Experience of Immune Tolerance Induction Therapy for Hemophilia A Patients with Inhibitors from a Single Center in India

Abstract

The availability of clotting factor concentrates of both factor VIII and factor IX have improved hemophilia treatment to a great extent. Many more improvements like physiotherapy, and comprehensive care are needed to give better care. One important complication that occurs, but is often set aside is the development of inhibitors. When an inhibitor develops in a patient of severe hemophilia then the care becomes more difficult and expensive. Eradication of the inhibitor is possible by Immune tolerance induction (ITI), this paper explains some important essential factors and practical issues during my experience with ITI.

Hemophilia treatment has made rapid strides in improving the quality of life of patients. The two major advances have been (i) safer factor concentrates and (ii) primary prophylaxis to maintain joint integrity and reduce bleeding episodes. Inhibitors are an infrequent but serious complication which may occur. These are neutralizing allo-antibodies [polyclonal high affinity IgG (IgG4)] directed against factor VIII (FVIII) or factor IX (FIX) and can render replacement therapy ineffective and compromise hemostasis. They occur in 25–30% of patients with severe hemophilia A and in 1–5% of those with severe hemophilia B [1, 2]. Though reported rates of inhibitors appear to be very low in Indian centers [3], it is important to note that a single time point study will under report the prevalence.

We already have data on the poor quality of life and high disability rate of patients with hemophilia patients without inhibitors from India and the significant barriers to care [4, 5]. Even in the West when an inhibitor develops, risk of life-threatening hemorrhages reappears; these recurrent and difficult to manage bleeds compromise joint health, quality of life even in a developed country [6, 7] (Table 1 consequence of inhibitor development). Hemophilia therapy is already a serious financial commitment by the government/health payers or family, which increases substantially if inhibitors are present [7, 8]. In a European study the costs for treating hemophilia patients with inhibitors was higher (€134,032) compared to the cost of therapy without inhibitors (€40,138, P = 0.03) [8]. Whenever management guidelines for hemophilia patients are made, it is important for each center to make budgetary allocation for bypassing agents while planning to procure clotting factors.

Table 1.

Consequence of development of inhibitors in a patient of inherited Hemophilia A or B (from Ref. [7])

Decreased efficacy of replacement therapy

Long-term inhibitors increase cost of therapy and increase both mortality and morbidity

High titer inhibitors can be life threatening

This article will cover only the practical issues on what we need to do once a patient has developed inhibitors [9, 10]. It is important to correctly identify when a patient develops an inhibitor. The diagnostic test most commonly used is Bethesda assay (BA) and 1 Bethesda Unit (BU) is defined as the amount of an inhibitor that will neutralize 50% of 1 unit of FVIII:C in normal plasma after 120 min of incubation at 37 °C. The Nijmegen modification (NBA) stabilizes FVIII in normal pooled plasma by pH buffering. If patients are on long acting products or Immune tolerance therapy then the residual factor interferes with the test. This can be overcome by heating the sample prior to inhibitor testing in such patients, the heat treatment removes exogenous factors. This modification is called pre-analytical heat treatment (PTH) [11, 12]. In order to reduce costs, we perform an incubated mixing study every two weeks at the beginning of prophylaxis. If this “inhibitor screen” is positive we then need to confirm with Nijmegen Bethesda assay (NBA).

Management

When we manage a patient of hemophilia with inhibitors, there are two facets- the management of acute bleeding episodes and the eradication of inhibitors, at present immune tolerance induction (ITI) is the standard of care for this.

Bleeding Episodes

When an inhibitor occurs in a patient of hemophilia, it requires a change in management of acute bleeding episodes. The usual clotting factor products (whether plasma derived or recombinant and FFP/Cryoprecipitate) become ineffective. Management of bleeds in a hemophilia patient with inhibitors is best be done with bypassing agents. In India these are even less widely available and more expensive, than clotting factor concentrates, resulting in logistic and financial issues, which usually results in inadequate medical care [5].

In the presence of low-titre, low-responding inhibitors (historical inhibitor peak at no time exceeding 5 BU) FVIII/FIX concentrates can be used in an emergency, but higher and more frequent doses are needed to achieve hemostasis and prevent bleeding. However, this is not the ideal management. If high-titre, high-responding inhibitors (historical inhibitor peak that exceeded 5 BU even once) are present, then clotting factor products are contraindicated and bypassing agents are necessary [13, 14].

