Low-dose Immune Tolerance Induction Research Articles

Treatment of Children with Severe Haemophilia A and Inhibitors: a Health Economic Evaluation for Germany

Decision makers request increasingly for high levels of evidence when allocating resources in medical care. This is hardly feasible for rare diseases. The objective was to analyze clinical and economic aspects of different immune tolerance induction (ITI) strategies for children with severe haemophilia A and inhibitors. A decision model, time frame 18 years (base case: 2 year old boy), was constructed from a German statutory health insurance (SHI) perspective. Compared were high-dose (HD) ITI, low-dose (LD) ITI, 'ITI with risk assessment', on-demand (OD) treatment with bypassing agents. Clinical data were derived from structured literature research and expert opinion. Sensitivity analyses were conducted for parameters with wide statistical ranges. Base case analysis: total costs for HD ITI amounted to €3.4 million with 40.9% ITI costs, 51 joint bleeds, 36 hospital days; LD ITI, €2.4 million with 21.4% ITI costs, 74 joint bleeds, 52 hospital days; 'ITI with risk assessment', €2.7 million with 27.6% ITI costs, 53 joint bleeds, 37 hospital days; OD treatment, €1.7 million, 146 joint bleeds, 104 hospital days. Incremental costs per bleed avoided with HD ITI decreased from €1 million to €0.15 million with increase of joint bleeds from 3 to 20 per year, when compared to 'ITI with risk assessment' in sensitivity analysis. 'ITI with risk assessment' is cost-saving with comparable outcomes to HD ITI. However, patient-related factors like bleeding frequency have to determine treatment decisions in individual patients. More clinical data is needed to increase the significance of model -calculations.

Rituximab for the treatment of high titre inhibitors in mild haemophilia A.

Rituximab for the treatment of high titre inhibitors in mild haemophilia A.

The immune tolerance induction (ITI) dose debate: does the International ITI Study provide a clearer picture?

Among the proposed predictors for immune tolerance induction (ITI) outcome, the therapeutic regimen - specifically the dose and frequency of administered factor VIII (FVIII) as well as FVIII product type - is intensely debated. Are there any advantages for low-dose regimens (50 IU FVIII kg(-1) three times a week) over high-dose regimens (200 IU FVIII kg day(-1)) or vice versa? Are von Willebrand factor (VWF)-containing plasma-derived concentrates superior to recombinant FVIII concentrates for tolerance induction? A review of the available literature indicates that patients with good prognostic factors can achieve success with either low-dose or high-dose ITI regimens. Retrospective data suggest that patient characteristics such as maximum historical inhibitor titres and pre-ITI inhibitor titres are better predictors of treatment success than dose. Results of the prospective International ITI Study have recently become available. In inhibitor patients with good prognosis, success rates were similar between low-dose (50 IU FVIII kg(-1) three times a week) and high-dose (200 IU FVIII kg(-1) daily) regimens. However, patients receiving low-dose ITI took longer to achieve various ITI milestones and had a significantly higher bleed rate per month compared with the high-dose group (0.62 vs. 0.28; P = 0.00024), findings with important clinical implications. Inhibitor patients with poor prognostic features should be treated with a high-dose protocol. This conclusion is supported by a meta-analysis of the International Immune Tolerance Registry and North American Immune Tolerance Registry and by data from Germany showing good success rates with the high-dose, high-frequency Bonn protocol in poor prognosis patients. Type of concentrate also appears to have an influence on ITI success rates in this patient subgroup, with evidence suggesting an advantage for VWF-containing plasma-derived FVIII concentrates over recombinant or VWF-free concentrates. The ongoing prospective studies REScue Immunotolerance STudy and Observational Immune Tolerance Induction are evaluating ITI outcome with respect to product type and are expected to answer this important clinical question as well as provide greater insight into patient- and therapy-related variables in inhibitor patients with poor prognostic features.

