June 3, 2025 | A new subtype of Castleman disease has been identified, the first such major discovery in 45 years. While it remains unclear how many individuals stand to benefit, this is a “hugely important” development for the proportion of patients who fit neither the “unicentric” nor “multicentric” criteria long used to describe the symptoms and disease experience, according to Sheila Pierson, senior research advisor for the Castleman Disease Collaborative Network (CDCN).
Castleman disease is a group of rare disorders that involve enlarged lymph nodes. Recent estimates suggest that less than 2,000 cases are diagnosed in the U.S. annually, says Pierson, who previously served as director of clinical research for the Center for Cytokine Storm Treatment & Laboratory (CSTL) at the University of Pennsylvania.
It is nonetheless one of the better-known rare diseases, thanks to the patient advocacy work of David Fajgenbaum, M.D., associate professor of translational medicine and human genetics at Penn and co-founder of the CDCN. Fajgenbaum was diagnosed with idiopathic Castleman disease, where the cause of the lymph node enlargement is unknown, in his third year of medical school, Pierson says. “Over the next several years, he nearly died from it five times.”
Fajgenbaum and Pierson took the lead on the latest study describing “oligocentric” Castleman disease (OligoCD), a subtype that has fewer and less severe symptoms than the unicentric and multicentric varieties and is believed to characterize about 15% of all cases (Blood Advances, DOI: /10.1182/bloodadvances.2024014391). Researchers used the ACCELERATE natural history registry to characterize the spectrum of Castleman disease based on disease features, symptomatology, and severity.
The main factor preventing this discovery up until now has been the small number of geographically dispersed patients, making it difficult to assemble a large, centralized cohort of patients. “Since 2016, [CSTL] has been building ACCELERATE... which allows Castleman disease patients to self-enroll into our research from anywhere in the U.S. and globally,” says Pierson. By consenting to the research, patients allow the research team to collect their medical records and extract data to identify patterns of disease characteristics and treatment approaches.
For the latest study, 343 Castleman disease cases were enrolled and extracted into the research database at Penn. After excluding those who lacked sufficient diagnostic radiologic data and documentation to undergo expert panel review, or were not panel-confirmed, 179 cases remained that fit a diagnosis consistent with the unicentric, multicentric, or oligocentric subtype.
“We are still trying to best understand the treatment approach for oligocentric patients, but our data suggests that these patients do not demonstrate the same degree of inflammation as multicentric patients and therefore may not require as aggressive an approach,” Pierson says. “Rather, they may benefit from a treatment approach more similar to that used in unicentric patients, but the incidence of subsequent disease involvement suggests additional monitoring may be needed. Ultimately, each patient deserves a personalized approach.”
ACCELERATE has been the backbone to Castleman disease research at Penn and currently has over 800 patients enrolled, reports Pierson. The registry is currently being supported by an R01 grant through the Food and Drug Administration’s Office of Orphan Products Development.
Pierson has been a pivotal figure in the Castleman disease field and has published extensively on disease subgroups and treatment patterns that inform clinical practice. Her contributions have included oversight of ACCELERATE and biostatistical analyses of large-scale proteomics datasets.
“For every patient that enrolls, it can take time to collect and extract all their medical data,” Pierson says. “Patients subsequently go through an adjudication process, where experts review their data and grade the likelihood of an accurate Castleman diagnosis.”
CDCN, the other big enabler of the OligoCD subtype discovery, was established in 2012 by Fajgenbaum and Frits van Rhee, M.D., Ph.D., professor of medicine and clinical director of the University of Arkansas for Medical Sciences Myeloma Center. They soon joined forces with Castleman’s Awareness & Research Effort, founded six years earlier by a pair of patient advocates.
Fajgenbaum has “worked tirelessly to understand alternative treatment approaches... after failing the known treatments,” Pierson says. “In doing so, he identified a drug called sirolimus that he thought might save him. He collaborated with his physicians at the time, who supported him in becoming his own test subject and, fortunately, his approach worked.”
Over the more than 10 years that Fajgenbaum has been in disease remission, he has “worked tirelessly” to build the CDCN as well as CSTL, which is devoted to better understanding and treating Castleman disease. Pierson has worked with him on both fronts since 2016.
Being a patient himself, Pierson notes, Fajgenbaum ensures that patients enrolled in the ACCELERATE registry get surveyed on topics that are important to them. The research team also holds regular meetings and community updates with that patient community to address their research questions. “We are lucky in that we have a very close relationship with the patient community as a whole, and we collaborate with them often so that we can ensure we are maximally benefiting them.”
The research team is still collecting data on the oligocentric patient population via ACCELERATE, since only a relatively small number (14) of patients with the OligoCD subtype were identified in the study cohort. “As we collect more data, we will continue to evaluate treatment approaches that are being used and that are working in this population,” says Pierson. “If we are able to identify a signal of a beneficial drug or treatment approach, it’s possible we will explore a [clinical] trial.”
Pierson says she feels “very fortunate” to work with Castleman disease patients. “[They] are so motivated to learn about their own disease, and they are eager to participate in our research because they want to find answers as much, or more, than we do.”
Castleman disease patients and parents of children with Castleman disease are encouraged to enroll in the registry. Pierson adds that she is hopeful that the ACCELERATE model will prove beneficial for other rare disease research, by allowing the participation of patients who would otherwise be excluded from studies conducted at a central location.