Aaron Goodman, MD, Tells Us the 'Crux' of Castleman Disease

Aaron Goodman, MD, an Associate Professor of Medicine at the University of California San Diego, joined Chadi Nabhan, MD, MBA, FACP, on “The HemOnc Pulse” to discuss Castleman disease and how each subtype is diagnosed and treated. The following excerpt is taken from this week’s episode.

Dr. Nabhan: We wanted to discuss today Castleman disease, because it’s not really a very common disease.

Dr. Goodman: The crux of Castleman, and why it’s horribly understood and mismanaged, is that it’s incredibly rare. It’s many different diseases, and it falls across many different specialties.

Patients with unicentric Castleman disease are asymptomatic other than an isolated or regional group of lymph nodes that are enlarged. When you resect [the lymph node], it’s gone and the patient’s done with the disease. They don’t have any B symptoms, inflammatory symptoms, or other lab abnormalities.

Dr. Nabhan: Is it a diagnosis of exclusion?

Dr. Goodman: Basically, it has to present. In unicentric Castleman disease, the pathologist has to have Castleman-like findings with one lymph node. Usually, it’s in the mediastinum or in the cervical chain. I’ve seen patients that presented with large intraabdominal masses. Most cases of unicentric Castleman that I’ve seen are incidental findings on imaging. What causes this? We have no idea. The suspicion is that there is a not cancer, but a clonal population of cells within the lymph node, particularly within the follicular dendritic meshwork.

Dr. Nabhan: Is Castleman cancer?

Dr. Goodman: No.

Dr. Nabhan: Why would you treat it then?

Dr. Goodman: Unicentric is asymptomatic other than the regional node.

The more confusing clinical scenario is the classic patient presents with fevers, B symptoms and fluid retention, and there’s a concern for an inflammatory disorder, bad infection, or even a malignancy. On that imaging study, they see modest lymphadenopathy. They’re referred for an excisional biopsy, which comes back with findings consistent with Castleman disease. They don’t see any Hodgkin lymphoma or follicular lymphoma. This patient has multicentric Castleman disease.

There are three flavors of multicentric Castleman disease. One is human herpesvirus-8 (HHV-8) associated multicentric Castleman disease, which is almost always found in the setting of a concurrent HIV or AIDS diagnosis. If they’re HHV-8 negative, then they have idiopathic multicentric Castleman disease, otherwise known as David Fajgenbaum disease.

Dr. Nabhan: How often do you see idiopathic versus HHV-8?

Dr. Goodman: With appropriate antivirals and less advanced HIV, we’re seeing more idiopathic.

In HHV-8 Castleman disease, these patients are sick. The HHV-8 infects plasma, blasts lymphocytes, then secretes high levels of virally encoded IL-6. High levels of viral IL-6 trigger large lymph nodes, fluid retention, swelling, and inflammatory symptoms. You need to eradicate the HHV-8 in the reservoirs in these B-cells. You give [patients] rituximab, then start them on antiviral. Most patients go on to live a completely normal life. It’s treated similar to lymphoma, because we use rituximab for B-cell lymphomas.

Dr. Nabhan: That’s why it made me wonder, do I need rituximab?

Dr. Goodman: You do. There’s been studies with antivirals directed toward this virus.

Idiopathic looks very similar clinically to HHV-8 positive, except they don’t have HIV and they’re HHV-8 negative. What causes it? We don’t know. For treatment, we have the IL-6-directed antibody, siltuximab. There’s a similar drug called tocilizumab, which we now use all the time for cytokine release syndrome after chimeric antigen receptor (CAR) T-cell therapy. In a phase II study, patients with idiopathic multicentric Castleman disease were randomized to siltuximab for best supportive care, and siltuximab won.

Dr. Nabhan: In multicentric idiopathic, is there no point of doing rituximab or chemotherapy?

Dr. Goodman: The recommended first-line treatment is siltuximab. 50%-60% of patients will respond. If you respond, you seem to respond nearly forever. It is a really easy drug to give. It’s a monoclonal. It’s not chemo. You give it every three weeks. It’s not immunosuppressive.

In multicentric idiopathic Castleman disease, there’s a flavor called tafro (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly). [Patients] don’t seem to respond as well to IL-6 directed therapy. We don’t really know how to treat them, so we treat them like lymphoma. If they’re really sick, the recommendations are multi-agent chemotherapy. Some doctors, like myself, favor R-CHOP or R-CVP. The field is desperately looking for alternative therapies in those who are not sensitive to siltuximab or chemo and rituximab.

There’s one other type of Castleman disease called POEMS-associated multicentric Castleman disease. [It] is truly a bona fide neoplastic process, due to clonal plasma cells. These patients present with symptoms of polyneuropathy, organomegaly, and endocrinopathy. They usually present with a sensory motor neuropathy that’s quite debilitating, and they have a monoclonal protein.

You treat POEMS with plasma cell-directed therapy, like daratumumab. We tend to avoid bortezomib because they already have neuropathy, which makes it worse. There used to be a push for transplant.

Dr. Nabhan: I was going to ask about transplant.

Dr. Goodman: With POEMS, It’s not a clonal problem. It’s usually a small burden of clonal cells, unlike myeloma, where you have a high burden of clonal plasma cells and need transplant aggressive therapies. You can get away with less aggressive therapies, wipe out that clone, and result in a very durable remission. I see no role of consolidating with a transplant.

Dr. Nabhan: How many Castleman disease cases are we talking about a year in the United States? How prevalent is this?

Dr. Goodman: If you lump them all together, it’s a few thousand or so.

Dr. Nabhan: So, it’s like a rare disease, or an orphan disease.

Dr. Goodman: It’s an orphan disease. I encourage anyone with Castleman disease to log onto the accelerate registry, which is a database made by Dr. Fajgenbaum, and their team will reach out to the patient. This is how we’re collecting longitudinal data. Dr. Fajgenbaum also has a study for relapsed Castleman.

Dr. Nabhan: Aaron, thank you so much for spending some time on the “HemOnc Pulse.” This was great.