Cost-utility analysis of immune tolerance induction therapy versus on-demand treatment with recombinant factor VII for hemophilia A with high titer inhibitors in Iran

BackgroundIn developing countries, the treatment of hemophilia patients with inhibitors is presently the most challenging and serious issue in hemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the health care of patients in this setting. In the setting of chronic diseases, cost-utility analysis, which takes into account the beneficial effects of a given treatment/health care intervention in terms of health-related quality of life, is likely to be the most appropriate approach.ObjectiveThe aim of this study was to assess the incremental cost-effectiveness ratios of immune tolerance induction (ITI) therapy with plasma-derived factor VIII concentrates versus on-demand treatment with recombinant-activated FVIIa (rFVIIa) in hemophilia A with high titer inhibitors from an Iranian Ministry of Health perspective.MethodsThis study was based on the study of Knight et al, which evaluated the cost- effectiveness ratios of different treatments for hemophilia A with high-responding inhibitors. To adapt Knight et al’s results to the Iranian context, a few clinical parameters were varied, and cost data were replaced with the corresponding Iranian estimates of resource use. The time horizon of the analysis was 10 years. One-way sensitivity analyses were performed, varying the cost of the clotting factor, the drug dose, and the administration frequency, to test the robustness of the analysis.ResultsComparison of the incremental cost-effectiveness ratios between the three ITI protocols and the on-demand regimen with rFVIIa shows that all three ITI protocols dominate the on-demand regimen with rFVIIa. Between the ITI protocols the low-dose ITI protocol dominates both the Bonn ITI protocol and the Malmö ITI protocol and would be the preferred ITI protocol. All of the three ITI protocols dominate the on-demand strategy, as they have both a lower average lifetime cost and higher quality-adjusted life-years (QALYs) gained. The cost per QALY gained for the Bonn ITI protocol compared with the Malmö ITI protocol was $249,391.84. The cost per QALY gained for the Bonn ITI protocol compared with the low-dose ITI protocol was $842,307.69.ConclusionThe results of data derived from our study suggest that the low-dose ITI protocol may be a less expensive and/or more cost-effective option compared with on-demand first-line treatment with rFVIIa.

Immune tolerance induction therapy for patients with hemophilia A and FVIII inhibitors particularly using low‐dose regimens

Inhibitory antibodies against infused clotting factor VIII concentrates (FVIII) developed in 20-30% of patients with hemophilia A. Bypass therapy may control the bleeds in patients with FVIII inhibitors, however, immune tolerance induction (ITI) therapy is the only proven modality for eradicating FVIII inhibitors. Since the cost of high-dose (200 IU/kg) ITI is extremely expansive, we conducted this study to identify whether low-dose ITI can be an alternative strategy besides high-dose ITI or bypass therapy. Patients with hemophilia A and FVIII inhibitors treated by ITI in Kaohsiung Medical University Hospital from January 2000 to January 2010 were enrolled. Regimens of ITI therapy included high-dose (100 IU/kg) and low-dose (30-50 IU/kg). High-dose ITI therapy for two high responders (HRs) and low-dose ITI therapy for three HRs and all low responders (LRs) were performed. Complete tolerance was achieved in 2 HRs with high-dose regimen, and in one HR and 19 LRs with low-dose regimens. We administered low-dose ITI combined with immune suppressants treatment for one of the patient with extremely high FVIII inhibitor titers and the inhibitor level markedly declined and no spontaneous bleeding episode was noticed during the treatment period. The outcome of ITI in our study was satisfactory without clinically significant complications. Low-dose ITI regimens can effectively treat patients with high responder inhibitors, including one patient with extremely high inhibitor levels over 700 BU. Low-dose ITI may be an alternative modality for FVIII inhibitors management, especially in countries with limited resources.

Successful low dose immune tolerance induction in severe haemophilia A with inhibitors below 40 Bethesda Units

