Intravenous Cyclophosphamide in ME/CFS, An Open-Label Phase II Study. (Rekeland, Fluge, Mella, 2020)

Murph

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https://www.frontiersin.org/articles/10.3389/fmed.2020.00162/full

Intravenous Cyclophosphamide in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An Open-Label Phase II Study

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Ingrid G. Rekeland1,
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Alexander Fosså2,
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Asgeir Lande3,
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Irini Ktoridou-Valen1, Kari Sørland1,
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Mari Holsen4,
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Karl J. Tronstad5,
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Kristin Risa1,
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Kine Alme1, Marte K. Viken3,6, Benedicte A. Lie3,6,
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Olav Dahl5,
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Olav Mella1,5 and Øystein Fluge1,5*

  • 1Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
  • 2Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
  • 3Department of Medical Genetics, Oslo University Hospital and Faculty of Medicine, University of Oslo, Oslo, Norway
  • 4Clinical Research Unit, Haukeland University Hospital, Bergen, Norway
  • 5Department of Biomedicine, University of Bergen, Bergen, Norway
  • 6Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease with high symptom burden, of unknown etiology, with no established treatment. We observed patients with long-standing ME/CFS who got cancer, and who reported improvement of ME/CFS symptoms after chemotherapy including cyclophosphamide, forming the basis for this prospective trial.


Materials and methods: This open-label phase II trial included 40 patients with ME/CFS diagnosed by Canadian criteria. Treatment consisted of six intravenous infusions of cyclophosphamide, 600–700 mg/m2, given at four-week intervals with follow-up for 18 months, extended to 4 years. Response was defined by self-reported improvements in symptoms by Fatigue score, supported by Short Form 36 (SF-36) scores, physical activity measures and other instruments. Repeated measures of outcome variables were assessed by General linear models. Responses were correlated with specific Human Leukocyte Antigen (HLA) alleles.


Results: The overall response rate by Fatigue score was 55.0% (22 of 40 patients). Fatigue score and other outcome variables showed significant improvements compared to baseline. The SF-36 Physical Function score increased from mean 33.0 at baseline to 51.5 at 18 months (all patients), and from mean 35.0 to 69.5 among responders. Mean steps per 24 h increased from mean 3,199 at baseline to 4,347 at 18 months (all patients), and from 3,622 to 5,589 among responders. At extended follow-up to 4 years 68% (15 of 22 responders) were still in remission. Patients positive for HLA-DQB1*03:03 and/or HLA-C*07:04 (n = 12) had significantly higher response rate compared to patients negative for these alleles (n = 28), 83 vs. 43%, respectively. Nausea and constipation were common grade 1–2 adverse events. There were one suspected unexpected serious adverse reaction (aggravated POTS) and 11 serious adverse events in eight patients.


Conclusion: Intravenous cyclophosphamide treatment was feasible for ME/CFS patients and associated with an acceptable toxicity profile. More than half of the patients responded and with prolonged follow-up, a considerable proportion of patients reported ongoing remission. Without a placebo group, clinical response data must be interpreted with caution. We nevertheless believe a future randomized trial is warranted.

https://www.frontiersin.org/articles/10.3389/fmed.2020.00162/full
 
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Murph

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This study! I believed it was imminent back in early 2017! How young I was, how optimstic.

Exciting and important work but of course the Phase III rituximab trial has poured loads of cold water over this avenue of inquiry, and especially shown us the importance of a control group.

Still, here's the results

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cyclo results primary.jpg


They sure do look good, and I can see why Fluge and Mella pursued this study.
 
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Murph

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It'd be tempting to just use the Rituximab Phase III control group as a sort of pseudo-control here. The problem there was that the control group included a lot of strong recoveries, i.e. the Placebo effect was huge. If you do that, you write this study off. The treated population gets a simialr result to the control group in the Ritux study.

And maybe that's valid - this study is on the same population, with the same scientists.

