V.R.T.
Senior Member (Voting Rights)
Was this all from the anktiva? How many injections were there for that?
Trial Report Plasma cell targeting with the anti-CD38 antibody daratumumab in ME/CFS -a clinical pilot study, 2025, Fluge et al
ryanc97
Senior Member (Voting Rights)
Like 4. Yes all from anktiva. Fever and chills are common if you look at the literature.
DiBelloBr
Established Member
Although it is a pilot study without a control group, it seems clear that Daratumumab works for some patients (and works very well).
And what also seems clear is that it may be a matter of time before symptoms return in these patients (there is already one responder being retreated in the study extension, and we have 6-year data from Cyclophosphamide and Rituximab where a significant proportion of responders eventually experienced a return of symptoms).
It does not seem feasible for Daratumumab to be used again at every relapse — both due to safety concerns (high risk of hypogammaglobulinemia, reduction of NK cells, and infections), and due to a potential reduction in efficacy with each new cycle (because of decreased NK cells and therefore reduced ADCC, but also due to the induction of resistance in plasma cells through lower expression of CD38).
I know that F/M are testing hypotheses, trying to identify the lowest effective dose of Daratumumab in order to maximize safety, and I deeply commend them for dedicating their lives and resources to this work even before the pandemic led to an explosion of cases, and at a time when governments and the vast majority of the medical community did not believe that CFS was an organic disease (many unfortunately still do not).
My impression is that an important next step, after demonstrating the benefit of Daratumumab in a subgroup in a phase 2 study, would be to determine how to maintain remission (or perhaps continue testing hypotheses with the participants who completed the pilot study?). My impression is that it may be useful to intervene before the disease evolves to AAB production by plasma cells, whether with Rituximab (which also has important safety concerns, but much more long-term experience and does not induce reduced expression of CD20 in B cells), or Belimumab (which is only approved for SLE, and unfortunately was not effective in Myasthenia Gravis, probably because it involves LLPCs).
With COVID-19, the eyes of the scientific community have begun to turn toward CFS, but at the same time that F/M struggle to secure research funding, they also hold the patent for the use of B-cell and plasma cell–targeted therapies in CFS (no judgment, since they were pioneers in this area when no one believed in it).
And what also seems clear is that it may be a matter of time before symptoms return in these patients (there is already one responder being retreated in the study extension, and we have 6-year data from Cyclophosphamide and Rituximab where a significant proportion of responders eventually experienced a return of symptoms).
It does not seem feasible for Daratumumab to be used again at every relapse — both due to safety concerns (high risk of hypogammaglobulinemia, reduction of NK cells, and infections), and due to a potential reduction in efficacy with each new cycle (because of decreased NK cells and therefore reduced ADCC, but also due to the induction of resistance in plasma cells through lower expression of CD38).
I know that F/M are testing hypotheses, trying to identify the lowest effective dose of Daratumumab in order to maximize safety, and I deeply commend them for dedicating their lives and resources to this work even before the pandemic led to an explosion of cases, and at a time when governments and the vast majority of the medical community did not believe that CFS was an organic disease (many unfortunately still do not).
My impression is that an important next step, after demonstrating the benefit of Daratumumab in a subgroup in a phase 2 study, would be to determine how to maintain remission (or perhaps continue testing hypotheses with the participants who completed the pilot study?). My impression is that it may be useful to intervene before the disease evolves to AAB production by plasma cells, whether with Rituximab (which also has important safety concerns, but much more long-term experience and does not induce reduced expression of CD20 in B cells), or Belimumab (which is only approved for SLE, and unfortunately was not effective in Myasthenia Gravis, probably because it involves LLPCs).
With COVID-19, the eyes of the scientific community have begun to turn toward CFS, but at the same time that F/M struggle to secure research funding, they also hold the patent for the use of B-cell and plasma cell–targeted therapies in CFS (no judgment, since they were pioneers in this area when no one believed in it).
OrganicChilli
Senior Member (Voting Rights)
Wouldn't they recover after a year or so?
