Castleman’s disease is a rare group of disorders that cause enlarged lymph nodes and affect the immune system in different ways. Treatment depends heavily on the specific type of the disease, ranging from surgical removal of affected lymph nodes to long-term medical therapy aimed at controlling inflammation and preventing organ damage.

Understanding the Approach to Treating Castleman’s Disease

When someone receives a diagnosis of Castleman’s disease, one of the first things doctors focus on is determining the exact subtype of the condition. This is essential because the treatment path can be completely different depending on whether the disease involves just one lymph node or many, and whether there’s a known cause or not. The main goal of treatment is to reduce symptoms, control the overactive immune system, and protect vital organs from long-term damage. Some patients can be cured with a single procedure, while others need ongoing medication to keep the disease under control^[1].

The approach to Castleman’s disease treatment is personalized. Doctors consider the patient’s specific subtype, how severe the symptoms are, which organs are affected, and the overall health of the patient. In cases where the disease is localized to one area, removing the affected lymph node might be enough. However, when multiple lymph nodes are involved and the immune system is producing high levels of inflammatory signals throughout the body, medications that target these inflammatory processes become necessary. Since Castleman’s disease is rare—with only about 4,300 to 5,200 new cases diagnosed each year in the United States—doctors often work closely with specialized centers and networks that have experience managing this complex condition^[1][4].

Treatment is not just about stopping symptoms; it’s also about preventing complications that can arise from ongoing inflammation. For example, in some forms of the disease, the immune system’s hyperactivity can lead to kidney problems, liver enlargement, anemia, or fluid buildup in the body. Managing these issues requires a careful balance of controlling the disease while minimizing side effects from treatment. Researchers continue to study new therapies and test medications that might work better or have fewer side effects than current options^[1].

Standard Treatment Methods for Different Subtypes

The treatment for unicentric Castleman disease, which affects only one lymph node or a group of lymph nodes in a single area, is typically surgical. Surgery to remove the enlarged lymph node is considered the first-line treatment and can often cure the disease completely. About three out of four cases of Castleman’s disease are unicentric. Most patients with this type don’t have noticeable symptoms—the enlarged lymph node may be discovered during imaging tests for other reasons. Once the affected lymph node is removed, patients usually do well, and their life expectancy is generally not affected^[2][10].

Sometimes, however, surgery isn’t possible because the lymph node is located in a difficult area, such as deep in the chest or near major blood vessels. In these cases, doctors may recommend other approaches. If the enlarged lymph node is pressing on nearby organs and causing symptoms, a medication called rituximab may be given to try to shrink the node. Rituximab is a type of antibody that targets a specific protein found on certain immune cells called B cells. By eliminating these cells, the medication can reduce lymph node swelling. If symptoms are due to inflammation rather than pressure, doctors might use anti-interleukin-6 therapy, which blocks a key inflammatory signal in the body. If these medications don’t work, radiation therapy is sometimes considered^[10][12].

For multicentric Castleman disease, which involves enlarged lymph nodes in multiple parts of the body, treatment is more complex and depends on the underlying cause. There are three main subtypes of multicentric disease: HHV-8-associated, POEMS-associated, and idiopathic (where the cause is unknown). Each requires a different treatment strategy because the mechanisms driving the disease differ^[1][4].

In HHV-8-associated multicentric Castleman disease, the condition is linked to infection with human herpesvirus-8. This subtype is more common in people who are HIV positive or have weakened immune systems. The recommended first-line treatment is rituximab, which targets B cells. Rituximab has proven highly effective for this form of the disease. For patients who also have HIV, doctors typically combine rituximab with antiretroviral therapy to control the viral infection and support the immune system. Some HIV-negative patients may also receive antiviral medications like ganciclovir. In severe cases where organs are failing or the patient’s condition is rapidly worsening, rituximab may be combined with chemotherapy drugs to achieve faster control^[10][12].