At present two by passing agents are commercially available plasma-derived aPCC (FEIBA^®), and rFVIIa (NovoSeven^®). These two are both clinically effective, however individual patients may respond to one product and have less or no response to the other. Reasons for this individual variation, is not known, if the patient does not respond to appropriate dose of one agent then the alternative agent is to be tried. The use of these bypassing agents according to prophylactic regimens has also been tried in order to prevent break through bleeds and several studies and regimens are available, but are very expensive [13, 14].

Indian experience: Cheap adjuncts have been described such as using platelet transfusions along with conventional bypassing agents to increase thrombin generation and factor Xa, this is useful specially to augment rFVIIa therapy [14]. We have used platelet transfusion and other senior colleagues have also reported the same benefit with adjunctive therapy. Caution must be used if combining treatments, as there may be complications. Though some reports of tranexemic acid use with bypassing agents or combination of FEIBA and rFVIIa are given, these are only isolated case reports and should be used only in critical situations as it may lead to complications of thrombosis.

Newer agents approved for prevention of bleeding episodes in inhibitor patients are Anti-factor IXa/X bispecific antibody (Emicizumab) now available in India, and anti-TFPI antibody which binds to the K2 domain of TFPI (Concizumab) [15, 16].

Eradication of Inhibitors

The only evidence based method, at present to eradicate inhibitors, has been immune tolerance induction (ITI). Up to 70% of patients can be rendered free of inhibitors which will be cost effective in the long term [9, 10, 13, 16, 17]. This requires planning, extensive factor support and close monitoring of the patients. Many experts feel that this is difficult to do in our Indian set up. Even though this is expensive it has been shown in the long run to be beneficial and cost saving [7, 8]. A modeling analysis using ITI regimen 100 IU/kg/day of FVIII for 420 days for 5 year-old boy with severe hemophilia and high-titer inhibitors was projected to increase his life expectancy by 4.6 years and result in a lifetime reduction in cost of $1.7 million [7].

We have been fortunate to participate in a hemophilia ITI study with Prof Mannucci. After the first two patients had their inhibitor eradicated on that study more than 2 years ago, an additional three patients have now successfully completed ITI. Though my experience of management of these fiveinhibitor patients of severe Hemophilia A, aged 3–10 years is small, I feel it is worthwhile to share my experience. There are several important points which I learned in both during my reading and practice of ITI of such patients. Below are important points to note, and some fallacies to avoid. Short vignettes are added to help you explain different care scenarios and problems faced.

Important Points to Ensure Before You Start Immune Tolerance Induction Therapy (ITI)

Before starting ITI, calculate the quantity of clotting factor concentrates required and ensure continuous supply as interruptions of the ITI regimen are linked to failure of ITI. Second access to some amount of bypassing agents is required to manage break through bleeds. Safety, efficacy and convenience should be considered while selecting bypassing agents.

Counselling of family is essential as this is a long term therapy and an increase in inhibitor titre may occur several times. Though some predictors of success of ITI exist there are no absolute predictors or tests which guarantee success [23–25]. Immune tolerance induction is expensive, but low dose ITI protocols are available. Eradication of the inhibitor will result in overall cost saving, increased life expectancy and reduce disability to the patient [7, 8]. This point needs to be explained to hospital, funding agency so that they understand and give support.

Regimens of Immune Tolerance Induction (ITI)

Immune tolerance induction (ITI) consists of repeated infusions of factor concentrate over a period of time, this tolerizes the body to factor and over time reduces the anti-body production. There are several regimens in current practice (Table 2), most studies report similar effectiveness in eradication of inhibitors- 70–80% [9, 10, 17–23]. The International ITI study [21] compared a High dose and low dose regimen, some data has been published. This study showed similar success rates, of ITI, though the time to success varied. In the international ITI study the time to a negative inhibitor titer was 9.2 months [interquartile range (IQR) 12.1] in the low-dose arm and 4.6 months (IQR 11) in the high-dose arm. This resulted in significantly greater bleeding episodes in the low-dose arm during this early phase (hazard ratio 2.27; 95% CI 1.29–4.01) [24, 27]. An economic analysis of the International ITI study is awaited. Most practice guidelines and hemophilia treatment center (HTC) etc. describe different protocols varying from 50 IU/kg to 200 IU/kg three times a week [21, 24].

Table 2.