Utsikt
Senior Member (Voting Rights)
Hi and welcome!
That was also said about Ritux which turner out to be a complete bust in the blinded trial. It’s too early to tell.
Depending on what the disease mechanisms are, that might not be possible with b-cell depletion. We don’t know if it targets the lynch pins or if something else is maintaining the cycles.
There is no evidence of auto-antibodies in ME/CFS as far as I’m aware.
Jonathan Edwards
Senior Member (Voting Rights)
I don't know of evidence of reduction in CD38 expression in plasma cell clones follwoing treatment. It would surprise me a bit. There might be selection by survival for lower expressing clones but presumably relapse would be due to new clones not yet exposed to selection?
jnmaciuch
Senior Member (Voting Rights)
I think the idea comes from cancer where that selection-by-survival dynamic is quite important because of the rapid proliferation and competition between cancerous cells harboring different mutations. I agree that the same dynamic probably doesn’t apply to a (suspected) antibody-mediated disease
Jonathan Edwards
Senior Member (Voting Rights)
Yup, that was my thought.
ryanc97
Senior Member (Voting Rights)
Why is this clear? One responder being retreated = 1/6 relapse. Cyclo and ritux are not the same drug. It is not comparable.
Jonathan Edwards
Senior Member (Voting Rights)
And these are not 'responders', merely people who improved subsequent to treatment!
DiBelloBr
Established Member
Yes, you are right. What applies to MM wouldn’t apply here. Thanks
DiBelloBr
Established Member
That’s a good point. Just using the same term that the authors of the paper we are discussing used to refer to the group of six volunteers who showed improvement.
They might be responders to the drug, but it’s inaccurate to call them that.
DiBelloBr
Established Member
Actually, 2/6 relapsed (one of them had a partial relapse during the study).
My point is that not everyone sustained the response over time (even after cyclophosphamide, rituximab, or daratumumab), so either retreatment should be considered (and it was) for those who relapse, or a strategy to maintain remission (e.g., after a second cycle of daratumumab). Since the authors suggest in the title of the paper that plasma cell depletion is being investigated, I was speculating about ways to avoid intermittent use of daratumumab over the years, as I’m not aware of this type of long-term application for this drug.
I mentioned rituximab (which might have a different effect following Daratumumabe) and cyclophosphamide together because both were included in the same 6-year follow-up article for the same disease.
I know it’s too soon, as we know little (or nothing) about the pathophysiology and we don’t have any drug approved in a phase 3 trial. I’m speaking from the perspective of a patient who hadn’t seen this degree of improvement following a drug tested in CFS before. Since everything is being tested based on hypotheses, I was simply putting forward another hypothesis: that a drug used after remission is achieved might have a different effect than if it were used during the symptomatic phase, for those who relapse and need it.
DiBelloBr
Established Member
Hi,
You’re right. I was speaking from the optimistic, not the scientific, perspective of a patient with CFS who had never seen this degree of improvement in daily step counts and scores following a drug treatment in a CFS publication.
It just seemed like too much of a coincidence not to mean something, even for a pilot study (scores can be easier to bias, but not having PEM despite such a large increase in steps, plus the correlation with NK cells and the sustained drop in IgG among those who remained well). I know there are many other possible biases that could be used to argue against the idea that the drug truly works (misdiagnosis, evaluator selection bias, and correlations based on such a small sample size, etc). In any case, anything is still possible, and this is simply my personal impression that some people with CFS might benefit from daratumumab—perhaps also a form of hope.
I suggested some maintenance treatment ideas based on the hypothesis of plasma cell, B-cell, and autoantibody involvement, which seems broadly aligned with what the authors may be considering, but it’s really a shot in the dark (even more so than the already speculative step of testing rituximab or daratumumab in the first place).
From my perspective, as a patient and also a physician, everything is still in the dark, and their line of thinking seems the most promising. I hope they find something conclusive soon.
Thanks for your thoughtful and polite comments.