Siltuximab works by blocking the pro-inflammatory signaling molecule interleukin-6 (IL-6), which is known to play a key role in driving iMCD in some patients. The medication was approved by the U.S. Food and Drug Administration (FDA) in 2014 following a pivotal randomized, placebo-controlled clinical trial. In this trial, 34% of patients treated with siltuximab improved on the medication compared to 0% in the placebo arm. However, no key laboratory test abnormalities were previously identified among patients who responded and those who didn’t.
“After the FDA approval of siltuximab, members of our physician community reported major successes with the medication, but also frustration at not being able to predict which patients would respond to the drug. It became clear that this was an important question for physicians on the front line and would reveal important clues to understanding the mechanisms of this challenging disease. I am so thankful to Tony Ressler for his generous donation that covered the entire cost of this ground-breaking study and for his commitment to helping patients with Castleman disease, like me. I am also thankful for our close collaboration with Janssen, which contributed their clinical trial data for our analysis so that we could move quickly to address this high priority research topic.”
—Dr. David Fajgenbaum, MD, director of the Castleman disease research group at the University of Pennsylvania (CSTL) and executive director of the CDCN
The study, titled “Predictors of response to anti-IL6 monoclonal antibody therapy (siltuximab) in idiopathic multicentric Castleman disease: secondary analyses of phase II clinical trial data,” built a statistical model that correctly predicted treatment response or treatment failure in 34/40 (85%) patients in the data set. The predictive model uses values from 4 commonly used blood tests in patients with iMCD to predict whether or not patients will improve on siltuximab.
- C-Reactive protein (CRP) – A protein produced by the liver. Levels of CRP often rise in response to inflammation, sometimes due to IL-6 signaling.
- Hemoglobin – The protein in red blood cells that carries oxygen molecules. Levels of hemoglobin reflect the total oxygen carrying capacity of the blood and can decrease during inflammation.
- Fibrinogen – A protein in the blood that helps form blood clots at sites of injury. Levels of fibrinogen can rise in response to inflammation.
- Immunoglobulin G (IgG) – The most common class of antibodies found in the blood. Elevated IgG levels are often seen in patients with iMCD and may be due to increased IL-6 activity.
“The key take away is that patients with a more severe inflammatory profile including higher fibrinogen, IgG, and lower hemoglobin were more likely to respond to Siltuximab. The results are exciting and reveal important new information about the role of IL-6 in iMCD. However, further validation of the model in other patients, such as those in our ACCELERATE study, is necessary before we can determine if this model can be used in clinical practice. This is a big step forward for our research community and CDCN projects like this will help us to create a truly personalized approach to treating patients with iMCD in the future.”
—Dr. David Fajgenbaum, MD