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A study published on Oct. 19, 2011 in PLoS ONE provides encouraging support for the potential benefit of treatment with rituximab (marketed in the U.S. as Rituxan and MabThera in Europe and other countries) in chronic fatigue syndrome (CFS). However, the number of patients studied was small and more research is needed to understand how this type of therapy might best be used to alleviate symptoms and modify the disease. The study has raised many questions. Weve asked Dr. John Sweetenham, an oncologist at the Cleveland Clinic and a recognized expert in the use of rituximab, to help address some of the most common questions.
Research1st (R1st): Rituximab is an anti-CD20 monoclonal antibody approved by the FDA to treat specific types of cancer and rheumatoid arthritis. How does the drug work?
Dr. John Sweetenham: Rituximab works by attaching itself to a particular type of white blood cell known as a B-lymphocyte or B-cell. B-cells have a substance called CD20 on their surface, which is recognized by rituximab. When rituximab sees the CD20, it latches onto it and this eventually results in the B-cell being damaged or destroyed.
Certain types of cancer known as lymphomas are cancers of lymphocytes, most commonly B-cells and have CD20 on their surface. Rituximab has proved to be very effective at treating B-cell lymphomas, either by itself, or when added to chemotherapy.
Autoimmune diseases such as rheumatoid arthritis occur when the bodys immune system starts to react against its own tissues. When this happens, B-cells are often part of the reason for the tissue damage which occurs. Because rituximab recognizes the B-cells and destroys them, it can prevent them from damaging tissues and therefore control the auto-immune disease.
R1st: What does it mean that rituximab is a biologic agent? Does this mean its not a drug?
Dr. Sweetenham: Rituximab is a drug. It is called a biological agent because it is very similar to a naturally occurring substance. We all have antibodies in our system naturally they are one of our first lines of defense against infection. For example, when we get a shot against, say measles, we make an antibody which stays in our system and if it ever sees the measles virus, will recognize it, attach to it and alert our bodys immune system to deal with it.
Rituximab is an antibody which is manufactured but which is almost identical to a naturally occurring antibody and is called a biological agent for that reason.
R1st: Subjects in the CFS study were given infusions (of either rituximab or saline) during an overnight stay in the hospital. Is rituximab always administered in the hospital, or was this a precaution taken only for the study? What is the usual procedure when rituximab is used in clinical practice?
Dr. Sweetenham: Rituximab is usually administered as an intravenous infusion in the outpatient area. Typically, patients do not need to be admitted to the hospital although this probably happens more commonly in Europe than in the USA.
R1st: Is the infusion itself uncomfortable or painful to receive, aside from the discomfort of placing the I.V.?
Dr. Sweetenham: The infusion is not uncomfortable although most patients receiving rituximab do experience some side effects during the infusion, especially the very first time they receive it. Typically, the reaction to the infusion includes chills and low grade fevers. Some people will experience itching or hives, tightness in the chest or throat and a fall in blood pressure. These are mainly effects of the first dose and can usually be managed using some simple premeds and, if necessary, slowing the rate of the infusion.
R1st: There is a lot of information on-line about harsh side effects of rituximab. What are the common side effects? (Do you lose your hair?) What about rare adverse events?
Dr. Sweetenham: The most common side effects are the infusion reactions listed above. Occasionally, this reaction can be very severe and require that the drug is stopped. Severe allergic type reactions can also occur and rarely, patients need to be admitted to the ICU. Nausea, vomiting and hair loss do not occur with Rituxan. Some patients experience some fatigue.
R1st: Are different side effects seen in patients with different conditions for which it is used?
Dr. Sweetenham: I am not aware of any differences.
R1st: What about the serious adverse events, including death, that have been reported? Are these more common in certain patient populations more than others?
Dr. Sweetenham: In some patients with certain lymphomas, there are rare reports of death occurring after severe infusion reactions because of a condition known as cytokine release syndrome. This is more likely to occur in patients with certain types of lymphoma in which the lymphoma cells have spilled over into the blood. It is now fairly easy to identify the patients at risk of this type of reaction and avoid using rituximab until the circulating B-cells have gone away.
