Dr. John Sweetenham
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. We’ve 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.
Illustration from www.cancer.gov
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 body’s 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 it’s 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 body’s 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.
Anne Tveiterås, an oncology nurse who participated in the Norway study, receives her infusion in the department in which she used to work. (Photo: TV2 in Norway)
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 can’t 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 like these would typically then be confirmed in a much larger study with more patients.
Taussig Cancer Institute at the Cleveland Clinic
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 Bartholomew’s 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.
For more information about the study of rituximab in CFS, please follow these links:
· “Rituximab Trial Shows Promise” (study summary and links to media coverage): http://www.research1st.com/2011/10/19/rituximab-trial/
· “Observations on Rituximab’s Early Success” by Gordon Broderick, PhD: http://www.research1st.com/2011/10/21/broderick/
· “Media Blitz by Norway’s TV2″ (links to reports from Norway’s second largest news channel): http://www.research1st.com/2011/10/23/media-blitz/
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Thanks for this ‘primer’ on Rituximab. It seems that there is a lot of confusion in the ME/CFS community about what kind of drug Rituximab is, whether its side effects are as severe as those of “chemotherapy” drugs, and how “toxic” it is – these are terms that people often throw around without a full understanding of what they mean, or whether/how they apply to Rituximab specifically.
I don’t suppose any *effective* treatment for ME/CFS would be 100% risk-free, and we shouldn’t have that expectation – however, I also haven’t seen much to convince me that Rituximab is an unwarrantedly “harsh” or “dangerous” drug, if it’s administered in the proper setting with the proper precautions. The side effect of “some fatigue” is worth a (fatigued) giggle.
(I’m guessing that for many ME/CFS patients, the side effects of Rituximab would not be any worse than an *average* PEM or “bad day.” But more research would be a lot better than all of us sitting around guessing!!)
Thanks, Anne. Glad to hear this Q&A is helpful. We have more planned, including one with Drs. Fluge and Mella, although they are (understandably) a bit overwhelmed right now and said it would take a couple of weeks.
I am sure Drs. Fluge and Melia have a lot on their plates right now!! But it would be great to hear from them eventually.
Tell them that in a few decades, they can at least enjoy the fact that the call from the Nobel Prize committee will come from within their own time zone, so it will come at a decent hour of the day.
Just to let all of you know that severe reactions can be real. Do your research (read closely) and be your own advocate; ask lots of questions, keep detailed treatment notes and find a well educated doctor with a good reputation in their field and experience. With any desease you have to out way the good be the bad and any possible long term effects and what you feel is right for you. Don’t let anyone, not even a doctor pressure you into a decision you haven’t had a chance to think thru clearly and aren’t ready to make immediately. I know all about Rituxan with Lymphoma NHL, my mother died not to long ago from a low immune system, poor monitoring and PML. Once diagnosed she died in 2 months a very horrific death too, it’s very real. Sadest thing is the cancer was in remission and we lost her anyway. Read the label warnings at the Rituxan website; age 70 and over, auto-immune disorders, infections, reactions, tell a doctor eveything you have had and been thru, be thurough. There is no guarentee to anything but usually a younger, healthy, first line user wouldn’t have the deadly outcome risks (PML, TLS) as an older geriactric person. But in time you can build resistance to the drug (many cancer patients do) but the treatments get easier once you get through the first few and depending on the dosage strength and whether it’s used alone or in a combo drug therapy can make a difference also. Decisions seem to be a little easier to make if there’s actual trial study data where a treatment was used for your same particular situation. Then it gives you a good feel for what to expect and long term.
But warnings are really there for a reason and PML has only realatively been recognized and recorded because many people thought it was the cancer that killed a person they didn’t understand about PML. I’m sure alot people have have died from it but it was diagnosed wrong or not on the death certificate so it the deaths were never recorded in FDA records. Only the last (close to 4yrs) it’s been listed as a warning. Like anything in life, there can always be a risk and unfotunately doctors make mistakes and can slack in care, there’s always some bad apples among the good ones!!!
Yet again science is focusing on curing a physical problem with a physical solution. The flaw in this is the cause of the problem is not physical. WAKE UP PEOPLE – illness is a state of dis-ease in the body which is the direct result of mental and emotional dis-ease. When you focus your attention on identifying and resolving the root cause (dis-ease), then the symptoms, which are only there to draw attention to those root causes, will disappear.
Kim Knight, this is a blog about science and research. If you don’t like science, you might not want to spend your time reading about it.
