New hope for Castleman disease


Five years ago, David C. Fajgenbaum, MD, MBA, MSc, both a Penn Medicine researcher and patient, tried an experimental treatment on himself based on his laboratory research findings in the hopes of saving his own life.

He has been in remission ever since. Now his research is shedding new light on why it worked, paving the way for further testing of a new treatment approach in Castleman disease, a rare and deadly condition with limited options for patients.

The work is led by Fajgenbaum, who is both the director of the Center for Study & Treatment of Castleman’s & Inflammatory Lymphadenopathies (CSTL) in the Perelman School of Medicine at the University of Pennsylvania as well as Patient 1 in the study.

The findings show patients who do not respond to the only drug currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of the disease may have another option that targets a specific pathway called PI3K/Akt/mTOR. The research is published in the Journal of Clinical Investigation today.

Castleman disease isn’t actually a single disease.

The term describes a group of inflammatory disorders that share a common 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), has similarities to both autoimmune conditions as well as cancer.

About 35 percent of patients with iMCD will die within five years of diagnosis.

In 2014, the FDA 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 for years.

“Patients who don’t respond to siltuximab have limited options.

They typically receive chemotherapy but often relapse,” said Fajgenbaum, who is also an assistant professor of Medicine in the division of Translational Medicine & Human Genetics at Penn and executive director of the Castleman Disease Collaborative Network.

The study’s senior authors are Thomas S. Uldrick, MD, MS, the deputy head of Global Oncology at Fred Hutchinson Cancer Research Center who was also Fajgenbaum’s treating physician while practicing at the National Institutes of Health, and Frits van Rhee, MD, Ph.D., the clinical director of the Myeloma Center at the University of Arkansas for Medical Sciences.

A med student, a former Division I quarterback, and a state-champion weight lifter, Fajgenbaum suddenly became sick in July 2010.

In 2012, after failing to respond to other therapies and having relapsed multiple times after chemo, Fajgenbaum’s research on his own condition suggested that an inhibitor drug called sirolimus that blocked the PI3K/Akt/mTOR pathway could be effective.

This drug is already available for the treatment of other conditions, particularly to prevent organ rejection after kidney transplantation.

Fajgenbaum’s decision to test it on himself, which was based on his own research and made in consultation with Uldrick, his treating physician, has kept him in remission ever since.

This study also examines two additional patients treated with the same approach who also achieved a sustained remission.

Research showed all three patients saw an increase in two aspects of the immune system—increased numbers of activated T cells and elevated levels of a protein called VEGF-A that causes blood vessel growth—before a flare up, then a return to normal levels once remission began.

“Our findings are the first to link T cells, VEGF-A, and the PI3K/Akt/mTOR pathway to iMCD,” Fajgenbaum said. “Most importantly, these patients improved when we inhibited mTOR. This is crucial because it gives us a therapeutic target for patients who don’t respond to siltuximab.”

Fajgenbaum and his team will test the treatment in a clinical trial (NCT03933904) set to open in the coming weeks at the University of Pennsylvania, with Sunita Nasta, MD, FACP, an associate professor of Hematology-Oncology, and Adam Cohen, MD, an assistant professor of Hematology-Oncology, enrolling and treating patients.

The University of Arkansas for Medical Sciences will also serve as a trial site under the direction of van Rhee.

Fajgenbaum also points out the larger implications this research has for the rare disease community.

“This highlights the potential for the approximately 1,500 drugs already approved for one condition to also be treatments or cures for the 7,000 diseases with no or insufficient treatment options like ALS and many pediatric cancers,” Fajgenbaum said.

Journal information: Journal of Clinical Investigation
Provided by Perelman School of Medicine at the University of Pennsylvania

The spectrum of Castleman disease (CD) has considerably extended since its first description in 1956. Recently, an international collaborative working group has reached consensus on the diagnostic criteria and classification of CD. We herein report 273 patients with lymph node histopathology consistent with CD and investigate the newly established diagnostic criteria.

Twenty of these patients with Castleman‐like histopathology were removed from analyses, because they were diagnosed with an exclusionary disorder (18 with haematological malignancy).

Among the 253 remaining patients, 57 were considered unicentric CD (UCD), 169 were multicentric CD associated with Human Herpesvirus 8 (HHV‐8+MCD), including 140 patients with human immunodeficiency virus (HIV) infection and 29 patients without HIV infection, and 27 were HHV‐8 negative/idiopathic multicentric CD (iMCD). 2‐(18F)fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography was useful in 62 patients for staging/classification of the disease and for excluding associated lymphoma. UCD was mainly associated with hyaline‐vascular histopathological features, and most patients were asymptomatic.

Of the 27 patients that we had originally diagnosed with iMCD, 26 met the newly established diagnostic criteria. Patients with iMCD and HHV‐8+ MCD demonstrated similar characteristics, including fever, splenomegaly, cytopenia and inflammatory symptoms. However, the disease was more aggressive in HHV‐8+ MCD, particularly in HIV‐infected patients.

Since the first description by Benjamin Castleman, 60 years ago, of a peculiar histological pattern observed in a series of lymph node lesions of the mediastinum, the spectrum of the diseases considered under his eponym has considerably extended (Castleman et al1956; Weisenburger et al1985; Waterston & Bower, 2004; Wang et al2016).

