Now that the XMRV myth has been put to rest, patients with Chronic Fatigue Syndrome (CFS) are no longer jumping the gun to demand anti-retroviral treatments. But they are jumping the gun in new ways, based on very preliminary data coming out of Norway.
A correspondent in Norway wrote to tell me patients from Norway with myalgic encephalitis/chronic fatigue syndrome (ME/CFS) are travelling to the US to have Dr. Andreas Kogelnik in San Francisco treat them with IV infusions of rituximab, apparently to no avail. A course of treatment costs over $6000, not to speak of travel and other expenses.
What is Rituximab?
It’s a chimeric monoclonal antibody against the protein CD20, and it destroys B cells. It is used to treat diseases with excessive, overactive, or dysfunctional B cells such as some lymphomas, leukemias, transplant rejection, and some autoimmune disorders, notably rheumatoid arthritis. It is expensive (several thousands of dollars per infusion), must be given IV, and can cause serious adverse effects including infusion reactions, reactivation of infections, and cardiac arrest.
Using it for CFS is not based on any clear scientific rationale, but only on a few observations of patient improvement and on speculation about a possible cause of CFS that might explain the observations. It has certainly not been established that CFS symptoms can be attributed to B cell abnormalities.
A Patient’s Story
A blogger in Canada has chronicled her experience at great length. She has been travelling to San Francisco for treatments, and she believes she is enrolled in a pilot study. A quote from her blog:
The treatments I would receive are not considered a clinical trial, but a pilot study because clinical trials are tightly regulated and operated. It needs a lot of work from investigators to establish guidelines and procedures, obtain approval from ethic boards, etc.
When questioned, she elaborated:
a pilot study is not a registered clinical trial. It’s a one person trial. It gives the opportunity for the physician and researcher to gain experience with the drug and to refine the protocol associated with its administration. The goal for this is to move forward with a very formal and well controlled clinical trial.
She is hopelessly confused about what constitutes a pilot study. I can’t tell whether she was misinformed or simply misunderstood what she was told, but it raises questions about informed consent. She had worked as a chemo nurse and had been involved in phase 1 studies of new drugs so she should know better.
She says Kogelnik told her he was in touch with the Norwegian researchers (see below) every two weeks; she got the impression that he was collaborating closely with them on pilot studies. But my Norwegian correspondent contacted those researchers and they told her that while they are in touch with Kogelnik now and then, they only have general discussions about ME and immunology. He has told them he is doing some kind of study; but they have never seen the protocol, don’t know how many patients are enrolled, and are concerned that he hasn’t officially registered his study.
The blogger has made multiple trips from Canada to San Francisco. The Genentech Foundation apparently pays for the drug under a patient assistance program if the patient can document 2 refusals by insurance, but the trips and special lab tests cost her around $6000 for the year. She vividly describes the difficulties of traveling with her symptoms, arranging for wheelchairs and oxygen, etc. She says travel makes her sicker.
She has come to hate the term CFS because of its associations. She prefers to call it ME. Now she says Kogelnik has changed her diagnosis to CVID (Common Variable Immune Dysfunction), but it seems to me neither her symptoms nor his treatment match very well with that diagnosis. Perhaps she means chronic fatigue immune dysfunction syndrome (CFIDS), which is essentially a synonym for CFS. She suggests that he is using a different diagnosis because it is more acceptable to insurance companies and regulators and helps to justify what he is doing.
Her B-cells were effectively eradicated by the drug, but she got worse instead of better. She says:
I have known to expect worsening of my symptoms. Dr K warned me about it….Dr K think that it takes about 3 months to start feeling durable effects of Ritux and they seem to taper the dose down as they go.
Here’s her protocol.
Rituximab induction: Day 1 and Day 15. Dose #3 at Week 8 (I got mine at Week 9). Dose #4 at Week 24. Dose #5 at Week 44 and Dose #6 at Week 60. Pretreatment for each infusion with Tylenol, IV Benadryl, and Phenergan (to reduce the risk or severity of infusion reactions).
Despite her initial enthusiasm, the drug has not helped her. In fact she has developed various new symptoms and abnormal liver function tests, but she refuses to attribute any of these to the treatment.
I am getting resigned that I may not respond from Rituximab- but then I guess if it happens, that’s totally fine too. I hope that this process can be of help to research, notably finding out who responds and why, and who doesn’t and why.
This is particularly sad, since she was not treated as part of a controlled study that might have actually accomplished those goals. She was merely a guinea pig in an irresponsible uncontrolled experiment.
What Is the Evidence?
An initial observation. Fluge and Mella observed that a patient with CFS had an unexpected, marked recovery of CFS symptoms lasting for 5 months during and after cytotoxic chemotherapy for Hodgkin’s disease. They reasoned that the improvement was probably related to her treatment with methotrexate, a drug known to induce immunomodulation in part through B-cell depletion.
