Karthik Ramasamy, MBBS, FRCP, FRCPath, PhD, is a consultant hematologist at Oxford University Hospitals National Health Services Trust and associate professor of hematology, Radcliffe Department of Medicine, University of Oxford, UK. He is the director of the Oxford Myeloma Translational Research Centre and a lead clinician for myeloma and other plasma cell dyscrasias at the Thames Valley Cancer Alliance group. He is the divisional lead for cancer research for the National Institute for Health and Care Research, Clinical Research Network Thames Valley and South Midlands. Dr Ramasamy completed his hematology training in London. Following this, he completed 3 years as a clinical research fellow working on bone marrow microenvironment in myeloma at King’s College London. Aptitude Health met with Dr Ramasamy to gain his perspectives on the management of Castleman disease, a rare hematologic condition. Here is a recap of our conversation:
Can you start by sharing your background in hematology and what sparked your interest in Castleman disease?
I’ve been a hematologist for about 20 years, and I took a real interest in plasma cell dyscrasias about 10–15 years ago, when I started doing research with patients who had very high immunoglobulins, a feature of patients with Castleman disease. We only recently determined that this is not a clonal or cancerous disorder, but rather an inflammatory condition. We now have a small cohort of patients with Castleman disease, and I contribute to both education and support for clinicians around the country treating patients with this condition.
For those who may not be familiar, could you provide an overview of Castleman disease and explain the different types, including unicentric disease and multicentric disease?
I would describe Castleman disease as a noncancerous proliferation of the lymphoid system, but we still don’t know what the main driver is, and there is wide variability in how patients with this disease present. Some present with unicentric Castleman disease, where 1 lymph node group is enlarged because of the proliferation. Others have multicentric Castleman disease, where there are multiple sites of enlarged lymph nodes. As you would expect, patients with multicentric Castleman disease have systemic symptoms because multiple lymph node systems are involved, and therefore often require treatment of a systemic nature. By contrast, in patients with unicentric Castleman disease, we can potentially surgically resect the area of lymph node that is involved. We are increasing our understanding of the different types of multicentric Castleman disease, but the condition is highly variable, and there is much more we have to learn.
What are the main challenges in diagnosing Castleman disease, and how can these challenges impact patient care?
Diagnosing Castleman disease is a significant challenge because it’s a rare disease with very limited research and expertise. In addition, its symptoms mimic those of other conditions such as rheumatologic disorders (which share an autoimmune etiology), infection-related disorders, or even blood cancer. Typically, a circuitous route is often taken before confirming a diagnosis of Castleman disease. Up until 5 or 6 years ago, we did not even have proper consensus criteria, treatments to offer these patients, or understanding of response. Now we have clear diagnostic criteria, and we’re educating clinicians around the country and across the world, using new technologies to diagnose patients faster.
What are the key considerations in treating a patient with Castleman disease, especially given the rarity of the disease and variability in presentation?
The main consideration in treating a patient with Castleman disease is getting the correct diagnosis. Once you’ve got your diagnosis right, you then need to understand whether the patient has a severe form or a less-severe form of the disease. There are now treatment guidelines that support clinicians in providing treatment for these patients, and we have a licensed therapeutic treatment for Castleman disease, siltuximab. Siltuximab blocks the IL-6 [interleukin-6] cytokine and therefore can cause regression of inflammatory features as well as regression of the lymph nodes. All this has given the whole diagnostic and treatment pathway a jump start, but not all patients see response to this type of treatment and some can experience relapse, so much more research is required in this disease.
How do rare hematologic diseases like Castleman disease influence the focus of research and development within the pharmaceutical and medical communities?
The critical thing with rare disorders with regard to research is that medical communities must come together as a consensus group and pool the data they have. They must also freely network, contribute, and bring in other specialties, including pathologists and radiologists. By doing so, we can develop very clear diagnostic criteria and then conduct basic biology research to determine what may be driving the illness and what therapeutic modalities may be effective.
Determining diagnostic criteria and developing a therapeutic have taken us a long, long time, and there’s more to be done in Castleman disease. Specifically, its biology is still not very well understood. We don’t know what drives the proliferation of these lymph cells and plasma cells within the lymph nodes. We also still need to determine why some people are susceptible to unicentric Castleman disease while others develop multicentric disease.
We know that IL-6 blockade does stop proliferation of lymph cells and plasma cells, but some patients lose response with these treatments, so we need newer therapies for those who develop progression after IL-6 blockade.
Lastly, we need to learn why clinical phenotypes such as TAFRO syndrome [thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly] develop and whether there may be more than 1 pathogenic driver in those patients. Now that we have clinical cohorts and databases of patients receiving treatment, we have samples that enable effective research in this space. I’m sure if we are able to uncover a few targets within this illness, we could work with pharmaceutical companies effectively to build clinical trials and evaluate new therapeutics.
What do you believe are the most critical steps healthcare systems can take to improve the diagnosis and treatment of rare hematologic diseases like Castleman disease?
On the basis of our experience with Castleman disease, I think the most important step is bringing clinicians together—not just in 1 country, but across the world—and building a consensus around diagnosis and treatment of rare hematologic diseases. Healthcare systems should enable collaboration and communication and build robust teams across the world so physicians can share their observations. Second, there would ideally be a global study where clinicians can share samples and create a robust network to study the biology of the condition. We can then begin to understand why certain ethnicities may be more likely to get certain illnesses, which may also help us understand what may be driving the disease (eg, environmental factors, genetics). Lastly, we need investments from pharmaceutical companies, diagnostic manufacturers, and governments to support this research.
Looking ahead, what advancements do you hope to see in the diagnosis and treatment of Castleman disease in the coming years?
We now have observational registries like ACCELERATE that collect clinical data to evaluate patients’ experience with treatment. They also provide samples for research, which along with well-developed technologies in genomics and proteomics are helping us understand what other targets there may be. The other thing I am excited about is the clinical trials we are building to treat Castleman disease in patients who develop progression after IL-6 antibody therapy, and we hope there are some good results with deeper remissions for those receiving new treatments either as monotherapy or in combination with anti–IL-6 therapies. I’m excited by these advances, but we still need to find a way to stop generation of multicentric disease and keep the disease unicentric so we can resect it and stop progression.
We’ve been on a long journey with Castleman disease. Given the challenges in managing rare disorders, I’d like to encourage researchers to stay curious about these conditions and to consider careers in rare disorders, where knowledge and treatment options are limited.