R1st: It appears from the literature that the most frequent adverse event is increased report of viral infections. What are the risks to patients?
Dr. Sweetenham: The problem of increased viral infections is not a common side effect of rituximab, but is a potentially serious one, especially for patients who receive the drug for many months. Patients with a previous history of some types of hepatitis are at risk of reactivating the hepatitis and for this reason everyone who is going to receive rituximab should be screened for hepatitis viruses. Some other rare viral infections of the brain have also been seen after rituximab, especially when it has been given for many months.
R1st: What are your impressions of the utility in treating CFS, based on data in the two small studies (one open label series of three patients and one controlled trial)?
Dr. Sweetenham: I cant comment on that; it is outside my area of expertise.
R1st: What would be the expected next steps to follow-up such a study?
Dr. Sweetenham: Again, this is outside my area but in general, data ike these would typically then be confirmed in a much larger study with more patients.
John Sweetenham, MD, FRCP, is Professor of Medicine and Director of Clinical Research at the Cleveland Clinic Taussig Cancer Institute. Dr. Sweetenham graduated BSc (Hons), MBBS from the St Bartholomews Hospital Medical College & University of London in 1980 and received a Doctorate in Medicine research degree from the University of Southampton in 1989. He is a fellow of the Royal College of Physicians of the UK, has served as head of Medical Oncology at the University of Southampton, director of Hematologic Malignancies/Bone Marrow Transplant at the University of Colorado Health Sciences Center, and subsequently was professor of Medicine and Director of Clinical Research, Arizona Cancer Center. He joined Cleveland Clinic in 2005.
Dr. Sweetenham has held extensive funding for research, has published a large body of work on hematologic malignancy, lectured in many countries on the management of lymphoma and the use of stem cell transplantation and is a member of several editorial boards and national committees.
A study published on Oct. 19, 2011 in PLoS ONE provides encouraging support for the potential benefit of treatment with rituximab (marketed in the U.S. as Rituxan and MabThera in Europe and other countries) in chronic fatigue syndrome (CFS). However, the number of patients studied was small and more research is needed to understand how this type of therapy might best be used to alleviate symptoms and modify the disease. The study has raised many questions. Weve asked Dr. John Sweetenham, an oncologist at the Cleveland Clinic and a recognized expert in the use of rituximab, to help address some of the most common questions.
Research1st (R1st): Rituximab is an anti-CD20 monoclonal antibody approved by the FDA to treat specific types of cancer and rheumatoid arthritis. How does the drug work?
Dr. John Sweetenham: Rituximab works by attaching itself to a particular type of white blood cell known as a B-lymphocyte or B-cell. B-cells have a substance called CD20 on their surface, which is recognized by rituximab. When rituximab sees the CD20, it latches onto it and this eventually results in the B-cell being damaged or destroyed.
Certain types of cancer known as lymphomas are cancers of lymphocytes, most commonly B-cells and have CD20 on their surface. Rituximab has proved to be very effective at treating B-cell lymphomas, either by itself, or when added to chemotherapy.
Autoimmune diseases such as rheumatoid arthritis occur when the bodys immune system starts to react against its own tissues. When this happens, B-cells are often part of the reason for the tissue damage which occurs. Because rituximab recognizes the B-cells and destroys them, it can prevent them from damaging tissues and therefore control the auto-immune disease.
R1st: What does it mean that rituximab is a biologic agent? Does this mean its not a drug?
Dr. Sweetenham: Rituximab is a drug. It is called a biological agent because it is very similar to a naturally occurring substance. We all have antibodies in our system naturally they are one of our first lines of defense against infection. For example, when we get a shot against, say measles, we make an antibody which stays in our system and if it ever sees the measles virus, will recognize it, attach to it and alert our bodys immune system to deal with it.
