Thirty percent of patients with severe hemophilia A will develop neutralizing antibodies against FVIII agents, increasing morbidity, the risk of death, and health care costs, Dr Batsuli said. He and his colleagues hypothesized that immune tolerance induction with emicizumab prophylaxis would eradicate inhibitor antibodies, restoring hemostatic responses to FVIII and preserving the possibility of later gene therapy in adulthood.
Seven patients aged 21 months to 12 years were enrolled and treated using the Atlanta Protocol: loading doses of 3 mg/kg emicizumab were administered weekly, for 4 weeks, and were followed by a maintenance emicizumab prophylaxis regimen (1.5 mg/kg once-weekly or 3 mg/kg every 2 weeks). Immune tolerance induction was then initiated using standard or extended half-life recombinant FVIII (rFVIII) or plasma-derived FVIII (100 units/kg, 3 times weekly).
After 12 weeks, inhibitor titers declined for all 7 patients during treatment, but the last inhibitor titer levels were low enough to meet the criteria for successful immune tolerance induction in only 2 patients. Three children had no bleeding events. Four patients experienced a total of 9 bleeds, 2 of which were severe.
Based on the findings, a phase 3 prospective multicenter trial is planned to confirm the safety of low-dose rFVIII immune tolerance induction with emicizumab prophylaxis in children with hemophilia A and newly diagnosed inhibitors, Dr Batsuli said.
The researchers also reported that among a small group of patients with severe hemophilia A and circulating inhibitors who were on emicizumab prophylaxis, invasive procedures and surgeries required decreased dosing of FVIII products and bypassing agents, with few complications in real world settings outside of clinical trials.4
The research team assessed a case series of 10 patients between the ages of 15 months and 60 years who underwent a range of invasive procedures, including circumcision, central venous access device (CVAD) placement and removal, elbow surgery, and a complex dental extraction. No patients experienced excessive perioperative blood loss, required blood products, or developed thrombosis or thrombotic microangiopathy.
A peripherally inserted central catheter (PICC) removal and a minor dental procedure were managed with observation alone. The other 8 patients underwent preoperative prophylactic hemostasis treatment with recombinant FVIIa or rFVIII. Three patients undergoing CVAD-related procedures received antifibrinolytic treatment after surgery.
Two patients experienced postoperative bleeding but did not experience excessive blood loss. Seven patients were admitted for postprocedure observation for a median duration of 48 hours but none had prolonged hospitalizations for hemostasis-associated complications, and no patient was rehospitalized after discharge.
The case series is the largest to date outside of the HAVEN clinical trials (ClinicalTrials.gov identifiers: NCT02622321, NCT02795767, NCT02847637, and NCT03020160) to assess perioperative management of patients with severe hemophilia A.
Disclosures: Multiple study authors declared affiliation with pharmaceutical industry. Please refer to the original studies for full lists of disclosures.
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1. Warren B, Thornhill D, Stein J, et al. Early prophylaxis provides continued joint protection in severe hemophilia A: Results of the Joint Outcome Continuation Study. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 382.
2. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. New Engl J Med. 2007;357(6):535-544.
3. Batsuli GM, Zimowski KL, Tickle K, et al. The Atlanta Protocol: Immune tolerance induction in pediatric patients with hemophilia A and inhibitors on emicizumab. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 634.
4. Zimowski KL, Batsuli GM, Reding MT, et al. Maintaining perioperative hemostasis in patients with severe hemophilia A and inhibitors receiving emicizumab prophylaxis. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 635.