But then there's this, which makes me wonder...
"Out of nine patients included in the trial who had received previous rituximab treatment without reporting improvement of ME/CFS symptoms, four achieved a clinical response after cyclophosphamide intervention"
 

Murph

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They found some genes were much more likely to be present in the people who were helped by Cyclophosphamide:

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"Interestingly, the presence of either of the two HLA risk alleles, previously shown to be associated with ME/CFS (HLA-DQB1*03:03 and HLA-C*07:04) (30), was predictive for response to cyclophosphamide. In contrast there was no association between presence of these HLA alleles and clinical improvement among patients included in the RituxME trial"
 

Wishful

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I wonder whether the patients had something else in common, such as time since developing ME. With a timeframe of 18 months, it's possible that some sort of 'getting tired of being tired' effect occurs, affecting how people respond to questions about how they feel. I think that's a valid problem when you lack a reliable quantifiable variable. I really don't know how my judgement of my fatigue or pain levels compares to how I felt 18 months ago, much less for 18 years ago.
 

pattismith

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I wonder whether the patients had something else in common, such as time since developing ME. With a timeframe of 18 months, it's possible that some sort of 'getting tired of being tired' effect occurs, affecting how people respond to questions about how they feel. I think that's a valid problem when you lack a reliable quantifiable variable. I really don't know how my judgement of my fatigue or pain levels compares to how I felt 18 months ago, much less for 18 years ago.
I agree with you. Studies without any datas are not better than psychoblabla studies...
 

andyguitar

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"Out of nine patients included in the trial who had received previous rituximab treatment without reporting improvement of ME/CFS symptoms, four achieved a clinical response after cyclophosphamide intervention"
So they are hinting that there was no placebo response in those patients as they didnt have one in the Ritux trial. Seems a bit weak to me.
 

Murph

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So they are hinting that there was no placebo response in those patients as they didnt have one in the Ritux trial. Seems a bit weak to me.

I don't think they're over-egging this. Obviously you have to interpret it in light of the rituximab failure but it is also important that is not the *only* context we use to interpret it.

There's a cognitive bias called recency bias, where we place too much weight on the most recent data point. This remains a very impressive piece of science and it shouldn't be completely discounted.

Also, there's this. It looks like more of their initial patients got cyclo than ritux:

"The initial patient observations in our cancer clinic, of patients with long-standing ME/CFS who developed cancer, and who reported relief of ME/CFS symptoms after cancer treatment, included seven cases treated with cyclophosphamide (or ifosfamide), and in one case the combination of cyclophosphamide and rituximab."
 
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Wishful

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"The initial patient observations in our cancer clinic, of patients with long-standing ME/CFS who developed cancer, and who reported relief of ME/CFS symptoms after cancer treatment, included seven cases treated with cyclophosphamide (or ifosfamide), and in one case the combination of cyclophosphamide and rituximab."

That makes me think that it might not be the drugs used in cancer treatment that worked on ME, but rather that the process of cancer being destroyed (releasing various chemical signals) that causes the improvement, or maybe the cancer cells were causing the ME symptoms to be more severe. I had a couple of viral infections during my ME, and they made my ME symptoms much more severe. I can easily imagine cancer triggering a similar effect.
 
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I read the full study. I would love if they tracked the population of T-reg cells in participants and see if there is any correlation between T-regs population change and remission since Cyclophosphamide is known for depleting T-reg cells at used dosage. Demonstrating any link between T-regs depletion and remission would be fantastic!
 

jaybee00

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There was no significant overall interaction between time and ME/CFS severity (p = 0.51), although the small group (n = 6) with severe disease had no clinically relevant increase in SF-36-PF, from 8.3 at baseline to a maximum of 11.7 at 12 months follow-up. The severe ME/CFS group included two patients with missing data (one withdrawal and one who failed to complete registration). However, seven patients with moderate-to-severe disease had similar improvements of the outcome measures as patients with either moderate or mild-to-moderate disease. Supplementary Figure 1 shows the courses during follow-up, for the SF-36 subscales Vitality, Social Function, and Bodily Pain (Supplementary Figures 1A–F), and also the Fatigue Severity Scale (Supplementary Figures 1G,H), all showing that the responders report improvement during follow-up which we interpret to be of clinical significance.
 
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