Idiopathic multicentric Castleman disease (iMCD) is the most common form of multicentric disease, but its causes remain unknown. This makes treatment particularly challenging. The preferred therapy is siltuximab, which is the only medication approved by the U.S. Food and Drug Administration specifically for this condition. Siltuximab works by blocking a protein called interleukin-6 (IL-6), which plays a major role in driving the inflammation and symptoms of the disease. IL-6 levels are often very high in patients with iMCD, and blocking this protein can lead to significant improvement. If siltuximab is not available, another IL-6 blocker called tocilizumab may be used instead. Treatment with these medications typically continues long-term to maintain remission and prevent relapse^[10][13].

Patients who don’t respond to siltuximab present a difficult treatment challenge. In such cases, doctors may try other approaches, including rituximab, chemotherapy drugs, or other immunomodulatory therapies. Chemotherapy can provide relief from symptoms and reduce disease activity, but symptoms often return when treatment is stopped, requiring ongoing or intermittent therapy. Medications such as corticosteroids can also be used to reduce inflammation and provide temporary relief, though they don’t typically shrink tumors or produce long-lasting effects on their own^[10][12].

In some cases of iMCD, patients develop a particularly severe subtype called TAFRO syndrome. The name comes from its main features: low platelets (thrombocytopenia), fluid buildup in the body (anasarca), fever, kidney problems, and enlarged liver or spleen. This form can be life-threatening and requires aggressive treatment^[1].

For POEMS-associated multicentric Castleman disease, the treatment approach is different because this form is linked to a rare blood disorder called POEMS syndrome, which involves nerve damage, enlarged organs, hormonal problems, abnormal plasma cells, and skin changes. Treatment typically targets the abnormal plasma cells and may include chemotherapy, radiation therapy, or even stem cell transplantation in some cases. Managing POEMS-associated disease often requires collaboration between specialists^[2].

Across all forms of multicentric disease, monitoring is essential. Patients typically undergo regular blood tests to check for signs of inflammation, anemia, kidney function, and liver health. Imaging tests such as CT scans may be performed to track the size of lymph nodes and check for organ involvement. The goal is to catch any disease progression early and adjust treatment as needed^[8].

Innovative Therapies and Clinical Trials

Because standard treatments don’t work for all patients with Castleman’s disease, researchers are actively testing new therapies in clinical trials. These studies explore medications that target different parts of the disease process, offering hope for patients who haven’t responded to existing options or who experience severe side effects. Clinical trials are conducted in phases: Phase I tests safety and determines the right dose, Phase II evaluates whether the drug works and continues to assess safety, and Phase III compares the new treatment to standard therapy to see if it’s more effective^[16][17].

One of the most promising areas of research involves biologic agents—medications that are designed to target specific molecules involved in the disease. Several of these agents are being studied or have shown promise in treating multicentric Castleman disease. Siltuximab and tocilizumab, which block IL-6, have already become standard therapy for many patients with iMCD, but they were once experimental drugs tested in clinical trials. Their success has paved the way for exploring other targeted therapies^[11].

Rituximab, which targets the CD20 protein on B cells, has proven effective not only for HHV-8-associated disease but is also being studied for use in other subtypes. This medication causes B cells to be destroyed, reducing the production of antibodies and inflammatory signals. Because rituximab is less toxic than traditional chemotherapy, it has become a preferred option in many cases. Research continues to refine the best dosing schedules and combination strategies with other medications^[11].

Another drug being explored is bortezomib, a medication originally developed for treating multiple myeloma (a type of cancer). Bortezomib is a proteasome inhibitor, meaning it interferes with a key system inside cells that breaks down proteins. By blocking this system, the drug can kill cells that are overactive or producing too many inflammatory signals. Early studies in patients with Castleman’s disease have shown some benefit, particularly in cases where other treatments have failed^[11].

Anakinra is another medication under investigation. It blocks the interleukin-1 receptor, a different inflammatory pathway from IL-6. Some patients with Castleman’s disease have inflammation driven by multiple pathways, and anakinra may help when IL-6 blockers alone are not sufficient. Clinical trials are testing whether combining anakinra with other therapies can improve outcomes^[11].

Researchers are also investigating the role of immunotherapy in Castleman’s disease. These treatments work by modulating the immune system in various ways—either by boosting certain protective responses or by dampening harmful ones. Some experimental approaches involve using antibodies that target different immune cell types or inflammatory signals. Others explore the use of drugs that affect how immune cells communicate with each other^[11].