Castleman disease (CD) now encompasses several distinct clinicopathological disorders at the intersection of haematology, immunology, oncology, rheumatology and virology that share a spectrum of histopathological features.

The initial description of the disease referred to a usually idiopathic and asymptomatic solitary lesion showing characteristic hyaline vascular histopathological changes. In the following decades « variants » have been described according to several dichotomies: unicentric versus multicentric, hyaline‐vascular versusplasmacytic, asymptomatic versus symptomatic, and the possible associations with haematological malignancies (Larroche et al2002), autoimmune disorders (Carrington et al1990; Miltenyi et al2009; Muskardin et al2012), human immunodeficiency virus (HIV) (Oksenhendler et al1996) or herpesvirus‐8 (HHV‐8) infections (Soulier et al1995; Bower, 2010). Recently, an international collaborative working group has reached consensus definitions and classification, defining diagnostic criteria for CD for the first time (Fajgenbaum et al2016).

Three distinct entities can now be considered at diagnosis (Fajgenbaum et al2017): (i) Unicentric CD (UCD), usually exhibiting hyaline vascular morphological changes, often asymptomatic, and surgical excision is often curative; (ii) Idiopathic multicentric CD (iMCD), usually associated with plasmacytic morphological changes and involving inflammatory symptoms, polyclonal lymphoproliferation, cytopenias and, in some cases, life‐threatening multiple organ dysfunction; (iii) HHV‐8 associated MCD (HHV‐8+ MCD), in which large plasmablastic cells infected with HHV‐8 – often in the context of HIV infection – drive a cytokine storm, presents with similar features to iMCD.

In parallel, and before considering the diagnosis of CD, a number of associated diseases that can exhibit Castleman‐like features on lymph node biopsy, should be ruled out, while some autoimmune diseases may actually be considered as true complications of CD. In most cases of MCD, interleukin‐6 (IL6), either human IL6 in iMCD or viral IL6 in HHV‐8+ MCD, plays a major role in the pathophysiology of the clinical and biological symptoms of the disease (Yoshizaki et al1989; Brandt et al1990; Oksenhendler et al2000; Uldrick et al2012).

Therefore the IL6 pathway has been considered as a major target for therapy in iMCD (Nishimoto et al2000; van Rhee et al2014), whereas targeting B cells with rituximab has been shown to be very effective in HHV‐8+ MCD (Bower et al2007; Gérard et al2007).

Herein, we review the largest series of CD patients from a single centre reported to date, investigate concordance with newly‐established diagnostic criteria, and discuss possible « grey zones » in the current classification.

Patients and methods


All patients with biopsy‐proven histopathological features consistent with a CD diagnosed at Hôpital Saint Louis (Paris, France) over a 20‐year period were reviewed for analysis. Patients with HIV infection had been included in a prospective registry on HIV‐associated lymphoproliferative disorders and HIV negative patients had been included in a national registry on CD.


Eligibility was based on the pathological diagnosis. The biopsy specimens have not been specifically reviewed for the present study but were discussed with the pathologist at entry in both registries.

The histopathological features consistent with a CD diagnosis included abnormal regressed or hyperplastic germinal centres, follicular dendritic cells prominence, hypervascularization, expanded mantle zones and interfollicular plasmacytosis. According to the grading of these pathological features, two ends of a pathological spectrum could be defined: a hyaline‐vascular subtype and a plasmacytic subtype, with some lesions exhibiting mixed characteristics. In addition, HHV‐8 specific staining (LANA‐1) allowed detection of HHV‐8 infected plasmablasts found in HHV‐8+ MCD.


Classification and diagnostic criteria were based on the criteria recently established by an international collaborative group, the Castleman Disease Collaborative Network ( Classification was based on 4 steps: (i) exclusion of diseases that can present with Castleman‐like histopathology on lymph node biopsy but that are considered to mimic CD; (ii) staging of the disease: Unicentric (one single lymph node station) versusMulticentric (disseminated disease); (iii) Testing for HHV‐8 using specific immunohistochemistry; (iv) context of HIV infection (Fajgenbaum et al2017). The newly‐established diagnostic criteria for iMCD were tested in this group for validation (Appendix S1).

Positron emission tomography/computed tomography (PET/CT) scans

A large number of patients were examined with a dual modality PET/computed tomography (PET/CT). PET using the glucose analogue 2‐(18F)fluoro‐2‐deoxy‐D‐glucose (FDG) was performed from the base of the skull to the upper thighs after a 6 h fast. The CT images were evaluated for the presence and distribution of enlarged lymph nodes (greater than 1 cm in short diameter) and splenomegaly. Nodes were designated positive if FDG activity was increased relative to that of adjacent normal soft‐tissue. The SUVmax corresponds to the maximum standardized uptake value in a voxel within a circular region of interest drawn for each nodal group with FDG uptake.


All patients with complete datasets were included in the analysis. Descriptive statistics were reported as medians (interquartile range) or numbers (%). Overall survival (OS) was calculated from CD diagnosis until June 2017 or death from any cause. Survival was estimated using the Kaplan–Meier product‐limit method and compared using log‐rank test. Statistical analysis was conducted using STATA Statistical Software version 14.2 (Stata Corp., College Station, TX, USA).


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