Systemic Review on Idiopathic MCD

Corey Casper, MD, MPH:There have been a number of different studies which have tried to characterize the manifestations of Castleman’s disease. These studies are generally single- or multi-site studies where patients’ records are abstracted from the medical record system, and retrospectively reviewed for associated characteristics. Some centers have enough volume to be able to look at enough cases to begin to put together a picture of what this disease looks like. I will say that there are some challenges to that approach.

Generally, patients are included in series like these because they have a pathologic diagnosis of Castleman’s disease. That’s important, and it’s actually critical but I would say that there are probably individuals who don’t meet strict pathologic criteria for Castleman’s, but a clinician will still treat them as if they have Castleman’s disease. Patients like that tend not to be included in these case series. And, of course, it only recognizes the patients that actually come to medical attention and actually have those symptoms. So, I think that bias is towards more severe cases.

But, in each of these reviews, I think a pretty compelling picture is presented which is that the multicentric disease often times can be minimally symptomatic, but at least in these series, hallmarked by abnormalities in blood cell counts, often times abnormalities in inflammatory biomarkers, associated symptoms like liver dysfunction or renal dysfunction. And, then, if you look at the natural history of the disease, many patients want to know what’s the prognosis and these series can be helpful in looking at that, but they range. Some of the series find that multicentric Castleman’s disease, when in the care of specialists that handle it properly, has an excellent long-term survival. Whereas, other studies have actually found that survival can be quite miserable. And, again, I think that more reflects the severity of the cases that are referred to that care center and less truly what happens in the natural history of the disease.

The prevalence of idiopathic versus the human herpesvirus-8(HHV-8)—associated disease is hard to estimate. First, I would say that in the setting of HIV, almost 100% of the cases are the HHV-8–related disease. And, we think that’s for a number of reasons. HHV-8 can be transmitted through sexual routes like HIV, so the two viruses often are found together in similar populations. But, also, I would say that there are other risk factors. For HIV, the immune dysfunction that accompanies the HIV may put you at higher risk for developing Castleman’s disease, as well. So, in the setting of HIV, nearly 100% of the cases are HHV-8–related. Outside of the setting of HIV, I think that it depends on the geographic setting where the cases are determined.

If you look in the medical literature, you may find that there are some places in Asia, some places in the Middle East, where 40% of the cases of Castleman’s disease, even in HIV-negative individuals, are related to the virus. But, if you look more broadly across the United States, you don’t find that same penetrance of the virus, and the majority of multicentric cases are idiopathic or not related to the virus. And that reflects across the world, there is a big variation in the prevalence of this virus in the underlying population. In the United States, 5% of random blood donors have evidence of infection with human herpesvirus-8. In some places in the Middle East or in Sub-Saharan Africa, it’s 50% or even 90% of the population.

When you’re looking at Castleman’s disease and you’re thinking of whether it’s idiopathic or related to human herpesvirus-8, it really depends on the underlying prevalence of the virus in that population. So, in general, I would say that the majority of HIV-negative multicentric Castleman’s disease cases are idiopathic, are not related to the virus. In the setting of HIV, it’s the opposite, almost all are related to the virus.

The clinical features of idiopathic multicentric Castleman’s disease are very variable. Many patients will present, almost all patients, by and large, will have enlarged lymph nodes in multiple chains, most will have constitutional symptoms, and, in my experience, almost the majority of them have fatigue and many, many of them will have sweats, most often at night. Across the board, patients with multicentric idiopathic Castleman’s disease have the enlarged lymph nodes in multiple chains, fatigue, and often times sweats. Those are, I would say, almost across the board. Almost all patients in the idiopathic multicentric Castleman’s disease also have associated blood abnormalities like anemia, either a very high or a very low platelet count, and elevated inflammatory markers like the C-reactive protein and the erythrocyte sedimentation rate. So, that I think is across the board almost all patients with idiopathic multicentric Castleman’s disease have those features. There are other patients with idiopathic multicentric Castleman’s disease that have a much more severe variant of the disease, and, in that variant, they present with renal failure, respiratory failure, and widespread ascites or anasarca and that’s again related to the overexpression of interleukin-6. But, they, too, will have those basic symptoms of fever, enlarge lymph nodes, and abnormalities in their blood tests.

In thinking about treatment for Castleman’s disease, it’s really important to think first about what is the underlying variant of the disease and second to think about what’s the cause of the disease. In my mind, I think about whether the first step is whether the virus is causing Castleman’s disease. I test for human herpesvirus-8. My ideal test is to stain a lymph node for the virus with immunohistochemistry. If that’s negative and there’s no evidence of the virus in the peripheral blood using the plasma, using a PCR test, then I consider the case to be idiopathic. For cases that are related to the virus, there are multiple strategies that are available including antiviral therapy or other biologics like rituximab. But, for the idiopathic version, again, we think that for whatever reason, the central dogma in the disease is that there’s an overexpression of interleukin-6. In these patients, the goal of treatment is to reduce the expression of interleukin-6, and there are multiple approaches to that.

Until a few years ago, the most common way to approach that would be to give a therapy broadly directed at B cells, a biologic therapy like rituximab which would destroy plasma cells and other cells bearing the CD20 marker. The problem with therapy like that is that not all plasma cells that express interleukin-6 express that CD20 marker, so not all plasma cells are destroyed by a therapy aimed at CD20. The other problem is that you’re destroying probably more cells than you need to be destroying because, again, many of the cells expressing CD20 are not involved in the pathogenesis of the disease.

There has been a search for more specific therapies, and I should mention that prior to rituximab, idiopathic multicentric Castleman’s disease was treated like lymphoma and was treated with conventional chemotherapy. So, moving from conventional chemotherapy to more targeted biologic therapy, we improved our response rates and decreased toxicities. But, unfortunately, both key conventional chemotherapy and biologics aimed at CD20, response rates were less than 50% and these responses were not durable. Many patients recurred, so certainly providers were searching a better way to treat this disease, and with the recognition of the importance of interleukin-6, and the biology of this disease, and the advent of drugs that actually target interleukin-6, we’ve been able to be much more specific about our treatment for idiopathic multicentric Castleman’s disease.

There are two drugs now which target interleukin-6 production. One targets the interleukin-6 receptor and that’s a drug known as tocilizumab, and another targets the soluble interleukin-6 in plasma and in other body sources, and that’s siltuximab. Of those two drugs, siltuximab is the only one that’s actually been studied and licensed in an FDA-approved usage. My approach now to patients with idiopathic multicentric Castleman’s disease is to start with the root of the problem, which is to offer patients therapy with an IL-6 inhibitor and siltuximab because of the FDA approval.

I would say that there are some patients who may not be good candidates for treatment with siltuximab as first-line therapy. In the licensure study, patients who had chronic ongoing infections were excluded because this is thought to be a biomodulator of immunity. So, for instance, for patients with chronic hepatitis or patients with HIV co-infection, even though they may have idiopathic multicentric Castleman’s disease, siltuximab may not be my first line of therapy. At this moment, siltuximab is really a lifelong therapy. This is a drug that patients need to take really every three weeks for the rest of their lives. That’s quite a commitment to many patients, and so some patients will say I simply can’t do that. And, in those patients, trying either biologic antibodies against CD20 or conventional chemotherapy. Even though their odds of cure are much lower, some patients want to take those odds to not necessarily be committed to lifelong therapy.

Corey Casper, MD, provides information on the diagnosis and treatment of patients with Castleman Disease (CD).