Low-dose ITI Successful in 80% of Hemophilia A Children, Study Shows

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by Steve Bryson, PhD |

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Low-dose immune tolerance induction (ITI) — a type of treatment that can be used to eliminate inhibitors that limit the effectiveness of replacement therapies — achieved partial success in 80% of children with severe hemophilia A and high inhibitor levels, according to a recent study.

The study, “Low-dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success,” was published in the journal Haemophilia.

Replacement therapy is one of the standard therapies used to treat hemophilia A, which involves supplying the blood-clotting protein factor VIII (FVIII), which is missing or defective in people with the condition.

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Up to 30% of patients with severe hemophilia A develop neutralizing antibodies that target FVIII, called inhibitors, and become resistant to FVIII replacement therapies. This in turn leads to an increased risk of severe bleeding and other complications.

ITI is a strategy to eliminate inhibitors that involves administering either low or high doses of FVIII on a regular basis to induce immune tolerance and prevent the generation of new anti-FVIII antibodies. Immune tolerance is the process by which the body’s immune system can be made to tolerate a specific substance, instead of identifying it as a potential threat and launching an attack against it.

The outcome of ITI depends on the treatment regimen used and the type of FVIII concentrates. High success rates have been achieved using FVIII concentrates derived from blood plasma containing von Willebrand factor (VWF), a protein that protects FVIII in circulation and helps platelets adhere to sites of blood vessel damage.

Patient-related factors can also negatively affect ITI outcomes, including having high inhibitor levels (titers) — usually greater than 10 Bethesda Units (BUs) — immediately before ITI. Patients with historical inhibitor peaks greater than 200 BUs and those age 7 and older are also more likely to have a poor outcome.

Although low-dose ITI regimens in patients without these factors can achieve long-term success similar to high-dose regimens, studies assessing low-dose ITI in patients with poor prognostic factors are scarce.

Further, costs associated with ITI are a factor that can influence the choice of low- or high-dose regiments, especially in regions with economic limitations. However, few published studies on ITI are from East Mediterranean countries.

Therefore, researchers at the Ain Shams University in Egypt wondered if low-dose ITI using highly purified plasma-derived FVIII with VWF (pdFVIII/VWF; sold under the brand name Koate-DVI) would be effective in hemophilia A patients with poor prognostic factors.

“The aim of this study was to assess the effectiveness of low-dose ITI regimen in children with severe [hemophilia A] suffering from high titre inhibitors,” the team wrote.

The study enrolled 20 patients with severe hemophilia, ages 3–12, all of whom had received FVIII/VWF concentrates and had inhibitor titers greater than 10 BU. The median time from inhibitor diagnosis to ITI was 8.5 months, and the median historical inhibitor peak was 41 (ranging from 8–320 BU).

During ITI, all participants received low-dose pdFVIII/VWF concentrate three times a week. For breakthrough bleeding episodes that occurred during ITI, patients were treated with bypassing agents — treatments that contain several clotting factors that can “bypass” the need for conventional replacement therapy in patients with inhibitors.

Total response was defined as attaining inhibitor levels lower than 0.6 BU and an FVIII recovery of more than 66%. A partial response was defined as achieving inhibitor levels between 0.6 and 5 BU and a less than 66% FVIII recovery. If patients did not reach those levels after two years, ITI was considered a failure and discontinued.

Overall, the total response rate, both total and partial, was 80%. Complete success was reached in 12 (60%) and partial success in four (20%) patients.

In those with complete or partial responses, the duration of ITI was one year or less in 45%, “indicating an early tolerization with the low-dose ITI strategy.” In patients with complete success, median FVIII recovery was 90%.

Patients with peak titers of up to 200 BUs had a 93% success rate compared with 40% of those with peak titers greater than 200 BU. The success rate in participants ages 7 or younger was 87.6%, while for those older than 7, it was 50%.

Similarly, patients who started ITI within two years of being diagnosed with inhibitors had a much higher success rate compared with those who started treatment later (88.2% vs. 33.3%). In contrast, two out of the four who failed ITI started treatment more than two years after inhibitor diagnosis.

Overall, 93.8% of those with a total or partial response had an initial titer less than 55 BU.

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There were 155 bleeding episodes reported in the year before ITI, with 65 of them considered severe, 45 moderate, and 45 mild. During ITI, there were 11 severe bleeding episodes, 22 moderate, and 55 mild episodes. Eight patients received bypassing agents.

The annual bleeding rate (ABR) was significantly reduced after ITI treatment. It dropped from a median of 7.5 to 3, corresponding to a 60% reduction. Consistently, the number of target joints — those where bleeds occurred — significantly dropped from a median of 2 before ITI to 1 after ITI, correspond to a 50% reduction.

School absences were considered a measure of health-related quality of life. There was a 41% relative reduction in school absences per year, dropping from a median of 17 days before ITI to 9.5 after ITI.

“In conclusion, these results confirmed that highly purified pdFVIII/VWF concentrates are effective in a low-dose ITI strategy in patients with poor prognosis factors,” the authors wrote.

“Adverse events were not recorded during the study period and the follow up period,” they wrote, and therefore, “confirmatory studies in a larger cohort of patients would be needed for broader interpretation of these results.”