factor VIII (FVIII) inhibitors in haemophilia patients with inhibitors. We performed a literature search to identify reports from January 1980 to October 2012 on the use of the plasma-derived, von Willebrand factor (VWF)-containing FVIII concentrate Haemate P/Humate-P in the setting of ITI. Six reports were identified that specifically evaluated the use of Haemate P/Humate-P including 32 children and 9 adults. Dosing regimens ranged from 20 IU kg(-1) every 2-3 days in patients with low-responding (LR; n = 5) inhibitors to 300 IU kg(-1) day(-1) in patients with high-responding (HR; n = 36) inhibitors. Complete success was achieved in all five LR patients, in all three HR patients with good prognostic factors (age ≤7 years, pre-ITI inhibitor titre <10 BU, historical inhibitor titre <200 BU, time between inhibitor detection and ITI start <2 years), and in 24 of 33 (73%) HR patients with poor prognostic factors. The time to complete success was 0.5-4 months in good-prognosis patients and 0.5-42 months in poor-prognosis patients. Few adverse events were observed during ITI, and no cases of inhibitor relapse were reported with follow-up periods of up to 12 years. On the basis of this retrospective review of a diverse range of studies and case reports, we conclude that Haemate P/Humate-P for ITI in patients with inhibitors is effective and produces high rates of ITI success.

Inhibitor Development In Patients with Mild and Moderate Hemophilia A: Results From a Single Centre.

AbstractAbstract 1407The development of factor VIII (FVIII) inhibitors is usually considered uncommon among patients with mild and moderate hemophilia A (HA) and less frequent than in patients with severe HA. We report here the prevalence of FVIII inhibitors and their caracteristics in 167 patients with mild and moderate HA followed in Caen Hemophilia Treatment Centre (Table). FVIII molecular defects were identified by direct sequencing in 167 patients including 30 and 137 with mild and moderate HA, respectively. Following FVIII concentrates infusions, FVIII inhibitors occured in 7.8% of patients (13/167). Fifteen percent (2/13) were low-responding inhibitors. The risk of inhibitor development appeared to be associated with high-risk FVIII genotypes clustered in the A2 and C2 domains, especially p.Arg2150His (50%) and p.Arg593Cys mutations. Interestingly, we described inhibitor development associated with novel missense-mutations (p.Tyr1786Ser, p.Asp115Tyr and -219C>T substitutions in FVIII gene promoter). In addition, high regimen infusion of FVIII concentrates appeared as risk factor for FVIII inhibitors development. Indeed, 60% (8/13) developped FVIII inhibitors following massive infusion of FVIII concentrates associated with FVIII:C levels above 1.2 UI/dL. Inhibitors in mild HA usually cross-react with endogenous factor VIII reducing the circulating basal FVIII:C level and are associated with more bleeding events. Similarly, we observed the evolution of bleeding patterns in our cohort to severe phenotypes. Bleedings were treated with FVIII concentrates and bypassing therapies (activated FVII and activated-prothrombin complex). About 25% (3/13) of these inhibitors disappeared spontaneously. Induction of Immune Tolerance (ITI) protocoles with high doses of FVIII were initiated for 7 high-responding patients with a success rate of 85 % (6/7). However, inhibitors persisted long-term and remained troublesome in 1 of these patients despite of ITI protocole. For two patients, immunosuppressive treatment with corticosteroids was started. Inhibitors disappeared and the levels of FVIII:C became detectable within 6 months. Development of FVIII inhibitors, their disappearance and the efficacy of ITI regimen seem to be different from our experience between patients with mild or moderate HA and severe HA. Disclosures:No relevant conflicts of interest to declare.

Current Opinion on Inhibitor Treatment Options

Inhibitor development in patients with hemophilia complicates hemostatic management. Currently, high doses of factor concentrates are used to override low-titer, low-responding inhibitors during acute bleeding episodes. Bypassing agents, such as the activated prothrombin complex concentrate (aPCC), Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA; Baxter AG, Vienna, Austria), and activated recombinant factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark), are commonly used to treat acute bleeding episodes in patients with high-titer, high-responding inhibitors, whereas long-term therapeutic options include inhibitor eradication using immune tolerance induction. Neither FEIBA nor rFVIIa can be monitored with a laboratory assay, making it difficult to establish optimal dosages. Comparative studies evaluating the efficacy of FEIBA and rFVIIa for bleed control have been sparse, prompting investigators to initiate crossover comparison studies to assess the efficacy and cost of aPCC and rFVIIa in the treatment of joint hemorrhages. Both the cost of therapy and the outcome of therapy will need to be considered in the development of future hemostatic agents for patients with inhibitors.