Regimens for Immune tolerance induction

	Regimen	Dose	Description and discussion	References
1	Bonn	FVIII 200–300 IU/kg daily + FEIBA 100 units/kg twice daily	This was a landmark paper and was shown to reduce time to eradication of inhibitor as well as bleeding But very costly to carry out	[17]
2	Dutch	van Crevald (Dutch or low dose) FVIII 25–50 IU/kg on alternate days and escalate…	In original article in patients with inhibitor level less than 10 BU/mL and bleeding, they used a high dose of factor VIII to neutralize the antibodies The neutralizing dosage was calculated $2\times \text{BW}\frac{\left[80\times \left(100-\text{Ht}\right)\right]}{100}\times 1$ Where BW is body weight in kilograms; Ht, hematocrit; and I, inhibitor titer Followed by infusion of factor VIII 25 IU/kg body weight twice daily for 1–2 weeks, depending on the clinical status of the patient and the anamnestic response to factor VIII	[18, 19]
3	Malmo	ITI with addition of immunomodulation  High Dose FVIII  Extra-corporeal immuno adsorption  Cyclophosphamide or azathioprine  & IVIG	Increased cost  Risk of infection  Cyclophosphamide- to be avoided if joint surgery planned, linked to more wound complications, pain and bleeding	[20]
4	International ITI study	High dose (HD) 200 IU/kg/day versus low dose (LD) 50 IU/kg/day	The time to tolerance for the entire study cohort was similar to that reported previously. However, HD subjects achieved a negative titer and normal recovery significantly more rapidly than LD subjects, LD subjects required 50% longer to achieve tolerance overall (nonsignificant) There were significantly more bleeds in the 684 versus 282 LD than in the HD treatment arm (Table 7), with a hazard ratio (HR) for all types of bleeds of 2.20 (< 0019)	[21]
5	ITI with long acting factors	rFVIIIFc at a dose of 100–200 IU/kg rFVIIIFc via central venous access device every other day or three times weekly	The time to anti-FVIII = 0 was 4–12 weeks, significantly shorter than with current rFVIII ITI. There were no adverse effects  In India we have compassionate use free long acting factor VIII products, this report is small but important	[22]

Success and Its Prediction

Almost all regimens have similar success rates in eradication of inhibitors. Immune Tolerance is reported to be highly effective and about 80% of patients become inhibitor free. Success is considered when -inhibitor titer can no longer be measured, factor VIII recovery is greater than 66% of normal and half-life of Factor VIII is greater than 6 h.

Predictors of success are still evolving, younger age, inhibitor titre less than 10 BU before start of ITI, historical peak titre < 200 BU, low-risk FVIII genotype (small insertions, small deletions, and missense mutations) are some important predictors of success (Table 3) [25]. Others are less consistent between different studies. However, these cannot always predict response in an individual patient. Interruption of ITI before successful eradication of inhibitors is adversely associated with failure of ITI.

Table 3.

When is it appropriate to stop immune tolerance induction therapy(ITI): What is Success of ITI?

International workshop on immune tolerance induction consensus states that successful ITI involves three things

1. The inhibitor titer can no longer be measured

2. Factor recovery is greater than 66% of normal

3. The half-life of Factor VIII is greater than 6 h

There is less data on ITI in patients with poor features like high-responding inhibitors. In a study patients with adverse characteristics such as-historical peak titres of ≤ 200 BU and/or pre-ITI titres of ≤ 20 BU showed that they had a higher probability of achieving tolerance with a high-dose (200 IU/kg/daily) regimen versus a lower dose ITI regimen [24].

Monitoring and Stopping ITI

The ability to test patients at any time through pre-analytic heat inactivation of infused clotting factors, without the need for 48 h wash out period for patients on ITI is an important improvement in clinical monitoring. Before stopping ITI not only should the NBA be negative at least twice, but also factor recovery should be > 66%. Once patients have completed ITI for inhibitors they should be put on prophylaxis [26].

If ITI fails, then plan a different strategy such as a different ITI regimen, different factor VIII product e.g. VWF rich plasma derived factor VIII, or addition of immunosuppressive/immune-modulation therapy [23]. Longer acting factor VIII products can also be used and few reports of success and lack of adverse events have been reported. Exact definitions of failure are being debated and though arbitrary time points such as at 36 month period with less than 20% reduction in titre is suggestive of failure, often a period of 3–5 years was necessary to fully assess ITI success/failure [27].