Different regimens are used to achieve immune tolerance in patients with severe haemophilia A and inhibitory allo-antibodies against factor VIII (FVIII). In this study, results of 26 years of low dose immune tolerance induction are evaluated. We evaluated 21 patients, who were treated with regular infusions of low dose FVIII (25-50 IU kg(-1) every other day or three times a week) to obtain immune tolerance. Several risk factors for success rate and time to success were analysed. In 18 of 21 patients (86%) immune tolerance induction (ITI) was successful. The median of the maximum inhibitor titre before start of ITI was 4.5 BU mL(-1). Success rate was associated with both a pre-ITI titre and a maximum titre during ITI below 40 BU mL(-1) (P = 0.003). The time to success was significantly shorter if the maximum inhibitor level during ITI was below 40 BU mL(-1) (P = 0.040). In low titre inhibitors (<5 BU mL(-1)) this effect was even stronger (P = 0.033). Low dose immune tolerance induction therapy was successful in severe haemophilia A patients with a pre-ITI titre below 40 BU mL(-1). The time to success is predicted by a maximum ITI titre below 40 BU mL(-1), and is even shorter in low titre inhibitors (<5 BU mL(-1)). We suggest that all patients with severe haemophilia A and a pre-ITI inhibitor titre below 5 BU mL(-1), should be treated with low dose immune tolerance induction therapy. Patients with a maximum titre below 40 BU mL(-1) may also strongly benefit from the beneficial effects of low dose immune tolerance induction therapy.

Discordant antibody response in monozygotic twins with severe haemophilia A caused by intensive treatment

Both genetic factors and environmental factors are suggested to play a role in the aetiology of inhibitor development in patients with severe haemophilia A. Monozygotic twins are ideal candidates to study the influence of environmental factors. We describe a pair of 3-year-old monozygotic twin brothers with severe haemophilia A. Prenatal diagnosis confirmed the presence of an intron 22 inversion. Other patient-related factors such as birth weight, vaccinations and the duration of breastfeeding were similar. At the age of 7 months, one boy suffered from a spontaneous subdural haematoma, which needed complete correction of haemostasis with continuous infusion of a third-generation recombinant factor VIII. A persistent high-titre inhibitor with severe clinical symptoms developed, that could only be eradicated with high-dose immune tolerance induction (ITI) for 36 months in combination with rituximab therapy. His twin brother first received treatment at 9 months of age with the same FVIII product. After treatment on nine exposure days, he developed a low-titre inhibitor at the age of 14.5 months. Unlike his brother, he was tolerized without difficulties with low-dose ITI within 2 months. The discordant antibody responses were underlined by dissimilar IgG1 and IgG4 levels in their plasma. The discordant immune response to FVIII in this pair of monozygotic twin brothers seemed to be related to intensity of treatment and severity of bleeds. This confirms that these environmental factors play an additional role in the development of inhibitors.

Optimising immune tolerance induction strategies in the management of haemophilia patients with inhibitors: a cost-minimisation analysis

ABSTRACTBackground: The objective of this study was to model the economic impact of optimal dosing of immune tolerance induction (ITI) in haemophilia patients with inhibitors. Evidence based research suggests that, in the right patient population characterised by ITI risk status, the use of high-dose ITI regimen in ‘poor risk’ patients, and the low-dose regimen in ‘good risk’ patients, would be the cost effective strategy. The model also explored the impact of anamnestic response (AR), a phenomenon which worsens patients’ ITI risks.Method: A cost-minimisation technique was used to compare the cost of managing inhibitor patients whose bleeds were managed pre-ITI with an immunogenic bypassing agent, activated prothrombin complex concentrate (APCC), with patients previously on a non-immunogenic product, recombinant activated factor VII (rFVIIa). Patients were subsequently offered a low-dose or high-dose ITI regime depending on their ITI risk status. The study perspective was that of the United Kingdom NHS, hence, all resources used were based on UK costs.Results: The model estimated the mean cost of managing inhibitor patients from detection of titres through ITI to be £959 250.39 and £770 834.17 in the APCC and rFVIIa treatment options, respectively. Meanwhile, the costs per effectively tolerised patients were £1 505 279 and £1 196 706 for APCC and rFVIIa treated patients, respectively. Of the incremental cost in the APCC-treated patients in the model, £129 367 (68%) represents additional ITI cost attributable to anamnestic response to earlier treatment with an immunogenic bypassing agent (APCC).Conclusion: The study concludes that decreasing factor VIII usage during ITI, through the identification and management of ‘good risk’ ITI patients with low-dose protocol, while managing ‘poor risk’ patients with high-dose regimen, will significantly lower the cost of ITI. Furthermore, avoiding AR prior to ITI by using non-immunogenic bypassing agents to manage spontaneous bleeds also has the potential for significant cost savings.