You might also want to question who benefits when you adopt an ideology that states that sick people are responsible for their own illnesses. I can think of a lot of large, powerful interests that benefit when we go along with that line of thinking. My personal opinion is that those large, powerful interests don’t need my active and willing participation in their efforts to make me a second-class citizen merely because I’m sick and disabled.
Kim [Knight], you couldn’t be farther from the truth. It is this theory that is preventing real research toward the viral or biological source of the neuroimmune disorder called ME/CFIDS/CFS
You and others like you who hold onto the psycholigical cause of this illness only serve to hold us back from getting to the real root of the cause. I am not saying there is no psychological part of this illness. I am saying as a result of this neuroimmune disorder, and the symptoms it creates such as brain impairment in memory, word finding, and consolidation of memories are caused by a biological reaction in the Brain and spinal column. reference the Cerebral Spinal Studies that were released May of 2011. Katie Couric took it to national press and said on the show that there is now “no reason to think it is all in there head”, “that this is biological has been proven by several studies, the one in May being the largest proof of biological source/s”. I would like to keep up this conversation with you and hopefully change your thinking on this so that better research toward the source and then treatment can occur. Dr Teresa Foley, Patient with ME/CFIDS for 11 years now. Green Valley AZ
I have a low level of Hep-c, contracted 3 yrs. ago. When I say a ‘low level’, I mean that I don’t qualify for any of the treatments that are offered for Hep C. My CFIDS, I’ve had since 1995 when I contracted mononucleosis. I’m concerned with any side effects from Rituximab having Hep C. Thank you.
Really Kim!!! You think you know this because: you had the illness and cured your physcoligcal illness and all it well!!! You know what the illnes is and if we just think differently all will heal. Do you know that I have been seriously ill with Myalgic Encephelemyalis for 27 years. I have tried psychiatric treatment, every specialist on the subject. Natuaral paths, chiropractic, needles, biofeedback, therapy, self help books, praying….and and on with no help. I have read and forgiven myself and others for my misgivings. I have went out of state twice. Out of country treatmnt that resulted in a blocked intestine (could of died), My daughter and I came very close to death (hours) during her delivery. I have lived with severe swollen brain/head, severe earaches, raw gums severe pounding headaches/vomiting. Living with these symptoms 24/7. Along with severe sleep disturbance with no answer because I can’t take sleep meds or put anything on my head. I live with raw sore throats, sore glands, severe 24/7 heavy flu, fatigue,. I am now house/bedridden. Can you say you have been through even a small percentage of this nightmare and it’s because we haven’t helped our mental disorder and that’s the reason we are so seriously ill. Is that the reason our lives have been taken away and suffer unbearbly by the hour??? Gene markers have been found convincing many medica professionals the disease is inherited. Out of my 4 siblings and I. Four of us have similar symptoms. Don’t speak about others disablilities until you know the facts. Maybe you need to look inside yourself befor you diagnose others. It;s shameful what you said about so manymiserable ill patient that have lost any quility of life. How dare you!!!!!!
More than 4000 articles proving the physical nature of ME….so glad that there is now a drug that is being used to treat this bio-medical disease. Like any drug the risks need to be weighed against the quality of life without it. For the severely ill living a living death the risks don’t seem very high at all.
Scientific research relies on repeating the same result over and over again, in order to then propose that the same solution can be applied to any person. The flaw in this is that every human being is a unique entity and one person’s problems can NEVER be addressed in the same way as the next. We have to treat people, not conditions, if we want to really help them.
Hi Kim (Knight),
Perhaps you’d be interested in learning more about personalized medicine, a major thrust in disease-based research and development of diagnostics/treatment that is described as follows: “Personalized medicine uses new methods of molecular analysis to better manage a patient’s disease or predisposition toward a disease. It aims to achieve optimal medical outcomes by helping physicians and patients choose the disease management approaches likely to work best in the context of a patient’s genetic and environmental profile. Such approaches may include genetic screening programs that more precisely diagnose diseases and their sub-types, or help physicians select the type and dose of medication best suited to a certain group of patients.” This approach relies on the following: “Through molecular analysis of ‘biomarkers’ — biological molecules that indicate a particular disease state — scientists can identify these sub-types within a disease. Biomarker analysis can also help classify sub-groups of patients who have the same molecular variation of the disease, enabling one to monitor its progression, select appropriate treatments, and measure the patient’s response to medication.”
