Thesis Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Clinical trials, medical treatment and pathomechanisms, 2024, Rekeland

https://bora.uib.no/bora-xmlui/handle/11250/3127770

Source: University of Bergen Date: May 2, 2024

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Clinical trials, medical treatment and pathomechanisms
------------------------------------------------------------
Ingrid Gurvin Rekeland - Department of Clinical Science, University of Bergen, Norway

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is an under-researched disease affecting 0.2-0.8 % of the population, of unknown aetiology, with high symptom burden, no validated specific and sensitive biomarker, and no standard approved effective treatment. The interest in ME/CFS in our cancer ward started in 2007, with observations of several patients with long-standing ME/CFS who got cancer and who independently reported that the cancer drug treatment had beneficial effects on their ME/CFS symptoms. The treatments included the cytotoxic drug cyclophosphamide and/or the monoclonal B-cell–depleting anti-CD20 antibody rituximab. The observations led to the working hypothesis that ME/CFS in a subgroup could be a variant of an autoimmune disease, with an immunological trigger, often with a post-infectious onset and with a role for B-cells/plasma cells and antibodies. The ME/CFS research group at Haukeland University Hospital have worked for 15 years trying to elucidate pathomechanisms, discover biomarkers and perform clinical trials to assess possible treatments.

In this project, we aimed to assess the therapeutic potential and possible side effects of rituximab and cyclophosphamide in two clinical trials, RituxME and CycloME (papers II and III). The placebo-controlled phase III RituxME study with 151 patients did not show a significant clinical benefit from rituximab compared to placebo. The open-label study with cyclophosphamide, CycloME, with 40 included patients, showed a beneficial effect on ME/CFS symptoms after treatment with a response rate of 55%. The 6-year follow-up study (Paper V) of both RituxME and CycloME showed that a significant number of patients treated with cyclophosphamide reported sustained, clinically meaningful improvement after 6 years. As part of the rituximab investigations, we retrospectively measured rituximab concentrations and anti-drug antibodies (ADAs) in serum samples from patients enrolled in a previous open-label phase II rituximab maintenance study (KTS-2-2010) to investigate possible associations with clinical and biochemical data (Paper I). We did not find that rituximab concentration and kinetics were significantly associated with patient symptoms or response in the trial. Finally, we investigated the combined use of activity monitoring and patient-reported outcome measures (PROMs) in a cohort of ME/CFS patients with no intervention, to assess symptom variation over time, attempting to develop new non-invasive tools to monitor patients and to improve future outcome measures in a trial context (Paper IV).

The effect of an immunomodulatory drug on symptoms supports the underlying hypothesis that in a subgroup of patients the immune system is involved in the pathomechanisms of ME/CFS.

 

Where is paper V?

Paper V: Rekeland IG, Sørland K, Neteland LL, Fosså A, Alme K, Risa K, Dahl O, Tronstad KJ, Mella O, Fluge Ø. Six-year follow-up of participants in two clinical trials of rituximab or cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. The article is not available in BORA.

 

It is submitted for publication so it has not been included.

 

Fluge has shown slides from this paper at one of the European conferences, but then the slides mysteriously vanished from the conference web site.

 

This is the important part. Cyclophosphamide continued to work for 6 years, which may contravene @Jonathan Edwards observation that cyclophosphamide generally only lasts for about 5 years.

 

they note here that the cyclo remission/effect group correlted with IgG and IgM reductions but that didnt hapen in ritux even though the IgG dipped. The anaylsis is good and is why i myself have started cyclo recently cos i think its possible that this is a novel autoimmune type disease we wont know the specifics for for a while, and I am not waiting a decade for them to be forced to do cyclo anyway cos its one of the few anti-t cell drugs off patent

 

It doesn't say that. It says that improvement was sustained for six years. But if the improvement had nothing much to do with the cyclophosphamide, as is perfectly possible, then the cycle just didn't work.

When cycle at very high dose works is followed by objective changes in autoimmune disease that tends not to last more than 5 years. At the doses the Norwegians used improvement rarely lasts for more than 3 months. But in a situation where we have no objective evidence of an effect on an immunopathology improvement might last any old time.

 

Where do they say that?
Not sure how one would interpret it.

 

This is a rather confusing statement. There is no reason to expect rituximab concentrations or kinetics to relate to improvement dynamics. You expect the B cell or antibody levels to correlate. Most of the rituximab is gone long before antibodies go down.

The phase three trial was set up because the phase two open label study showed pharmacodynamics very similar to those I had found in RA and had commented on that in response to the phase II Plos One paper. The irony is that this repeated correlated dynamics in the open study that fitted what was 'expected' so well turned out to be spurious. In the blinded phase III there was no efficacy at all.

