70 Years after Discovery, UAMS Myeloma Center, Castleman Disease Collaborative Network Lead the Way in Understanding Disease
| By Frits van Rhee, M.D., Ph.D.
Castleman disease was first described in 1954 by Benjamin Castleman, M.D., longtime chief of the Division of Anatomic Pathology at Massachusetts General Hospital in Boston. Patients with Castleman disease have enlargement of one or more lymph node areas.
Patients who have the disease in one area, unicentric Castleman disease, can be effectively treated by surgery. Those with enlargement of multiple areas have flu-like symptoms such as fatigue, fever, loss of appetite and weight loss. This is referred to as multicentric Castleman disease. In severe cases, these patients can develop kidney and other organ failures or may even succumb to the disease. In some cases, especially with HIV patients, the disease is caused by a virus called human herpesvirus type 8. However, in many cases the cause is unknown, and in these cases the disease is referred to idiopathic multicentric Castleman disease (iMCD).
Researchers in Japan showed in the early 1990s that a cytokine called interleukin 6 (IL6) was in many cases responsible for the clinical symptoms and lymph node enlargement in iMCD. In 1994, the Myeloma Center treated the first patient with a monoclonal antibody targeting IL6, a seminal finding that was published that year in the New England Journal of Medicine. This study proved proof of principle that targeting IL6 was a valid therapeutic approach. However, the first antibody proved difficult to administer and the effects were temporary. Researchers in the Netherlands developed an improved antibody, now known as siltuximab, that neutralizes IL6 in the peripheral blood.
The first book on Castleman disease was published in 2018.
The initial results in a dose finding Phase 1 study were positive and followed by a large international study, the first ever in Castleman disease, conducted in Brazil, Canada, New Zealand, Australia, Egypt, Taiwan, Hong Kong, Singapore and the United States, as well as in Europe. As a result, siltuximab became the first treatment for Castleman disease approved by the Food and Drug Administration (FDA). UAMS played a leading role in these studies on which I was the principal investigator.
However, not all patients responded to siltuximab, and the cause of the disease was still elusive. A patient of mine, medical student David Fajgenbaum, and I founded the Castleman Disease Collaborative Network (CDCN) in 2015. Fajgenbaum, now a physician-scientist at the University of Pennsylvania and the co-founder and president of Every Cure, details his personal journey in his book, “Chasing My Cure.”
The CDCN is a worldwide network of researchers and physicians who collaborate to advance our understanding of Castleman disease. Patient advocacy is an important component of the CDCN, which aims to facilitate patient education and provides a portal for patients to connect with Castleman disease experts. Patients can further participate by submitting their medical record data to CDCN’s ACCELERATE registry, established to develop a better picture of the natural history of the disease. This has already led to a better understanding and classification of the disease. Patients and their doctors can further help by submitting blood and lymph node samples to a large biorepository (CastleBank), which is utilized for research studies funded by the CDCN. Protein studies done on the peripheral blood have identified biomarkers that are predictive of response to siltuximab.
The CDCN developed the first international consensus diagnostic criteria for iMCD to accurately define the disease and to distinguish it from other disorders that give rise to similar clinical and lymph node findings. Historically, as many as one-third of patients died from iMCD, partly because there was no uniform approach to treatment based on sound clinical evidence. That lack of guidance resulted in a wide variety of treatments being used to manage the condition. The CDCN’s treatment guidelines recommend drugs such as siltuximab as first-line therapy.
Because not all patients respond to siltuximab, the search for additional treatments continues. Detailed studies have shown that some patients may benefit from sirolimus, an immunosuppressive drug that is used to prevent organ rejection after a kidney transplant. More recently, laboratory studies guided by the CDCN have discovered that some patients may benefit from targeting IL6 in a different way. A new clinical trial is being developed by the CDCN with a class of drugs that targets IL6 signaling inside the cell.
Overall, our understanding of Castleman disease has greatly improved since the disease was first identified in 1954.
We have improved the classification of Castleman disease and developed both diagnostic criteria and a therapeutic algorithm. We now have an FDA-approved drug available for iMCD.
Research has also uncovered potential novel drugs for siltuximab non-responders. The cause of iMCD has remained elusive, but a viral cause has been confidently excluded. Detailed single cell sequencing studies and other state-of-the-art analyses of lymph nodes are in progress, which hopefully will shed further light on this complex and enigmatic disorder.