Initial treatment with emicizumab improves factor VIII tolerance in hemophilia A
Immune tolerance induction with standard or extended half-life recombinant factor VIII after initial treatment with emicizumab appears safe and effective in pediatric patients with hemophilia A and active inhibitors, according to findings presented at the ASH Annual Meeting and Exposition.
“While novel non-factor therapies significantly reduce bleeding symptoms in patients with hemophilia A and inhibitors, the absence of [factor] VIII tolerance remains unchanged. Additionally, there are concerns regarding the hemostatic efficacy and safety of bypassing agents necessary for the management of breakthrough bleeds in patients with inhibitors on these novel therapies,” the researchers wrote. “Immune tolerance induction remains the primary method for eradicating inhibitors and restoring the hemostatic response to [factor] VIII.”
Glaivy M. Batsuli, MD, assistant professor in the division of hematology and oncology at Emory University and pediatric hematologist/oncologist at Aflac Cancer and Blood Disorders Center in Atlanta, and colleagues examined this approach, known as the Atlanta Protocol, in eight patients aged 13 months to 11 years with hemophilia A and an active inhibitor ( 0.6 BU/mL). All but one patient had severe hemophilia and most patients (n = 5) had at least one prior attempt at immune tolerance induction. Three patients needed central venous access for factor VIII infusions during this process.
Immune tolerance induction began after four weekly loading doses with emicizumab and standard or extended half-life recombinant or plasma-derived factor VIII at 100 units/kg administered three times per week. The researchers selected a factor product based on the agent used in prior immune tolerance induction attempts; a standard half-life, third-generation recombinant factor VIII product was used if the patient had not attempted immune tolerance induction before.
Pharmacokinetics measured during immune tolerance induction included estimated factor VIII half-life, expected factor VIII incremental recovery and inhibitor titers. These measurements were taken with chromogenic-based assays that used bovine reagents. The researchers also monitored bleeding symptoms and treatment regimens for bleeds/procedures.
The researchers reported “historical” peak inhibitor titers, ranging from 2 to 198 BU/mL, among all patients in the study. Historical was defined as the highest inhibitor titer prior to the start of the immune tolerance induction done in the study.
Immune tolerance induction has been initiated in four patients. The other patients received treatment with emicizumab and immune tolerance induction for a median period of 15 weeks (range, 13 to 18 weeks).
The researchers presented data on the four patients undergoing immune tolerance induction. Two of those patients are receiving a standard half-life, third-generation recombinant factor VIII product; one patient is being treated with a standard half-life, third generation B domain-deleted recombinant factor VIII product and one is being treated with an extended half-life recombinant factor VIII-Fc fusion product.
The most recent measurement of inhibitor titers following the start of immune tolerance induction and prior to publication of the results ranged from 0.3 to 3.7 chromogenic BU. A decrease in all inhibitor titers was observed after the start of immune tolerance therapy; no amnestic responses were reported.
Three of the four patients experienced an improvement in factor VIII incremental recovery, from a median of 30% of expected (range, 17% to 69%) before emicizumab with immune tolerance induction to 85% of expected (range, 67% to 85%) at the final assessment. The fourth patient experienced an improvement in factor VIII incremental recovery of less than 10% of what was anticipated at the final assessment.
Treatment with a sole dose of recombinant activated factor VII was necessary for one patient who experienced hemarthrosis in the right knee during immune tolerance induction without complication. Three other mild bleeding symptoms occurred in two patients, including one trauma-induced forehead hematoma and two episodes of epistaxis that lasted for less than 5 minutes. All three events resolved on their own.
No bleeding symptoms were reported in two of the four patients. There were no cases of thrombosis or thrombotic microangiopathy.
This is the first report to describe the Atlanta Protocol for immune tolerance induction in pediatric patients with hemophilia A and inhibitors who are being treated with emicizumab prophylaxis, according to the researchers.
“Although early, these results suggest that immune tolerance induction can be safely administered in these patients and is able to achieve continued improvement in clinical indicators of tolerance,” Batsuli and colleagues wrote. - by Julia Ernst, MS
Batsuli GM, et al. Abstract 634. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures: Batsuli reports advisory board and other roles with Bayer, Genentech and Octapharma. Please see the abstract for all other authors’ relevant financial disclosures.