Daratumumab, isatuximab (CD38 drugs)

[Verity]

Does anyone know when we’ll get information about this, either when the trial reports or when we might hear about the severe patient expansion?

 

[N_Dina]

I have another thought I’d like to discuss, as I’m not well versed in immunology and may be missing something obvious.

I remember a very severe person who self-administered daratumumab. As I understand it, his PEM resolved, but his orthostatic intolerance did not improve.

Cyclophosphamide has a broader and somewhat different mechanism of action than daratumumab, and some profoundly severe ME/CFS patients have reportedly entered remission after cyclophosphamide-based treatment.

Does this suggest that PEM and orthostatic intolerance may not necessarily share the same underlying driver? For example, could a treatment that removes one immune component (such as a plasma-cell/antibody-mediated process) improve PEM while leaving another mechanism - perhaps one more relevant to dysautonomia or orthostatic intolerance - largely untouched?

Could it also be that patients have somewhat different autoantibody or immune profiles, so that the most appropriate approach might differ between individuals? For example, in some patients a plasma-cell/antibody-mediated component may be a major driver, and targeted plasma-cell depletion with daratumumab might be enough to produce a remission. In others, a broader immunomodulatory effect (cyclophosphamide) might be needed because several immune mechanisms are contributing.

I’m mainly trying to understand whether the differing responses to daratumumab and cyclophosphamide are consistent with the idea that ME/CFS theoretically may involve several partially separable pathophysiological mechanisms.

 

[V.R.T.]

I remember a very severe person who self-administered daratumumab. As I understand it, his PEM resolved, but his orthostatic intolerance did not improve.

I haven't heard about this case. Do you remember where you saw it? The only improvers stories I'm aware of outside of the trial were two people (Ryan on here and that Abraham (?) guy on X) who bothimproved much later - like 6 months, so the improvement is harder to ascribe to dara (ofc we can't be sure of anything without rct).

To be fair almost everyone else i've seen who's tried dara has only done one or two doses, which we know from the pilot expansion with LC patients isnt enough even if the effect is real.

So I'd be very interested if someone very severe has had their PEM resolve after trying daratumumab. Especially considering how rare remission is for people who are very severe.

 

[Jonathan Edwards]

I’m mainly trying to understand whether the differing responses to daratumumab and cyclophosphamide are consistent with the idea that ME/CFS theoretically may involve several partially separable pathophysiological mechanisms.

It is consistent. But all the data we have are also consistent with none of these treatments having any real immunological effects. DecodeME has made me much less convinced that specific immune mechanisms are involved. That is partly because of the lack of an MHC Class I or DR link but also because of the similarity in risk factors in men and women. If there were distinct driving mechanisms involved I would expect some sex bias.

 

[V.R.T.]

Cyclophosphamide has a broader and somewhat different mechanism of action than daratumumab, and some profoundly severe ME/CFS patients have reportedly entered remission after cyclophosphamide-based treatment.

I've not heard of these profoundly severe improvement stories, but I remember the cyclo improver who spoke to us here last year said she still had POTS but otherwise was fully living and travelling again.