Control of bleeding in patients with haemophilia A with inhibitors: a systematic review.

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high-dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low-titre, low-responding inhibitors although not reliable for high-responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high-titre or high-responding inhibitors (100%) and in 60-90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70-100% of mild to severe bleeding episodes with high-responding inhibitors, and achieved better results when used early. It was effective in 60-100% of surgical episodes. Doses varied from study to study, and side-effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.

Treatment of the bleeding inhibitor patient.

The development of inhibitory antibodies to factor (F) VIII and FIX continues to be a major challenge in the treatment of patients with hemophilia. In patients with low-responding inhibitors, it is usually possible to saturate the inhibitor with the deficient factor and to achieve hemostasis, but in patients with high-responding inhibitors, two major tasks have to be considered. One is how to treat the acute bleedings and the other is how to permanently eliminate the immune response, in other words, to induce tolerance. There are several hemostatic agents available for bleeding patients with high-responding inhibitors. Nonactivated and activated prothrombin complex concentrates (PCCs) have been used for almost 30 years, and since the beginning of the 1980s, porcine FVIII has also been used. In more recent years, recombinant FVIIa has been added to the therapeutic armamentarium and has been shown to control hemostasis in most patients. Immunoadsorption may temporarily reduce the inhibitor, enabling replacement therapy for several days. Available data on these alternative regimens will be discussed with a focus on the mechanisms of action, pharmacokinetics, safety, monitoring, and clinical experience.

Treatment of patients with inhibitors: cost issues

The management of bleeding episodes and surgery in haemophilia patients who develop inhibitors is specially difficult and also has major impact on therapeutic costs. We assessed the costs of coagulation factors in noninhibitor haemophilia A and B patients (0 Inh; n=103), patients with low responding inhibitors (LR; n=24), patients with high responding inhibitors (HR; n=17) in our centre between 1988 and 1998 during two periods: 1988-1995 and 1996-1998, before and after the introduction of recombinant factor VIIa in France (1996). From 1988 to 1995 the mean annual cost of 0 inh and LR patients was 43 234 and 49 422, respectively, with more than 90% as home treatment, whereas the mean cost of HR patients was 56 262 (1.3 time more than 0 Inh), half of this cost being related to treatment administered in hospital. From 1996 to 1998, the mean cost of HR patients was 186 482, approximately three times more than that of 0 Inh (59 887) and LR patients (54 226) with half of the cost due to treatment administered in hospital. So rFVIIa seems to exert a major economic effect on both the cost of home treatment and treatment administered in hospital. It must be pointed out that particularly severe bleeding episodes were effectively treated with rFVIIa during this period and that rFVIIa allowed surgery to be undertaken: including two elective orthopaedic surgeries. So there is no doubt that rFVIIa offers new perspectives in the therapeutic management of HR patients, but creates a new economic situation which needs further evaluation.

Pharmaco-economic aspects of inhibitor treatment.

The management of bleeding episodes and surgery in haemophilia patients who develop inhibitors is especially difficult. Haemostasis is typically achieved using high doses of factor VIII (FVIII) or FIX to overcome the inhibitor, or by using activated products, or by inhibitor eradication by immune tolerance induction. We assessed the costs of coagulation factors for non-inhibitor haemophilia A and B patients (ACneg; n = 104), patients with low responding inhibitors (LR; n = 24) and patients with high responding inhibitors (HR; n = 17) in our centre between 1988 and 1995. In ACneg and LR patients, > 90% of costs were attributed to home treatment, compared with 54% for HR patients. The costs of treatment were $US 36.8 m total, $US 41,000 mean per patient for ACneg patients; $US 10 m total, $US 46,000 mean per patient for LR patients; and $US 7.6 m total, $US 59,000 mean per patient for HR patients. The mean cost of hospital treatment per HR patient was more than 10 times that for ACneg or LR patients and this was influenced by the occurrence of 4 very severe bleeding episodes in these patients. This analysis highlights the different costs and treatment patterns for inhibitor patients and should enable us to evaluate the impact of new treatments such as recombinant activated rFVII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) on treatment at our centre in the future.