Treating KSHV-Associated Multicentric Castleman Disease
Name of the Trial
Pilot Study of Tocilizumab in Patients with Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-Associated Multicentric Castleman Disease (NCI-11-C-0233). See the protocol summary.
Dr. Thomas Uldrick, NCI Center for Cancer Research
Why This Trial Is Important
Multicentric Castleman disease (MCD) is a group of rare diseases of the lymphatic system. One form is associated with infection by a virus called human herpesvirus 8. This virus is also associated with a type of cancer called Kaposi sarcoma, so it is sometimes known as Kaposi sarcoma herpesvirus (KSHV). Kaposi sarcoma and KSHV-associated MCD are much more common in people who are infected with the human immunodeficiency virus (HIV).
People with KSHV-associated MCD often have Kaposi sarcoma, and some treatments for KSHV-associated MCD can make Kaposi sarcoma worse. NCI researchers in the HIV and AIDS Malignancy Branch at NCI’s Center for Cancer Research are studying new approaches to treating KSHV-associated MCD and are trying to find better ways to manage it in patients who have both conditions.
People with KSHV-associated MCD may develop a variety of symptoms, such as low blood-cell counts (cytopenias), low levels of albumin (hypoalbuminemia), fever, fatigue, weight loss and muscle wasting (cachexia), fluid buildup (edema) in the legs and abdomen, and enlarged lymph nodes and spleen. Untreated, these inflammatory symptoms can be life threatening.
Currently, KSHV-associated MCD is usually managed with one of two treatments: the biological agent rituximab or antiviral therapy. Rituximab may improve symptoms, but it can also cause considerable side effects and lead to worsening Kaposi sarcoma. Virus-activated cytotoxic therapy, which was developed at NCI and consists of high-dose zidovudine (AZT) and valganciclovir, is one type of antiviral therapy that has shown some effectiveness against KSHV-associated MCD.
Although antiviral treatment targets the cause of the disease, it may not rapidly control the inflammatory symptoms. Therefore, doctors want to explore new approaches that may offer more effective and less-toxic treatment.
A monoclonal antibody called tocilizumab (Acterma) interferes with a molecular pathway that is important in MCD. The disease and many of its symptoms are driven by abnormal production of an inflammatory cytokine called interleukin-6 (IL-6). Tocilizumab attaches to the IL-6 receptor and prevents the molecular signaling that leads to IL-6-associated inflammation. This antibody was initially evaluated in the United States to treat rheumatoid arthritis and is approved by the Food and Drug Administration for that condition.
In this pilot study, patients with KSHV-associated MCD will receive intravenous tocilizumab every other week for up to 12 weeks. Patients who do not benefit from tocilizumab therapy alone may go on to receive high-dose AZT and valganciclovir in addition to tocilizumab. Doctors will assess the safety and effectiveness of tocilizumab alone and in combination with virus-activated cytotoxic therapy.
“Tocilizumab has been evaluated in other forms of MCD not related to KSHV and was effective in controlling the symptoms of the disease, including rapid resolution of hypoalbuminemia and anemia,” said Dr. Uldrick. “However, KSHV-associated MCD and other types of MCD are distinct diseases with overlapping clinical features. Tocilizumab may or may not be sufficient therapy in this setting, and that’s why we’re studying it, both alone and in combination with virus-activated cytotoxic therapy,” he said.
“The safety of tocilizumab is part of what we want to evaluate here; the major side effect we’d like to avoid is worsening Kaposi sarcoma in response to treating MCD,” Dr. Uldrick explained. “With rituximab, about half of the patients treated end up with worsening Kaposi sarcoma. That’s the yin-yang of treating these diseases; trying to manage KSHV-associated MCD without making Kaposi sarcoma worse.”
For More Information
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