Child With Inhibitors Against Alprolix Returns to Therapy After ITI
The first documented case of a previously untreated hemophilia B patient developing inhibitors against the extended half-life therapy Alprolix was described in a report from Canada.
The report also shows how combining routine administration of Alprolix with medications that suppress the immune system can be used to stop the production of inhibitors.
“Immune tolerance induction using Fc-fusion-protein recombinant factor IX in severe haemophilia B” was published as a letter to the editor in the journal Haemophilia.
Hemophilia B is caused by the lack of the factor IX (FIX) clotting protein. One of its standard treatments is replacement therapy, which involves administering a version of the clotting factor patients are missing.
Alprolix, sold by Sanofi, is an extended half-life therapy for hemophilia B. In essence, it is a replacement therapy that has been engineered to last longer in the body, allowing for less frequent dosing.
Some patients treated with replacement therapies will develop inhibitors — neutralizing antibodies made by the immune system that lower the therapy’s effectiveness and, in some cases, render it useless.
When people with hemophilia develop inhibitors, they often undergo immune tolerance induction (ITI). The goal of ITI is to “teach” the patients’ immune system to recognize the therapy as something that is not harmful, in order to prevent an immune response and the formation of inhibitors.
While methods for ITI in hemophilia A are well-established and have generally high success rates, ITI has historically been less successful in those with hemophilia B.
Researchers in Canada described the case of a 20-month-old boy diagnosed with severe hemophilia B who ended up developing inhibitors against Alprolix.
The child was born to parents with no family history of hemophilia. Yet, genetic testing revealed the boy’s mother, who did not have hemophilia but had a history of unusually heavy periods, carried a disease-causing mutation.
The boy’s parents were both Indigenous Canadians, and the family lived in a reservation community several hours away from the nearest hospital. To minimize the number of treatment sessions, the boy was started on once-weekly prophylactic (preventive) treatment with Alprolix, which at the time was the only extended half-life therapy approved for hemophilia B in Canada.
Due to difficulties accessing the toddler’s veins to deliver the infused therapy, doctors put in place a vein catheter, allowing for easier access to his bloodstream. However, he developed a severe allergic reaction during the procedure. His blood pressure dropped, welts started to appear on his body, and he had difficulty breathing.
Subsequent testing revealed he had high levels of inhibitors against Alprolix.
After a two-week “holiday” with no further treatments, the child was started on ITI. The clinical team used an ITI method known as the “Beutel protocol.”
Put simply, this involves using a cocktail of immune-suppressing medications (intravenous immune globulins, dexamethasone, rituximab, and mycophenolate mofetil), and then routinely giving treatment (Alprolix in this case) so that, as the immune system recovers, it can “learn” that the therapy is harmless.
The procedure was successful: two weeks after starting ITI, the boy achieved Bethesda negativity, meaning his inhibitor levels were very low.
Over the next 44 weeks — nearly a year — Alprolix infusions were given less and less frequently, in accordance with the Beutel protocol. By the end of this time, the toddler was responding to treatment in a manner “comparable to reported results of children on [Alprolix] without inhibitors.”
Over the course of ITI, the boy had two non-allergic infusion reactions (irritability and low grade fever), and an infection that required the vein catheter’s removal and re-insertion. However, throughout the entire treatment course, including catheter removal and re-insertion, he “did not have any noted bleeding.”
“To our knowledge, this is the first report of inhibitor development with the use of [Alprolix] in a previously untreated patient with haemophilia B … and the successful use of [Alprolix] in conjunction with immunosuppressive therapy for ITI leading to a complete and durable eradication of inhibitor,” the researchers concluded.
The team added that these results, combined with the success of extended half-life products for use in ITI in hemophilia A patients, indicate that Alprolix “should be considered an attractive option for ITI in haemophilia B.”
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