Their findings were published in a letter to the editor, titled “Daratumumab rapidly reduces high‐titre factor VIII inhibitors in haemophilia A patients during life‐threatening haemorrhages,” in the journal Haemophilia.
Hemophilia A is characterized by lack or a defect in FVIII, a blood clotting protein. Treatment commonly involves infusions of this protein, which can restore clotting ability.
However, some patients will develop antibodies against the administered protein, which prevents the treatment from working. These antibodies are called inhibitors.
To some extent, inhibitors can be circumvented with bypassing agents — which “bypass” the need for clotting factor treatment — but these therapies are expensive.
An alternative strategy for dealing with inhibitors is to use immune tolerance induction (ITI), in which FVIII is given regularly until no adverse reaction is seen. However, this approach often fails to adequately reduce very high inhibitor levels.
Daratumumab is a monoclonal antibody that targets the protein CD38 on the cell surface. The therapy is approved in the U.S. to treat multiple myeloma under the brand name Darzalex (marketed by Janssen Pharmaceuticals).
Besides myeloma cells, CD38 is also found on the surface of certain immune cells. In particular, the protein is expressed on plasma cells, which are primarily responsible for making antibodies, including inhibitors. As such, daratumumab could reduce inhibitor levels in people with hemophilia who require treatment.
In the article, researchers in Thailand reported on three patients with hemophilia A (all male, ages 16 to 21) who were given daratumumab from October 2018 to August 2019 as part of emergency treatment to control bleeding. In all cases, the patients had detectable inhibitors prior to daratumumab treatment, and they had been given bypassing agents for at least five days, without adequate bleeding control. Daratumumab was given under compassionate use supported by Janssen.
Based on the regimen used for myeloma, daratumumab was given intravenously (directly into the bloodstream) at 16 mg/kg for the first four weeks, followed by 8 mg/kg weekly or 16 mg/kg every other week for up to eight weeks. All three patients were also given other immune-suppressing medications, including ITIs and rituximab, at the discretion of the physicians.
In all three patients, inhibitor levels were effectively suppressed following treatment with daratumumab.
“Within 3-6 daratumumab infusions, high-titre FVIII inhibitors … were successfully suppressed, indicating partial responses in all three [patients],” the researchers wrote.
In two patients, the combination of treatments was able to effectively control bleeding without major adverse events.
In the third patient, despite inhibitor levels becoming undetectable with daratumumab and rituximab, bleeding continued to pose a challenge. He developed lung inflammation induced by rituximab and died of ventilator-associated pneumonia.
“Our first-in-human evidence depicted a new promising strategy to rapidly eliminate high-titre FVIII inhibitors in [people with hemophilia A] with life-threatening bleeding using daratumumab,” the scientists concluded.
According to the team, the study’s limitations include the fact that other immune-affecting therapies were used with daratumumab. As such, further research is needed to clarify the utility of daratumumab in hemophilia treatment.
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