For more information: http://www.personalizedmedicinecoalition.org/about/about-personalized-medicine — particularly the the Science of Personalized Medicine page (http://www.personalizedmedicinecoalition.org/about/about-personalized-medicine/personalized-medicine-101/science)
Kim Knight
When we treat conditions, we ARE treating people. My life is MUCH better, now that I am receiving medical treatment, than it was before. I was in utter torment. So much so that I was suicidal but my faith kept me hanging on. Now I am not. And it was all because no one believed that what I had (and have) at that time was real and serious. Consequently I received no physical treatment for many years. I still have my bad days but I am doing much better, as a rule, physically as well as cognitively,than I ever have in the last 25 years. I think it is safe to say many people’s lives are much better when they receive adaquate treatment for their illnesses. Do you use glasses? Have dental work done? Get a flu shot during flu season or allergy vaccines? These physical treatments make a world of difference in many people’s lives. I do believe praying helps in conjunction with medical treatment. As a matter of fact, I pray for my medicines and medical care as well, since I am a Christian and am admonished to “come boldly before the Throne of Grace for help in time of need” and God definitely does answer me.
This line of thinking leads people nowhere. It is a horrific thing to say to people who have lost loved ones at young ages to cancer or seen loved ones battle cancer with everything they — and medical science — can muster. And how can anyone who has dealt with horrible cancer and gone through lots of difficult treatment possible
read this? It’s insulting!
A friend said this years ago as a 35-year-old friend of ours, a devoted mother of two young children, lay dying of melanoma.
These statements are just completely ignorant and ridiculous. And
it hurts people who either suffer or see loved ones suffer.
Disease is real. It can and does kill people and/or make their
lives miserable, limited, difficult, etc.
CFIDS creates so many problems for us. I’m just being educated to the situation of many people with CFIDS being completely homebound, stuck in one room, not even able to get their own meals or go downstairs or walk their pets, and some can’t even get to the bathroom without help or take a shower or wash their hair.
Let’s live in reality and support whatever can be learned about this disease and how to treat it, maybe cure it.
I read an interesting article about Ribuximab at Phoenix Rising, which taught me a lot. At the very least, this drug can help figure out why some people were helped and some weren’t, what it is about each person’s particular disease and immune system that determines whether that drug helps or not.
With determined investigators, they can find out a lot about how the immune system works in CFIDS, what is impacted by the disease, maybe even if there is a viral cause, and if so, what it is.
I read something by Nancy Klimas about EBV’s affect on B-cells.
There is so much to be learned here.
Even if this drug won’t help everyone, it will be a learning device, which can open up new information and possible treatments.
It’s exciting as a step in scientific discovery. That’s what interests me.
I’m skeptical about using this drug, as I had liver involvement early on with CFIDS, a hepatitis unclassified, but with high liver enzymes, swollen and sore liver, which made me nauseous if touched. My skin yellows, and I had to stop all medications, vitamins, and eat very plain food.
And I have had horrible side effects to lots of medications.
But for what can be learned, for the dedication of these Norwegian doctors to help people with CFIDS, for the help that can be rendered to our community, I’m excited.
But lots more needs to be studied, tested, learned, etc.
Scientific discovery is never a straight line, always full of zigs and zags, but always building on prior knowledge. This is good!
Another point to raise is that every living thing, human, animal, is born and dies, mostly from disease. This is not imaginary or psychological. This is reality. To discover ways to put off death until an older age and try to eliminate or minimize suffering is a worthy cause, entrusted to medical science. This is a good thing.
Thanks for printing this. I found it very informative and reassuring as I too was concerned about the side effects of Rituximab. I’m looking forward to the results of the next clinical trial.
Thank you for this compact yet detailed summary. It has not been easy to sift thru the incomplete info available to the layman on Rituximab.
A question I would have is: How long does it typically take for the Rituximab to have effect on a disease? And what possible reasons can he think of why it might take longer to have effect on a disease?
thanks.
Oh yes, have they been able to blind past studies if they get those kinds of reactions on first infusion?
