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Switching to Different FVIII Product Not Associated with Anti-FVIII Inhibitor Development

August 30, 2023

September 2023

Anna Azvolinsky, PhD

Anna Azvolinsky, PhD, is a freelance medical and science journalist based in New York City.

Individuals with hemophilia A who switched to a different factor VIII (FVIII) product did not develop anti-FVIII inhibitors nor did their immune profile change, according to study results published in Haemophilia.

“These are reassuring results for clinicians and individuals with hemophilia A who are worried about inhibitor formation upon switching FVIII products,” said study author Kathelijn Fischer, MD, PhD, a pediatric hematologist and clinical epidemiologist at University Medical Center Utrecht in the Netherlands.

FVIII replacement therapy, either plasma-​derived or recombinant, is the current therapeutic approach for individuals with hemophilia A. Recently, extended-life fusion of a recombinant B-domain-deleted FVIII and the dimeric constant region (rFVIII-Fc), including Elocta, ALTUVIIIO, and Eloctate, have also become available.

A challenging complication in the treatment of people with hemophilia A with FVIII products is the formation of neutralizing anti-FVIII antibodies, called inhibitors, which renders the prophylactic replacement therapy and treatment of bleeds ineffective. “Patients must then be treated with very expensive and less effective bypassing agents, resulting in a marked increase in bleeding and decrease in quality of life,” Dr. Fischer explained.

The researchers sought to understand whether patients with hemophilia A who switch to a different FVIII product are more likely to develop anti-FVIII inhibitors and whether their immune profile changed after the product switch.

The study analyzed 100 patients with hemophilia A at a single center, between 2017 and 2019, who switched between various FVIII concentrates for inhibitors and immunologic changes.

The median age of the cohort was 39 years (range = 22-54), and 97% of patients had severe hemophilia A. Fifteen patients had previously had an inhibitor.

Of the 100 patients, 31% switched from plasma-derived (pdFVIII) to recombinant standard half-life FVIII (SHL-rFVIII), 47% switched between different SHL-rFVIII products, and 22% switched from pdFVIII or SHL-rFVIII to an rFVIII-Fc. Of the 100 patients, 39 were included in a prospective cohort that was analyzed for immunological changes after the product switch.

Before the switch, the study participants were using four different FVIII products; 33% were using a pdFVIII product, and the remaining 67% were using one of three rFVIII products: third-generation full-length rFVIII octocog alfa (61%), single-chain B-domain-truncated (BDT) rFVIII lonoctocog (5%), and BDT-rFVIII turoctocog alfa (1%). Seventy-eight percent of patients switched to turoctocog alfa, and 22% switched from SHL-FVIII to rFVIII-Fc (efmoroctocog alfa).

None of the patients developed an inhibitor after switching to a different FVIII product. After switching from SHL-FVIII to an rFVIII-Fc, both FVIII consumption and the number of weekly injections remained stable, while bleeding rates were significantly reduced.

Of the 39 patients whose immunological profile could be studied prospectively, the number of regulatory B cells and regulatory T cells, expression of PD-L1 and HLA-DR on monocytes, and expression of PD1 and ICOS on T cells did not change in the 12 months after an FVIIII product switch.

The percentage of myeloid-derived suppressor cells slightly increased (p=0.032), and the expression of CTLA4 on CD4+ T cells showed a significant decrease from the switch to 12 months post-switch (p=0.018).

The study authors did not find any changes in the distribution of immune cells or markers assayed after any of the product switches, neither from a standard to a long-acting FVIII nor from pdFVIII to rFVIII.

Adverse events or dissatisfaction with the new FVIII product were seen among 14 patients, including 10 who switched from pdFVIII to rFVIII, two who switched from rFVIII to another rFVIII product, and two who switched from rFVIII to rFVIII-Fc. Most individuals reported higher bleeding tendency, although the registered annual bleeding rate (ABR) did not significantly increase in these patients (median ABR pre-switch and post-switch = 4.0 and 3.0, respectively).

“In summary, switching was not a problem in either clinic inhibitor assays or in the laboratory tests that measured immunoregulatory cells,” Dr. Fischer said.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Schep SJ, Fisher K, Boes M, et al. No immunological changes after factor VIII product switch: an in depth analysis in haemophilia A patients. Haemophilia. 2023;29(4):1039-1048.

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