David C. Fajgenbaum, MD, MBA, MSc
How do you cure a disease when you don’t know what kind of disease it is or what causes it? It’s a problem that sounds unsolvable. But when researchers unlock the mysteries of Castleman disease, they may single out 2018 as one of the years in which they laid the foundation to help them turn the key, and the University of Pennsylvania has been the epicenter. From the creation of treatment guidelines to potentially identifying a way to predict responses to the only FDA-approved therapy, as well as the establishment of a center devoted to Castleman disease and the receipt of the first ever federal grant to study a promising new therapy, 2018 was a banner year for those who research the rare disorder, and it hints at the promise of what’s to come.
The effort is led by David C. Fajgenbaum, MD, MBA, MSc, an assistant professor of Medicine in the division of Translational Medicine & Human Genetics, who not only studies Castleman disease, but also has the disease himself. From finding better treatments to better understanding and categorizing the disease, Fajgenbaum’s unique perspective has driven him to find answers, even as the unknowns surrounding Castleman itself have proven to be a unique challenge.
“There are some elements of the most severe type of Castleman disease that make it similar to autoimmune conditions like lupus, while others are closer to cancers like lymphoma,” Fajgenbaum said. “The mechanisms are so poorly understood that even trying to classify the illness has proven difficult.”
Part of the problem is that Castleman disease isn’t actually a single disease. The term describes a group of inflammatory disorders that share a common histopathological appearance under the microscope. It’s diagnosed in about 5,000 people of all ages each year in the United States, which makes it roughly as common as Lou Gehrig’s disease, also called ALS. Patients experience a range of symptoms – from a single abnormal lymph node with mild flu-like symptoms to abnormal lymph nodes located throughout their entire body, abnormal blood cell counts, and life-threatening failure of multiple organ systems, such as the kidneys, liver, heart, and lungs.
The most severe subtype, idiopathic multicentric Castleman disease (iMCD), is similar to both autoimmune conditions as well as malignancies, as Fajgenbaum described. Approximately 35 percent of patients with iMCD will die within five years of diagnosis. In 2014, the U.S. Food and Drug Administration approved the drug siltuximab to treat iMCD, and studies have shown it can send between one-third and one-half of patients into a remission that generally lasts.
“Patients who do not respond to siltuximab have few therapeutic options and typically receive chemotherapy, but they often relapse,” Fajgenbaum said.
In a disease like cancer, experimental treatments can start in the lab, proceed to animal models, then move into humans after extensive testing. That’s not the case with Castleman disease, which doesn’t have the benefit of going bench-to-bedside.
“There are no cell lines for experimentation because we haven’t unlocked critical aspects of the disease itself, such as the cell type responsible for driving it,” Fajgenbaum said. “That means we have to start by studying samples from patients in the clinic to generate clues.”
Just the same, 2018 saw a remarkable amount of progress. A group of 42 experts from 10 different countries came together to publish the first ever treatment guidelines for iMCD, standardizing first, second, and third line therapies for the disease. Fajgenbaum was the senior author on the guidelines, which were published in the journal Blood.
In addition, Fajgenbaum led a group that identified a set of abnormal clinical laboratory tests that are associated with respond to siltuximab in a group of iMCD patients. That study, published in the British Journal of Haematology, showed that the team’s statistical model correctly predicted response or failure, retrospectively, to siltuximab therapy in 34 out of 40 patients, or 85 percent. If these results are validated in a separate cohort, these routinely conducted clinical laboratory tests may be used to help predict which patients will respond to siltuximab.
This progress, along with further studies aimed at identifying the mechanisms causing Castleman disease, helped lead to three other milestones this year. The first is a five year grant from the National Institutes of Health (NIH) – the first of its kind ever awarded for iMCD research. Fajgenbaum and his team will use it as the foundation for a clinical trial, set to begin enrollment in 2019, of a promising new therapeutic for iMCD patients who fail siltuximab therapy.
“The investment in our work from the Penn Center for Precision Medicine’s Accelerator Fund generated the preliminary data we needed to secure this grant, and it’s a great example of how internal support can help research in rare diseases receive national attention,” Fajgenbaum said.
Fajgenbaum and his team also led or co-led studies that resulted in five poster presentations on iMCD at the American Society of Hematology’s 2018 annual meeting. The posters include data related to cell types, signaling pathways, and circulating factors discovered in iMCD patients. The results from those abstracts will likely go on to be published in 2019.
All of this progress built to a monumental moment in October, with the announcement of a new Castleman Disease Program of Excellence at the University of Pennsylvania. The program will be housed in the Castleman Disease Center, led by Fajgenbaum, and involves a multi-disciplinary team that will focus on clinical care, translational research, education, and clinical trials – including the one set to open in 2019. The ability to bring experts together through the Center will be critical given the unanswered questions about Castleman disease. Dustin Shilling, PhD, will serve as the Director of Operations, Research, and Strategic Planning for the Center.
“We’re fortunate to have researchers and clinicians with different backgrounds and areas of expertise all collaborating to solve this problem,” Shilling said. “In a way, we’re working backwards as we translate our experience with patients into the lab, and then use what we learn in the lab to improve outcomes for future patients.”
How do you cure a disease without knowing how it works? The first steps would be to standardize what you know, predict who can benefit from existing treatments, bring together an international group of experts who think about the problem differently, and secure funding to research the problem further. To do all of that in one year means you’ve moved the needle.