Rituximab is an antibody which is manufactured but which is almost identical to a naturally occurring antibody and is called a biological agent for that reason.
R1st: Subjects in the CFS study were given infusions (of either rituximab or saline) during an overnight stay in the hospital. Is rituximab always administered in the hospital, or was this a precaution taken only for the study? What is the usual procedure when rituximab is used in clinical practice?
Dr. Sweetenham: Rituximab is usually administered as an intravenous infusion in the outpatient area. Typically, patients do not need to be admitted to the hospital although this probably happens more commonly in Europe than in the USA.
R1st: Is the infusion itself uncomfortable or painful to receive, aside from the discomfort of placing the I.V.?
Dr. Sweetenham: The infusion is not uncomfortable although most patients receiving rituximab do experience some side effects during the infusion, especially the very first time they receive it. Typically, the reaction to the infusion includes chills and low grade fevers. Some people will experience itching or hives, tightness in the chest or throat and a fall in blood pressure. These are mainly effects of the first dose and can usually be managed using some simple premeds and, if necessary, slowing the rate of the infusion.
R1st: There is a lot of information on-line about harsh side effects of rituximab. What are the common side effects? (Do you lose your hair?) What about rare adverse events?
Dr. Sweetenham: The most common side effects are the infusion reactions listed above. Occasionally, this reaction can be very severe and require that the drug is stopped. Severe allergic type reactions can also occur and rarely, patients need to be admitted to the ICU. Nausea, vomiting and hair loss do not occur with Rituxan. Some patients experience some fatigue.
R1st: Are different side effects seen in patients with different conditions for which it is used?
Dr. Sweetenham: I am not aware of any differences.
R1st: What about the serious adverse events, including death, that have been reported? Are these more common in certain patient populations more than others?
Dr. Sweetenham: In some patients with certain lymphomas, there are rare reports of death occurring after severe infusion reactions because of a condition known as cytokine release syndrome. This is more likely to occur in patients with certain types of lymphoma in which the lymphoma cells have spilled over into the blood. It is now fairly easy to identify the patients at risk of this type of reaction and avoid using rituximab until the circulating B-cells have gone away.
R1st: It appears from the literature that the most frequent adverse event is increased report of viral infections. What are the risks to patients?
Dr. Sweetenham: The problem of increased viral infections is not a common side effect of rituximab, but is a potentially serious one, especially for patients who receive the drug for many months. Patients with a previous history of some types of hepatitis are at risk of reactivating the hepatitis and for this reason everyone who is going to receive rituximab should be screened for hepatitis viruses. Some other rare viral infections of the brain have also been seen after rituximab, especially when it has been given for many months.
R1st: What are your impressions of the utility in treating CFS, based on data in the two small studies (one open label series of three patients and one controlled trial)?
Dr. Sweetenham: I cant comment on that; it is outside my area of expertise.
R1st: What would be the expected next steps to follow-up such a study?
Dr. Sweetenham: Again, this is outside my area but in general, data ike these would typically then be confirmed in a much larger study with more patients.
John Sweetenham, MD, FRCP, is Professor of Medicine and Director of Clinical Research at the Cleveland Clinic Taussig Cancer Institute. Dr. Sweetenham graduated BSc (Hons), MBBS from the St Bartholomews Hospital Medical College & University of London in 1980 and received a Doctorate in Medicine research degree from the University of Southampton in 1989. He is a fellow of the Royal College of Physicians of the UK, has served as head of Medical Oncology at the University of Southampton, director of Hematologic Malignancies/Bone Marrow Transplant at the University of Colorado Health Sciences Center, and subsequently was professor of Medicine and Director of Clinical Research, Arizona Cancer Center. He joined Cleveland Clinic in 2005.
Dr. Sweetenham has held extensive funding for research, has published a large body of work on hematologic malignancy, lectured in many countries on the management of lymphoma and the use of stem cell transplantation and is a member of several editorial boards and national committees.
