B Cell Activating Factor Identified as Key Target in Treatment-Resistant Hemophilia A

Investigators at the Children’s Hospital of Philadelphia (CHOP) have found B cell activating factor (BAFF) in 30% of patients with hemophilia A who do not respond to coagulation protein therapy, a finding that could lead to better treatments and outcomes, according to a press release.

BAFF appears to promote antibodies against, and inhibitors of, the missing blood clotting factor that is given to these patients to control their bleeding episodes. With these findings, investigators said anti-BAFF therapies could be used in combination with immune tolerance therapies to tame the immune response in some patients with severe hemophilia A.

Hemophilia A is the most common inherited bleeding disorder, impacting 1 in 10,000 worldwide according to the study. It is the result of missing coagulation factor VIII (FVIII), which leads to uncontrolled bleeding episodes, joint disease, and increased risk of death. Patients typically receive infusions of the FVIII protein to replace the missing coagulation factor, although approximately 30% of patients with hemophilia A develop neutralizing antibodies known as FVIII inhibitors, which prevent the treatment from working.

Some of these treatment-resistant patients receive immune tolerance induction (ITI), in which high doses of FVIII are given over a period of 1 to 2 years to build up tolerance. This treatment is both financially and physically demanding, however, and is not always effective.

To both investigate the mechanism behind the anti-FVIII immune response and to expose a potential target, the investigators explored the potential role of BAFF in regulating FVIII inhibitors. Earlier research has found that high plasma BAFF levels are implicated in some autoimmune diseases, as well as antibody-mediated transplant rejections.

The team used both adult and pediatric hemophilia A patient samples to explore their hypothesis that BAFF may play a role in the generation and maintenance of FVIII antibodies. They found that BAFF levels were elevated in the patients who were resistant to FVIII replacement therapy, although after successful ITI, those levels decreased to levels similar to non-inhibitor patients. In patients for whom ITI was unsuccessful, those BAFF levels remained elevated, according to the study.

“Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors, as well as anti-FVIII B cells,” said co-senior author Valder R. Arruda, MD, PhD, a researcher in the Division of Hematology at CHOP and director of the Center for the Investigation of Factor VIII Immunogenicity, in the press release. “Given that an FDA-approved anti-BAFF antibody is currently used to suppress the immune response in autoimmune diseases, future research should explore the use of this treatment in combination with rituximab to achieve better outcomes for hemophilia A patients resistant to FVIII protein replacement therapy.”

REFERENCE

CHOP-led Research Study Identifies Key Target in Treatment-Resistant Hemophilia A [news release]. Children’s Hospital of Philadelphia; April 15, 2021. https://www.chop.edu/news/chop-led-research-study-identifies-key-target-treatment-resistant-hemophilia. Accessed April 16, 2021.