A small case series. So they decided to try depleting B-cells with rituximab in the original patient plus two others. This was published as a case series in 2009. The treatment was 2 IV infusions given 2 weeks apart, with a maximum dose of 1000mg. 2 of the 3 patients were also given oral methotrexate for recurrent symptoms.
All three patients, with 7–10 years of CFS disease duration, had substantial relief of all symptoms related to CFS after rituximab intervention. Patients 1 and 2 had a marked symptom improvement after approximately 6 to 12–16 weeks, followed by slowly increasing symptoms (yet still a benefit 6 months after treatment). Patient 3 had slight symptom improvement from 6 to 26 weeks after treatment, thereafter a major recovery of all symptoms lasting until 40 weeks after treatment, followed by a gradual worsening the following month.
One randomized controlled trial. Their next step was to do a randomized, double-blind, placebo-controlled comparison of rituximab to IV saline. 2 infusions were given 2 weeks apart to 30 patients. All patients were pre-treated with cetirizine, paracetamol and dexamethasone to minimize the risk of reactions.
They are calling it a positive study; but for their primary end-point (effect on self-reported CFS symptoms three months after intervention) the results were actually negative. They continued to observe the patients for secondary endpoints, and other secondary endpoints were added to the protocol mid-stream. They found a significant difference between the groups at 6-10 months after treatment.
They characterized this as:
significant, though generally transient clinical responses, with CFS symptom improvement in two thirds of the included patients.
Of the patients on rituximab, 10 had a major or moderate response lasting from 8–44 weeks; the other third failed to respond. Two patients in the placebo group had a major or moderate response.
The study design could have been better. There were some significant differences between the patient characteristics in the two groups, and it doesn’t appear that they questioned patients to see if they could guess which group they were in (i.e., whether blinding was adequate).
More studies in progress. They announced:
Based on new pilot patient experiences [what does this mean? Are they, too, confusing pilot studies with anecdotal evidence?] we have now started two new open-label phase-II studies investigating Rituximab treatment with two infusions two weeks apart (as in the present study) followed by maintenance Rituximab infusions at 3, 6, 10 and 15 months, to further explore this treatment principle in CFS (ClinicalTrials.gov, NCT01156909 and NCT01156922).
Strangely, both of these studies are open-label, with no control group and no blinding. What were they thinking?
What Is Kogelnik Doing?
Kogelnik founded the Open Medicine Institute to facilitate electronic information sharing in a community-based process. It is crowd-sourcing private funds. It has great plans for research, but as yet no studies have been registered at ClinicalTrials.gov. As far as I have been able to determine, he is offering individual patients treatment outside of any legitimate study. I don’t know how he is representing this to his patients, but at least one medically trained patient believed she was participating in a pilot study Kogelnik was doing in collaboration with researchers in Norway. I have no way of knowing whether the misunderstanding was on her part or his.
Some of this reminds me of Burzynski’s deceptive tactics, but Kugelnik is no Burzynski. I’m willing to believe he is sincerely trying to help patients who have no other options. But I think he’s on the wrong track. The way to really help these patients is to insist on providing the drug only in the context of well-designed clinical studies to establish once and for all whether rituximab treatment is effective. Jumping the gun is not scientifically or ethically justified.
Don’t expect anyone to try to stop him. Rituximab is an FDA-approved drug for other indications, and it is not illegal to prescribe the drug off-label. Offering experimental treatments to patients is not illegal. Medical boards have disciplinary power: the infamous Dr. Mark Geier, chemical castrator of autistic children, lost his license for “almost total disregard of basic medical and ethical standards,” but that kind of medical board action is the exception to the rule. Similar malfeasance (Dr. William Rea, for example) has typically been ignored or punished only with a mild slap on the wrist. Even Burzynski has not lost his license. In the absence of regulatory action, the only remedy would be a lawsuit if a patient died or was seriously harmed by the treatments.
So basically, the evidence consists of one case report (involving a different drug!), a case series of 3, and one preliminary controlled study with 30 patients showing a 2/3 response that was delayed and transient. Preliminary studies serve to justify further studies but they are not sufficient to justify forging ahead with offering the treatments in clinical practice. All too often, attempts to replicate preliminary studies fail, and initially promising results are discredited by larger, better studies. XMRV was a prime example of that.
The protocol in the studies was 2 IV infusions 2 weeks apart. The protocol that Kogelnik is using (treatments 2 weeks apart, then at 8, 24, 44 and 60 weeks) doesn’t correspond to the published study or even to the Norwegian studies in progress.
In my opinion, what he is doing is not based on acceptable evidence and is not ethical. He is indulging in irresponsible, uncontrolled experimentation. He is knocking out a vital part of his patients’ immune systems (B cells produce antibodies to fight off infections) with little understanding of what he is accomplishing, of whether it addresses some basic underlying causal mechanism of CFS, or of what the possible long-term consequences might be. By jumping the gun he is putting patients at risk; exposing them to considerable cost, discomfort, and inconvenience; and by running around the track prematurely by himself, he is missing out on the real race to understand and treat patients diagnosed with CFS/ME/CFIDS.