Case Vignettes

Case 1: Low titer inhibitor in a 10 year old child with severe hemophilia A.

• Ten year old boy was referred to our center. Review of his medical records showed diagnosis at about 2.5 years of age with Hemophilia A, factor level > 1%, had received infrequent doses of factor.

• He had been diagnosed with an inhibitor approximately 2 years ago. Peak titre 12BU. The child had been given FEIBA or rfVIIa for bleeding episodes depending on availability. Bypassing agents were not always available, home therapy was not available.

• Before starting ITI therapy he had two consecutive reports one month apart of inhibitor screen positive and inhibitor of 4BU.

• ITI 50 IU/kg, three times a week–1 month, repeat inhibitor 8 BU/ml.

• ITI 50 IU/kg, three times a week– 3 months- inhibitor screen negative.

• After 6 month- pre-analytic heat inactive NBA test inhibitor 0. But factor recovery was only 50%.

• Continued at 50 IU/kg three times a week × 2 months, pre-analytic heat inactivation inhibitor 0, factor recovery assay 70%.

• Now back on primary prophylaxis three times weekly. No inhibitor for 12 months of ITI.

Case 2: High titer inhibitor and surgery in a 7 year old boy with severe hemophilia A

• Seven year old boy from another city presented to his local hospital with a swollen painful left knee, low grade fever, pain.

• He was thought to have a septic joint and aspiration was performed by an orthopedic surgeon. He developed prolonged bleeding post surgery. No family history of hemophilia.

• APTT grossly prolonged and FVIII < 1%. He appropriately received injection factor VIII continuously for 1 week

• The boy had a good response to the factor initially, but after 5 days had then increase in bleeding and discharge from the wound.

• He was referred to our center with a large open wound in his knee with purulent discharge and a bleeding open wound.

• At our center his Inhibitor titer 512 BU.

• We sent wound cultures, blood cultures and started empiric iv antibiotics

• The bleeding not controlled with FEIBA 75–100 units/kg maximal dose.

• He was given rFVIIa 90 μg/kg, this resulted in speedy control of bleeding.

• Surgery and orthopedic consultation taken and debridement of wound recommended, done with rFVIIa support. The wound culture reported both- Acinetobactor, and E. coli, antibiotics given as per sensitivity report.

• A few days later, rFVIIa was unavailable. Bleeding from the wound restarted, we were concerned that this would compromise his wound healing.

• The child was given FEIBA, as only this was available during this time, again despite maximal doses the bleeding was not controlled.

• We cautiously added anti- fibrinolytic agent—injection Tranexemic acid 10 mg/kg iv., as this has a risk of thrombosis, however the patient still continued to bleed.

• In view of poor response, thenext day platelet transfusionswere given along with FEIBA, this combination resulted in control of bleeding and this was continued for 2 days.

• Then switched to rFVIIa as soon as it again became available.

• The repeat wound cultures were sterile and wound healthy. Surgeons planned a Vacuum closure of wound, we arranged for the required rFVIIa for the peri-operative period. During and post procedure there was good hemostasis, ambulation initiated and patient was discharged after hospital stay of 1 month.

Key point

1. In patients with inhibitors bypassing agents are expensive, but necessary. If one product fails after recommended dose may need to switch to alternative. Use products only in maximal recommended doses, as there is risk of serious thrombosis, which may even be life threatening.

2. Unless a life threatening bleeding scenario, avoid combinations of products.

3. Other measures to halt bleeding if bypassing agents inadequate-

   • Platelet transfusions

     • increases thrombin generation,
     • and FX on platelet surface- (rFVIIa)
   • Use of Anti Fibrinolytics (must be used with caution if also used in combination with bypassing agents) e.g. EACA, tranexamic acid
   • High dose FVIII- continuous infusion (CI) to stop life threatening bleeding

     • may also be useful in surgical patients
     • though more effective if low titer inhibitor, but even in high titer may reduce bleeding in an emergency.

4. Newer bypassing agents will help in management, though will pose newer challenges in monitoring response, especially for patients on ITI therapy.

5. Low Dose ITI useful to eradicate inhibitors in many patients.

Conclusion

These strategies of monitoring and management will continue unless a paradigm shift occurs in which prophylaxis with non- factor products or gene therapy supplants the current clotting factor product regimens for hemophilia. Data on ITI from India should be collected, this will help in formulating our own recommendations, cost effective strategies and other newer strategies may be needed to make it more widely available.