Hi Zac,
Great questions! In the CFS study done in Norway, according to the PLoS ONE paper, only one of the responders in the rituximab group showed an “early” response pattern (within 3 months), while the other nine started to improve 3-7 months after treatment. The responders in the rituximab group experienced a mean duration of improvement for 25 weeks. Two patients in the rituximab group and one in the placebo group have had “lasting major responses for all CFS-related symptoms without signs of relapse, 32, 30 and 23 months after intervention, respectively.” The authors state that the results support the concept of CFS as an autoimmune disease. They are working to identify the target for the autoimmune process. Additionally, they comment that the delayed response to B-cell depletion with rituximab is “difficult to explain from a viral elimination mechanism” and that the pattern is more consistent with “gradual elimination of an autoantibody, perhaps by preferential elimination of short-lived pre-plasma cells.” (More at http://www.research1st.com/2011/10/19/rituximab-trial/)
The delayed pattern of treatment response is also common in rheumatoid arthritis (RA). According to a comment posted on the PLoS ONE site by Dr. Jonathan Edwards, one of the researchers who pioneered the use of rituximab in RA, “There is nothing peculiar about the late response. It is to be expected. I was responsible for both the phase I and the proof of concept phase II (NEJM 2004) studies in rheumatoid disease, which formally established the validity of B cell depletion in autoimmune disorders. From the very outset in 2000 we reported that responses could take many months to develop, in line with autoantibody decline. An partial early response element was usually seen as well but was consistent with adjuvant use of corticosteroid or other agents. I am not aware of any hard evidence for rituximab working in autoimmune disorders not mediated by autoantibodies. Where there have been proper trials, as for psoriatic arthropathy, the results have been clearly negative as far as I am aware. The suggestion that rituximab works through an action on antigen presentation is pure speculation for which I cannot think of any positive supportive evidence and there is much unsupportive evidence, including the very common very slow response kinetics that follow antibody decline. This is an idea popularised before we actually had any data and still often repeated in reviews despite the wealth of evidence against. It is hard to see how killing B cells at day one would affect antigen presentation by B cells six months later, putatively responsible for further decline in inflammation to nine months. The trial’s authors give the account that is by far the most consistent with the data – that benefit occurs as short lived plasma cells die off and autoantibodies decline but that benefit is often incomplete as expected from the existence of long lived plasma cells and continued lower levels of antibody.” (More of Dr. Edwards’ response at http://bit.ly/sgutnc; there is also an interesting article about his work posted at http://bit.ly/u9aZOQ)
We’ll try to get an answer regarding the ability to blind studies of rituximab; however, the large REFLEX study that led to approval for RA therapy used a double-blind placebo-controlled study design (http://onlinelibrary.wiley.com/doi/10.1002/art.22025/full) and there have been double-blind studies (using saline as the placebo) for ulcerative colitis, scleroderma, multiple sclerosis, and other conditions (that are more similar to CFS than the cancers the drug is used to treat). This review article about the RA trials includes a section on placebo control: http://arthritis-research.com/content/11/1/205#sec8. It’s notable that in the REFLEX study, there was a positive response among 18% of the subjects who received placebo, compared to 51% of those who got rituximab, so it’s not uncommon to see some benefit from placebo in these kinds of studies.
There’s one severe side effect of Rituximab not mentioned here. I’d seriously like to see hard figures on the risk of developing PML, (sorry if that’s wrong too brain fogged to Google it again) there doesn’t seem to be any data on how many people in total have developed this condition as a result of taking Rituximab and how many people in total have taken it without any problems. I don’t want percentages per cond
ition it was prescribed for, I want cold hard numbers so I have some idea of the real risks involved.
Yes, I agree that absolute numbers for PML would be nice to have. I think I remember reading somewhere that PML might be an under-detected occurance in cancer treatment- the person dies and they think the cancer got them but it was really PML, although I don’t remember how legit the source was. Also any advances on diagnosis and/or who’s likely to get it would be great to have too.
PML is a terrifying possibility and I was of the mind when the first study came out that it was much more common than it seems like after reading around based on the second study. Also I think I remember someone posting a link to a recent paper on a 2011 case study of one which was on successfully treating a patient with PML with an anti-malarial drug. You could tell it was deadly serious though, they did spinal taps and a brain biopsy just to confirm the diagnosis!
Hi bekijane and John,
The safety profile of any drug being considered for therapy is important to carefully evaluate. Rituximab was approved in 1997 for patients with specific types of lymphoma, so use and safety data has been accumulating for more than 14 years in a variety of conditions and settings. I was not able to find data for how many total people have been treated with rituximab; it is used internationally and there is considerable off-label use in a wide variety of conditions in addition to those for which it has regulatory approval (by FDA in the U.S. and various authorities in other countries).
For readers who may not be familiar with the term PML, it stands for progressive multifocal leukoencephalopathy. It is one of the serious, but fairly uncommon, adverse events associated with rituximab. I have not been able to locate a current total for the number of reported cases of PML connected to rituximab, but there has been considerable effort dedicated to and multiple publications about PML as a concern. It has been most often reported in patients with rheumatoid arthritis. A large study called RADAR (Research on Adverse Drug Events and Reports) is following this issue closely.