In addition to testing individual drugs, scientists are exploring combination therapies. For example, using rituximab together with chemotherapy has been studied for severe cases of HHV-8-associated disease. Similarly, combining anti-IL-6 therapy with other immunomodulatory drugs is being tested for patients with idiopathic disease who don’t respond to siltuximab alone. The goal is to find combinations that are more effective while keeping side effects manageable^[12].

Clinical trials for Castleman’s disease are being conducted in multiple countries, including the United States and Europe. Patients interested in participating should discuss options with their doctors and consider reaching out to specialized centers or networks that focus on this rare condition. Organizations like the Castleman Disease Collaborative Network maintain registries and provide information about ongoing trials. Participation in clinical trials not only gives patients access to cutting-edge treatments but also contributes valuable data that helps researchers better understand the disease^[16][17].

One innovative approach gaining attention is drug repurposing. This involves testing medications that are already approved for other conditions to see if they can help treat Castleman’s disease. Because these drugs have already been proven safe in humans, they can potentially be brought to patients faster than entirely new medications. Researchers use advanced techniques, including artificial intelligence, to analyze which existing drugs might work based on their mechanisms of action and how they interact with the biological pathways involved in Castleman’s disease^[17].

The study of Castleman’s disease is also benefiting from improved understanding of the immune system and inflammation. Scientists are identifying specific molecules and pathways that drive the disease, which opens the door to developing highly targeted therapies. For example, research has shown that in addition to IL-6, other cytokines and growth factors may contribute to symptoms and organ damage. Identifying these targets allows for the development of new drugs or the repurposing of existing ones that affect these pathways^[13].

Most Common Treatment Methods

• Surgical Removal of Lymph Nodes
  • The primary treatment for unicentric Castleman disease, involving removal of the affected lymph node or group of nodes. Often curative and associated with good long-term outcomes^[10].
  • May require presurgical preparation in cases where lymph nodes are highly vascular, to make surgery safer^[10].
• Rituximab Therapy
  • A monoclonal antibody that targets CD20 protein on B cells, causing their destruction. First-line treatment for HHV-8-associated multicentric Castleman disease^[10][11].
  • Also used in unicentric disease when surgery is not possible and symptoms are due to lymph node compression^[12].
  • Often combined with antiretroviral therapy in HIV-positive patients^[12].
• Anti-IL-6 Therapy
  • Siltuximab is the only FDA-approved treatment specifically for idiopathic multicentric Castleman disease. It blocks interleukin-6, a key inflammatory protein^[10][13].
  • Tocilizumab is an alternative IL-6 blocker used when siltuximab is not available^[10].
  • Treatment typically continues long-term to maintain remission and prevent relapse^[10].
• Chemotherapy
  • Used in severe cases of multicentric Castleman disease, especially when there is life-threatening organ failure or poor performance status^[12].
  • May be combined with rituximab for aggressive HHV-8-associated disease^[12].
  • Provides symptom relief but often requires ongoing or intermittent maintenance therapy as symptoms tend to return when treatment stops^[10].
• Corticosteroid Therapy
  • Systemic corticosteroids can provide symptomatic relief by reducing inflammation^[12].
  • Do not predictably reduce tumor size and are not typically used as sole therapy^[12].
• Antiviral Therapy
  • Used in HHV-8-associated disease, particularly in HIV-negative patients, where antiviral drugs like ganciclovir may be given along with other treatments^[12].
  • Antiretroviral therapy is essential for HIV-positive patients with low CD4 counts or high viral loads^[12].
• Radiation Therapy
  • May be used in unicentric disease when surgery is not possible and other treatments have failed^[10].
  • Doses of 30-45 Gy can result in complete or partial remission in some cases^[12].
  • Can cause radiation-induced fibrosis, which may complicate future surgical intervention^[12].
• Other Immunomodulatory Agents
  • Bortezomib, a proteasome inhibitor, is being studied for use in Castleman’s disease, particularly in cases resistant to other treatments^[11].
  • Anakinra, an interleukin-1 receptor antagonist, is under investigation for patients with inflammation driven by multiple pathways^[11].