Low‐dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitors

The development of an inhibitor against factor VIII (FVIII) is a serious complication in children with haemophilia A. Immune tolerance induction (ITI) therapy is generally considered to be the best approach to eradicate the inhibitor. In this paper, the low-dose (< or =50 IU kg(-1) twice or three times weekly with plasma-derived factor concentrates) ITI regimen used in Turkey is discussed. This regimen was given to 21 haemophilia A patients with high titer inhibitors. The median age at the beginning of ITI was 9 years and exposure days were 25. The median pre-ITI historical peak inhibitor titer, and inhibitor titer when ITI started were 80 BU (range 6.0-517), 19.2 BU (range 3.6-515), respectively. Complete immune tolerance was defined as the time at which at least two negative inhibitor assays was obtained with no anamnestic response. Our two cases were not reached in follow-up period. Immune tolerance could be achieved in 5 of 19 (26.3%) patients within a median time of 6 months. Partial tolerance was obtained in 7 patients while treatment failed in spite of significant decreased inhibitor levels in the other patients. A relapse developed in one immune-tolerized patient, one year later. The level of inhibitor titer at the beginning of ITI (< or =10 BU), the pre-ITI historical peak inhibitor titer (<50 BU), and the time between the first diagnosis inhibitor to starting ITI (<12 months) were main factors in the success (complete or partial tolerance) of ITI. In conclusion, the outcome of low-dose ITI protocol was not satisfactory in this retrospective study.

Immune Tolerance Induction in 28 Children with Hemophilia Awith Inhibitors.

Aim: To study the characteristics, treatment, and outcome of patients with hemophilia with inhibitors who have undergone immune tolerance induction (ITI) at the Children's Hospital of Michigan over the past 14 years.Methods: In compliance with local IRB regulations, patient charts and laboratory databases were reviewed and salient data extracted. 28 boys underwent 29 attempts at immune tolerance induction.Results:Hemophilia A26 boys with severe hemophilia A with inhibitors underwent 27 trials of ITI. In this cohort of 26 patients the average age at which patients developed an inhibitor was 22 months and the average age at start of ITI was 5 years 4 months (range 2 months to 17 years 5 months). The average number of exposure days prior to inhibitor development was 10 (1–47). The average time between development of an inhibitor and initiation of ITI was 43 months, with no difference between those who successfully completed ITI and those who did not. Six patients had low titer inhibitors (0.8–6.5 BU) and successfully completed ITI using a modified low dose ITI regimen of factor infusions 3–7 times per week. 20 of the patients with high titer inhibitors (6.4–1280 BU) were treated with daily infusions of 50–200 units/kg/d of factor VIII (FVIII) products. For ITI, 4 patients received high purity plasma derived FVIII (PD-FVIII) and 21 received recombinant FVIII (rFVIII) and one received both. In patients who became tolerized to FVIII, the average time to achieve an inhibitor titer of 0 Bethesda Units (BU) was 211 days. In those who were unable to achieve tolerance, the average length of the trial was 263 days. 21 of the ITI trials employed a central venous catheter and in 5 patients ITI was stopped after removal of the line because of recurrent infections. 14 boys received FEIBA, rFVIIa, or porcine FVIII for bleeding episodes during ITI; 8 of them failed ITI and one is still on therapy. Seven trials of ITI were in Caucasian patients (26 %), 17 in African American (AA) (63 %), and 3 in Middle Eastern patients (11 %). 19 patients achieved complete tolerance (73 %), 6 patients failed (23 %), one failed twice, and one patient continues on therapy. All but 2 patients who successfully completed ITI went on prophylaxis with FVIII. All patients who successfully completed ITI have maintained tolerance with a mean follow-up of 101 months (range 7–168).Table I:Hemophilia AFailed ITISuccessful ITINumber of trials*7 (23 %)19 (73 %)African Americans7 (41 %)10 (59 %)Non-AA010 (100 %)Historical Peak Titer (mean)345 BU47 BUTiter at Start of ITI (mean)62 BU5 BUPeak Titer on ITI (mean)168 BU46 BUAge at inhibitor development (mean)26 months12 monthsITI with PD-FVIII14ITI with rFVIII715*One still ongoingHemophilia BDuring this time period, 2 boys with severe hemophilia B underwent ITI. Both had severe allergic reactions at the time of inhibitor development; both underwent desensitization successfully but both failed ITI. Both started ITI with plasma derived factor nine at age 15 months. One developed nephrotic syndrome while on ITI.Conclusions:Most patients with Hemophilia A were able to achieve and maintain tolerance (73%). Higher titer inhibitors, hemophilia B, younger age at development of inhibitor, AA race and treatment of bleeds with bypass agents or porcine factor while on ITI were risk factors for ITI failures. Loss of central venous access with recurrent infections was also a common reason for ITI failure.