This 2009 publication in the journal Blood reports on a multi-year analysis of PML in non-HIV patients following rituximab (Carson KR et al, “PML after rituximab therapy in HIV-negative patients: a report of 57 cases from the RADAR project, Blood, Mar. 5, 2009. Link to full text: http://bloodjournal.hematologylibrary.org/content/113/20/4834.long). “We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab.”
In the discussion section of the paper they make the following assessment: “Epidemiologic estimates of PML incidence are difficult to derive. In the general population, PML is estimated to occur at 1 case per 200 000 persons. Among HIV-infected populations, incidence rates decreased from 3.3 cases per 1000 person-years at risk in 1995 to 1996 to 1.3 cases per 1000 person-years at risk in 2000 to 2006, after the introduction of highly active antiretroviral therapy. Among persons with multiple sclerosis or Crohn disease, the estimated incidence of natalizumab-associated PML is 1 PML case per 1000 natalizumab-treated patients. For PML-associated with rituximab, Kavanaugh and Matteson reported 2 PML cases per 8000 rituximab-treated SLE patients.68 It is not possible to accurately estimate the incidence of rituximab-associated PML among persons with hematologic malignancies because of incomplete reporting of PML cases among rituximab-treated patients and incomplete data on the number of unique patients with lymphoid malignancies who have received rituximab. It should also be noted that the epidemiology of PML in the setting of lymphoid malignancies has changed over time. Before 1990, most PML cases occurred among persons with Hodgkin disease, whereas in recent years, with the development of purine analogs, hematopoietic stem cell transplantation procedures, and rituximab, most PML cases occur among non–HIV-infected persons with NHL or chronic lymphocytic leukemia. Consideration should be given to conducting epidemiologic studies to prospectively evaluate incidence rates and risk factors for PML among cohorts of rituximab-treated patients with NHL, autoimmune diseases, SLE, rheumatoid arthritis, and multiple sclerosis. Finally, causation assessment is more difficult when PML occurs among rituximab- versus natalizumab-treated persons because PML occurs in the absence of rituximab therapy among persons with NHL or autoimmune diseases, whereas it has not been reported in the absence of natalizumab therapy among persons with multiple sclerosis or Crohn disease.”
There are more recent reports in the literature that estimate the risk of PML at 1 in 15,000 to 1 in 25,000 patients treated with rituximab. In most of the reports, the individuals diagnosed with PML were treated with other forms of aggressive therapy (including surgery, radiation, chemotherapy, antivirals, antiretrovials, other immunosuppresants) in addition (before, during or after) treatment with rituximab, so the cause and effect relationships are challenging to sort out, as reported in the RADAR report above.
A multi-national study of long-term safety in RA conducted by van Vollenhoven et al. was reported in the Journal of Rheumatology (http://www.jrheum.org/content/37/3/558.full.pdf) Objective. To evaluate the longterm safety of rituximab in clinical trials in patients with rheumatoid arthritis (RA). Here is information about that study and its conclusions: “Methods. Pooled analysis of safety data, including adverse events (AE) and infections, from patients treated with rituximab in combination with methotrexate in a global clinical trial program. Results. A total of 2578 patients with RA received at least 1 course of rituximab. Safety analyses were based on 5013 patient-years of rituximab exposure. The most frequent AE was infusion-related reactions (25% of patients during the first infusion of Course 1). Less than 1% of infusion-related reactions were considered serious. Rates of AE and serious AE (SAE; 17.85 events/100 patient-yrs, 95% CI 16.72, 19.06) were stable following each course. The overall serious infection rate was 4.31/100 patient-years (95% CI 3.77, 4.92). Infections and serious infections over time remained stable across 5 courses at 4-6 events/100 patient-years. Compared with other patients with RA and with the general US population, there was no increased risk of malignancy. Conclusion. In this longterm safety update in RA clinical trial patients, rituximab remained well tolerated over multiple courses. SAE and infections remained stable over time and by treatment course.”
