Advances in Treatment and Prevention of Hemophilia A: Takeaways From the 2018 ASH Annual Meeting
Research presented at the 2018 ASH Annual Meeting provided insights into the role of factor VIII as a therapeutic agent for severe hemophilia A.
Early Prophylaxis as a Standard of Care
Prophylactic therapy for severe hemophilia A offers multiple long-term benefits for pediatric patients, according to research reported at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California. These benefits include joint protection throughout childhood, the ability to manage the emergence of antifactor VIII (FVIII) antibodies (called inhibitors), and feasibility of invasive surgical procedures.
“The findings show that it's really, really important to start prophylaxis as early as possible,” said Beth Boulden Warren, MD, MS, of the Hemophilia and Thrombosis Center at the University of Colorado Anschutz Medical Campus, in Aurora, in an interview with Hematology Advisor. Dr Warren and colleagues found in the Joint Outcome Continuation Study (JOS-C) that initiating prophylactic fVIII therapy before age 2.5 years provided improved protection from joint destruction to early adulthood.1
Repeated, spontaneous hemophilia-related bleeding into joints can cause hemophilic arthropathy — joint damage that affects up to a third of people with hemophilia A. The JOS-C study was an extension of the earlier Joint Outcome Study (JOS; ClinicalTrials.gov Identifier: NCT00207597), which had found benefits for joint health with early prophylaxis with FVIII.2
Patients who had participated in JOS were allowed to join the JOS-C trial upon turning 6 years old, where they could continue prophylactic therapy until adulthood (15 patients; the “early prophylaxis” group) or cross over to prophylaxis treatment if they had been in the JOS enhanced-episodic management control group (18 patients; the “delayed prophylaxis” group). MRI scans were conducted for each patient's ankle, knee, and elbow joints.
Delaying prophylaxis to age 6 was associated with increased MRI osteochondral joint damage by age 18. MRI evidence of osteochondral damage increased over time for all JOS and JOS-C participants but was significantly less severe among patients in the early prophylaxis group. At age 18, 77% of patients undergoing delayed prophylaxis had joint damage, compared with 33% of patients in the early prophylaxis group (P =0.02).
The degree of MRI osteochondral damage did not predict the number of reported joint bleeding episodes per year, however, which may suggest undetected microbleeding-associated damage, according to Dr Warren.
It is important that similar studies with newer agents be conducted using similar methods to allow comparison with the JOS-C study, Dr Warren said. She also cautioned that standard prophylaxis regimens are “not perfect,” but noted that the effectiveness of other treatment modalities like emicizumab or gene therapy compared with older regimens remains to be seen.
However, clinicians and patients might not wait for the evidence base to mature before employing newer agents.
“JOS-C used an intravenous injection every other day,” she explained. “With newer agents, you don't need a central line. They can be administered subcutaneously. I don't think anybody will wait for a clinical trial before adopting newer agents for that increased convenience. But I think it's important to collect the data so that we can compare — so we can see, down the line in 18 years, if somebody who starts on emicizumab prophylaxis in toddlerhood will have similar outcomes.”
Prophylactic Therapy for Inhibitors
Pediatric patients may also experience benefits from immune tolerance induction during emicizumab prophylaxis if they have developed neutralizing inhibitors, according to preliminary findings reported at the 2018 ASH Annual Meeting.3
However, the optimal FVIII infusion frequency to maintain tolerance is still unclear, cautioned lead study author Glaivy M Batsuli, MD, of the Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and the Department of Pediatrics at Emory University in Georgia.