Economic modelling of different treatment strategies for haemophilia A with high-responding inhibitors.

This paper reports a systematic review of the cost-effectiveness of treatment options in patients with haemophilia A with inhibitors. As very little relevant published evidence was identified, an economic modelling exercise was undertaken to calculate the cost-effectiveness of different strategies in the treatment of high-responding haemophilia A patients with inhibitors. A decision analysis approach was used to model the expected lifetime clinical outcomes and costs of the more common regimens currently used in UK in treating severe haemophiliacs with inhibitors. The model attempts to reflect the outcomes of clinical events, costs and life expectancy for each different treatment regimen for haemophilic boys with inhibitors who are high responders (defined as inhibitor level >/=10 BU) throughout their life. The basic model structure is centred on a Markov decision process, which was used to simulate, at quarter-yearly intervals, the movement through discrete health states and their complications. The model allows a comparison of cost-effectiveness between three immune tolerance induction (ITI) regimens (Bonn, Mälmo and Low-Dose protocols) and against a relevant 'on-demand' (OD) regimen. It also shows the cost-effectiveness of different OD regimens using different bypassing agents. The results of the economic modelling indicate that treating haemophilia A patients who have high-responding inhibitors OD with recombinant activated factor VII is cost-effective compared to treatment with activated prothrombin complex concentrates. However, when OD treatment regimens are compared with the three ITI protocols, the Malmö ITI protocol is the preferred treatment strategy, generating more quality adjusted life-years (QALYs) and less cost than either an OD regimen or the Bonn or Low-Dose ITI protocols.

Frequency of inhibitor development in severe haemophilia A children treated with cryoprecipitate and low-dose immune tolerance induction.

The frequency of factor VIII inhibitor development was evaluated in a hundred severe haemophilia A patients < 18 years of age (mean 10.4 +/- 5.1 years); 25 were previously untreated patients (PUPs), with a mean age of 11.2 +/- 2.9 months. All were followed up for 3 years from December 1996. Immune tolerance (IT) was induced with low-dose factor VIII (FVIII); 25-50 IU kg(-1) every other day for the 10 haemophiliacs who developed persistent inhibitors. The incidence of inhibitors for PUPs was 3/25 (12%; 95% confidence interval [CI], 0. 7-24.7%) and were detected after 4, 15 and 20 exposure days (mean 13 +/- 8.2 days; 95% CI, 3.7-22.2%). Children with maximum inhibitor levels of > 40 Bethesda units (BU) per mL (n=4) received IT therapy as 25 U kg(-1) FVIII in the form of cryoprecipitate every other day for 1-4 months (mean 2.4 +/- 1.6 months; 95% CI, 0.8-3.9%), which was successful in all of them. FVIII (50 U kg(-1)) was given every other day for six patients with maximum inhibitor level > 40 BU mL(-1) for 3-9 months (mean 5.4 +/- 3.2 months; 95% CI, 2.9 -7.9%) with success in 4/6 (66.6%; 95% CI, 28.8-104.3%). Patients who showed a good IT response had an inhibitor level < or = 30 BU mL(-1), were < or = 9 years of age at inhibitor development with few exposure days to FVIII and had an early immune tolerance. In conclusion, inhibitor development in severe haemophilia A children exclusively treated with cryoprecipitate is low. Early low-dose IT induction for high responders may be achieved successfully if inhibitor level is < or = 50 BU mL(-1).