Drs. Oystein Fluge and Olav Mella, the lead investigators of the study of rituximab in CFS patients replied to a letter to the editor of PLoS ONE about their study, making the following statement about relative risks and benefits: “CFS/ME according to Fukuda or Canadian criteria is in many patients a very serious and debilitating disease. Current treatment is for many patients highly unsatisfactory and we believe it is justified to find new interventions and learn more of the pathophysiology, of which we at the time being know little. The side effects of Rituximab in this particular patient group of patients is of course presently largely unknown, although there is vast experience with the drug in B-cell lymphomas and established autoimmune diseases. We believe the severity of disease in many CFS/ME patients balances the known risks. That was also the opinion of most patients who were given the option to participate in the current study at a time when only three pilot patients had been treated with the drug.” (See http://www.plosone.org/annotation/listThread.action?inReplyTo=info:doi/10.1371/annotation/43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c&root=info:doi/10.1371/annotation/43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c)
There is much more to be learned and hopefully with this report other studies will commence in addition to the two open label trials being conducted by Drs. Fluge and Mella, as well as the new Norwegian initiative to conduct a larger Phase III trial they report in the comment noted above.
“No Guts, No Glory”……where and when can I sign up to be on the research trial list when becomes available here in the US?
An article at Phoenix Rising (I think that’s it, brain fog today) explains some of the risks with Rituximab, including a very serious one. There are risks of getting certain infections with the B-cell suppression. That article explains some of this.
Does anyone know when Øystein Fluge and Olav Mella
will have the results of their current Phase II study?
Hi Brent,
The two follow-up phase II studies began in June 2010 and will follow subjects for 36 months, so that suggests final results will not be available until after June 2013. (see http://clinicaltrials.gov/ct2/show/NCT01156909?term=Rituximab+AND+chronic+fatigue+syndrome&rank=2 and http://clinicaltrials.gov/ct2/show?term=Rituximab+AND+chronic+fatigue+syndrome&rank=1) Since it is an open-label study design with the objective of understanding dosing, safety and effectiveness, Drs. Fluge and Mella may be able to make interim reports.
Unfortunatley, that is simply way too long to wait. Given your interview with Dr. John Sweetenham who confirmed side effects of Rituxan are limited to temporary and controllable infusion side effects, and serious side effects are with patients with lymphoma or other conditions, this treatment should be made available widely by doctors on an off label basis. The risk/benefit analysis is clear when compared to the debilitating side effects of CFS. Furthermore, ethically speaking any such risk/benefit analysis should, as a final decision, be made by the person suffering CFS.
Thank you for bringing information to CFS sufferers like myself who need this information to make an informed decision.
As a next step can your organization compile names of doctors who agree with the foregoing and are willing to prescribe Rituxan on an off label basis – including in Canada where I am from.
Thank you.
Thanks, Brent. We are working hard to bring reliable information about this study and the drug to our readers.
For those who aren’t familiar with the term “off label,” it refers to the fact that in the United States and some other countries, physicians have legal authority to prescribe medications for uses other than those which are approved by regulatory agencies. From wikipedia, “once a drug has been approved for sale for one purpose, physicians are free to prescribe it for any other purpose that in their professional judgment is both safe and effective, and are not limited to official, FDA-approved indications. This off-label prescribing is most commonly done with older, generic medications that have found new uses but have not had the formal (and often costly) applications and studies required by the FDA to formally approve the drug for these new indications. However, there is usually extensive medical literature to support the off-label use.”
Drs. Mella and Fluge have repeated the caution that, “Rituximab should not be used to treat CFS/ME outside of clinical studies at present. We also agree that more research is needed.” (Quote from their response to a letter to the PLoS ONE editor at http://bit.ly/sgutnc) There is certainly a lot of off-label use of rituximab documented in the literature for a diverse spectrum of conditions. We will pass along information that physicians (in the U.S. or other countries) may wish to broadly share about their willingness to prescribe off-label. We agree that the issue of personal treatment remains a decision between an individual and his/her provider that should be based on the best information available and that person’s particular medical needs and tolerance for risk/benefit, no matter what the medication.
Please a list of drugs for each country in the world!!!!
Thank you for your in put Kathy D! It was very uplifting!
Opps I meant a list of open minded doctors who will prescribe rituximab for ME (severe at least) it is so weird when the doctors are worried about your immune system and all have done is lie in bed for 2 years…your major achievement being able to go to the toilet!!!!
Hi Fred,
We are very sympathetic to the interest in having a list of doctors willing to prescribe Rituxan (or any other drug), but it really isn’t possible since any decision about treatment would need to be based on a thorough clinical evaluation and weighing of the potential benefits and risks for that individual. That said, Dr. Andy Kogelnik of the Open Medicine Clinic in northern California has started several of his CFS patients on rituximab therapy. One of his patients, Kati, is blogging about her experience: http://bikechick06.blogspot.com/.