 

OK—what is the mechanism by which HIGH dose cyclophosphamide works in autoimmune disease (if known) and what leads to attenuation after about 5 years (if known)?

 

Maybe the low dose cyclophosphamide is treating this?

 

Nobody knows but we are talking about doses that kill a high proportion of all types of immune cell including quite a lot of plasma cells. Doses that kill you unless you have stem cell rescue.

 

It might but we simply don't know that cyclo is doing anything useful.

A major contribution that Fluge and Bella made to clinical research in ME/CFS was to show that if you enrol people with ME/CFS into drug trials, at least in their hands quite a few are likely to appear to show very major benefit even with a drug subsequently shown to be ineffective.

So, since the cyclo trials are unblinded we have no way of knowing whether the drug has any useful effect.

The irony is that Fluge is such a careful scientist and such a well-meaning and humble clinician that it may be that he has a rather powerful placebo effect!!

 

Do seronegative cases of classical autoimmune diseases have the same response to drugs such as RTX and Cyclo?

 

For rituximab: in my experience no. We treated 5 seronegative rheumatoid cases in the first cohort of 22 and none responded. We did get responses in patients without autoantibody but other evidence of B cell dysregulation though - like high Ig levels. That is pretty much what we expected since autoantibody assays do not necessarily pick up exactly what property an antibody population might have that drives disease.

Put another way there are no seronegative cases of classical autoimmune disease, since they show no evidence of autoimmunity! Also diseases like ankylosing spondylitis and psoriasis, that have no autoantibodies, do not respond.

For cyclo I am not sure we have much evidence. It has generally been used for diseases with B cell abnormalities. That includes MS, where the Cells are in the wrong place and make antibodies of unknown specificity. I am not sure that cyclo has been shown to be much use for MS though other than as part of an immunoablative high dose schedule.

 

Wow, thanks - noticed folks online suggesting that others try "cyclo" [cyclophosphamide?], rituximab---.

 

For MECFS, it would be low dose cyclophosphamide like the Fluge paper, not the high doses for AA disease—stem cells not needed. Might be different mechanisms between low dose and high dose cyclo.

 

These are the six year rituximab and cyclophosphamide follow up slides from Fluge’s talk at the 2023 Charite conference. I am posting them because the data has now been made public.

Cyc is impossible to blind, so trials for autoimmune diseases use alternative treatment or historical control groups. At six years there was little difference between rituximab and placebo patients so they can be treated as one large group. This is as good of a control sample as would be found in many studies of cyc for autoimmune disease. Both groups are individually big enough as a control sample.

At six years the cyc patients had improved by an average of 13.7 points more than the combined rtx study patients. There is a 1/20 chance the group difference is pure coincidence. Half of the cyc patients account for most of this difference, improving by an average of 24.4 points more than rtx combined group. This is a huge difference in quality of life.

Fewer cyc patients reported worsening than combined rtx study patients. The sample is too small prove a reduced risk, but it does suggest that the risk is probably not increased.

“At six-year follow-up in the cyclophosphamide group, 44.1% had an SF-36 PF > 70 at six years, compared to 27.6% in the rituximab group and 20.4 % in the placebo group. We chose a cutoff for at 70 points, because that would indicate a substantial improvement. The mean SF-36 PF at baseline was in the range 30-35 (for all groups).

SF-36 PF > 90, i.e., scores close to the normal population range, was achieved by 17.6% of the cyclophosphamide patients, 8.6% of the rituximab patients, and 7.4% of the placebo patients.”

It is difficult to dismiss the group difference as placebo for the following reasons.

1. Average time to first response in cyc patients was five and a half months which is not typical for a placebo effect. There was no prior data that would have made anyone expect this.

2. Cyclophosphamide outperformed rtx & placebo before unblinding. There was more hype and prior data for rituximab which could in theory have promoted a stronger placebo effect than cyclophosphamide.

3. Cyc patients improved by 5 points between 18 months and six years, while rtx active patients declined by about 4. It is understandable that placebo patients would stop improving or relapse after unblinding, but there is no explanation for cyc patients experiencing a long term placebo effect but not rtx active patients.



“In the CycloME study 15.0% worked part-time and no-one worked full-time at baseline. At six years (among 34 participants), six were working part-time and four were working full-time (29.4% in total). In the RituxME trial, four worked part-time, one worked full-time and three were students at baseline (5.3% in total). After six years (among 112 participants), one worked part-time, three worked full-time and two were students (4.5%). Doubling the number of people working part or full-time in the CycloME trial is important both for the patients and society.”