Immune tolerance induction in the treatment of paediatric haemophilia A patients with factor VIII inhibitors.

The development of an inhibitor to transfused factor VIII (FVIII) is a serious treatment-related problem in haemophiliac children. The management of patients with high titre FVIII inhibitors is difficult, and immune tolerance induction (ITI) is the only method available for the eradication of these inhibitors. The results of the ITI regimen used at the Children's Hospital of Michigan Haemophilia Treatment Center are described and discussed. ITI was attempted in 14 children with severe haemophilia A (13 high responders, one low responder), with daily doses of FVIII alone. FVIII dosage was chosen according to the patient's historical peak inhibitor titre. ITI included three phases; induction phase, dose reduction phase and maintenance phase. During the first phase, the starting dose was 50 or 100 U kg-1 d-1; during the second phase the FVIII dosage was reduced gradually to 25 U kg-1 every other day according to the inhibitor titre, FVIII recovery and/or half-life study. In the third (maintenance) phase, the children received either prophylactic therapy or episodic therapy for 12 months. The inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. Immune tolerance was achieved in 11 of 14 patients (79%) patients within a median time of 6 months; two children are still on therapy, three failed ITI. We observed either failure or prolongation of immune tolerance if the historical peak titre or the maximum titre during ITI was >200 BU. The success rate of our low dose ITI regimen is not different from that reported by other investigators and the inhibitor elimination time is similar to some of the studies reported previously.

Low-dose immune tolerance induction in hemophilia A patients with inhibitors

In patients with hemophilia A and inhibitory alloantibodies against factor VIII, various dosage schedules are used to obtain immune tolerance. In this study, we have evaluated the results of 13 years of low-dose immune tolerance induction and factors that are predictive of a positive result. The effect of immune tolerance induction in relation to age at inhibitor development, number of exposure days, age at start of therapy, maximum inhibitor titer, factor VIII products involved, and virologic status were determined. We evaluated 24 patients with severe hemophilia A and inhibitors who were treated with regular infusions with low-dose (25 U/kg every other day) factor VIII to obtain immune tolerance. In 21 of 24 patients (87%), immune tolerance induction was successful. The response time was determined by two factors: the highest inhibitor level and the age at inhibitor development. In patients with maximum inhibitor levels of less than 40 Bethesda units (BU)/mL, immune tolerance was obtained sooner than in patients with inhibitor levels exceeding 40 BU/mL (P = .005). Patients in whom an inhibitor developed before the age of 2.5 years also tended to have a quick immune response (P = .014). Immune tolerance with low-dose factor VIII is often successful in hemophilia A patients with inhibitors. Young children and patients with maximum inhibitors of less than 40 BU/mL show a relatively rapid response.

Low-Dose Immune Tolerance Induction in Hemophilia A Patients With Inhibitors

In patients with hemophilia A and inhibitory alloantibodies against factor VIII, various dosage schedules are used to obtain immune tolerance. In this study, we have evaluated the results of 13 years of low-dose immune tolerance induction and factors that are predictive of a positive result. The effect of immune tolerance induction in relation to age at inhibitor development, number of exposure days, age at start of therapy, maximum inhibitor titer, factor VIII products involved, and virologic status were determined. We evaluated 24 patients with severe hemophilia A and inhibitors who were treated with regular infusions with low-dose (25 U/kg every other day) factor VIII to obtain immune tolerance. In 21 of 24 patients (87%), immune tolerance induction was successful. The response time was determined by two factors: the highest inhibitor level and the age at inhibitor development. In patients with maximum inhibitor levels of less than 40 Bethesda units (BU)/mL, immune tolerance was obtained sooner than in patients with inhibitor levels exceeding 40 BU/mL (P = .005). Patients in whom an inhibitor developed before the age of 2.5 years also tended to have a quick immune response (P = .014). Immune tolerance with low-dose factor VIII is often successful in hemophilia A patients with inhibitors. Young children and patients with maximum inhibitors of less than 40 BU/mL show a relatively rapid response.