Alemtuzumab 8y outcomes (ECTRIMS 2018)

A
  UK NHS England MS Treatment algorithm
If you don’t know where you are going, all roads lead there; and in this case to alemtuzumab! 

But can alemtuzumab puts its money where it’s mouth is? 

In ECTRIMS we saw the publication of one their original clinical trial (CARE-MS II) follow up results after an 8 year period (see poster below).
  • 56% (77% of the original participants were included in this analysis) required no further doses of alemtuzumab, i.e. only the first 2 cycles an year apart
  • 88% relapse-free
  • 78% with disease stability, i.e. stable or improved EDSS scores
  • 67% free of MRI activity
  • Brain volume loss from baseline though to yr8 was -1.83% (i.e. normal rate as those without MS)
  • Side effects were the same as previously described

I’ll leave you to come to your own conclusions on these findings, but alemtuzumab is here to stay.

About the author

Neuro Doc Gnanapavan

35 comments

  • Great news for those newly diagnosed with MS. Hopefully approval of new drugs will be compared to the gold standards like alemtuzumab or ocrezulimab instead of the low lying fruit, the CRAB drugs. This way research moves forward and not sideways.

  • I am curious about the patients who have had worsening EDSS. Ok they might had or have had worsening sympthoms but maybe this sympthoms growed or growing much more slowly…
    So the results about the percentage of +1, +2 etc. EDSS worsening, and the dinamics of this worsening would be also a very informative result.

    • It’s important that Alemtuzumab is used in early EDSS scores <2.5, and this was apparent in the start of the study. It’s probably the same patients who are progressing in the follow up study. Delay even with IFNB previously impacts on the overall effectiveness of Alemtuzumab action.

    • The ocrelizumab extension trials shows that the people with PPMS or RRMS who went on beta interferon first, lost two years of brain health. From thre to five years on ocrelizumab the rate of change was the same as the ocrelizumab only treated group but the 11% difference at the satrt was still there three years later. Time is brain.

      Alemtuzumab shows up well on brain atrophy measures but one thing that is clear that in the alemtuzumab trials people were on drug signficantly earlier than people in the ocrelizumab and cladribine trials, indeed about two years earlier. So they will have had more brain reserve

    • If there is evidence of inflammatory activity (i.e. increase in the number of MRI lesions or lesion activity) then I see a place for it. However, when there is already walking difficulties that are progressive in the background and not linked to relapses I don't think an anti-inflammatory therapy is going to stop this. We need axonal protection at this stage, or combination of anti-inflammatory plus neuroprotectant.

  • But wait. Prof G said on this blog earlier this year that if he had MS and was JCV-, he would choose natalizumab as its efficacy is on par with alemtuzumab without the nasty surprises associated to secondary autoimmunity.
    Is the algo drafted by NICE purely commercial (i.e alem is cheaper) or has Prof G missed the ball?

    • Natalizumab buys you time to think, wait and see. It may also do something to the microenvironment that prevents inflammation priming neurodegeneration. The problem is we don't have natalizumab 1st-line.

    • Alemtuzumab is only cheaper because it is an IRT, i.e. the costs are front loaded and you don't need that many courses.

    • Let's say you buy 10 years with natalizumab and have been NEDA-3 ever since you have started. Now what?
      (I appreciate that your attempt to answer this question will exclude the specificity of pregnancy, inconvenience, patient preference….for the sake of simplicity)

    • "nothing? :("

      There's no treatment for the neurodegeneration in ALS..ALZ..or MS. It's why they are progressive disease. 🙁

    • Let's say you buy 10 years with natalizumab and have been NEDA-3 ever since you have started. Now what?
      If it is working and you are JC virus negative, why change?

    • Disease remission (including the background progression) is a good outcome. Since we know that activity in the first 5years contribute significantly to the neurodegeneration, then this is achievable by stopping it. If you're a purist and focused only on this then hitting the disease hard at the outset is the option. We have achieved a lot already with this strategy. As clinicians and PwMS, we can't wait for those selling us cures – remyelination/regenerative therapies to catch up with us. Clinical trials takes a certain EDSS range, so those at the top end are expected to progress, as we start to randomize everyone at diagnosis to the best available therapies then we will start to see a big difference.

    • "As clinicians and PwMS, we can't wait for those selling us cures – remyelination/regenerative therapies to catch up with us."

      Immuno suppresives are the low hanging fruit. Patients on them
      and those w/ benign ms can do well for decades. But there is
      no treatment for nuerodegeneration..so waiting for secondary
      progression and new treatments winds up happening.

  • There is one strategy that beats alemtuzumab in relation to preventing end-organ damage and that is myeloablative HSCT. The problem with the latter is that it is really high-risk and very few centres offer it, Ottawa being the exception.

    • I don't think myelo is high risk, the only one died in the Ottawa-Trial was before they switched to intravenous busulfan. The Beam/ATG is safe too, and Dr. Burt's Cy/ATG, what about that? The real issue with bone marrow transplants is the beating up of the hormone system. Also interesting to see that you do not anymore ask for a head-to-head trial HSCT-Campath. How come?

    • Also interesting to see that you do not anymore ask for a head-to-head trial HSCT-Campath. How come?

      The trial has been requested and a grant has gone into funding bodies for approval so it is a case of "watch this space as we will know the outcome soon".

  • Because latter maybe only equivalent to alemtuzumab as both leave b cells in marrow untouched. Hence the "perceived" higher efficacy of the former.

  • Interested to see substantiation of that. Non-myelo HSCT results (event free survival/NEDA) are substantially better than Alemtuzumab?
    Also, there’s not a huge difference in outcomes between myelo and non-myelo based on current protocols (though I’m not claiming no difference).

    On a side note, if Alemtuzumab levels atrophy to normal rates, eliminates relapse and progression, and prevents lesions on MRI at 8 years… How long until we can call it “the cure”?.

    • Alemtuzumab data for phase II was far better than the phase III. The HSCT studies have significant bias in them (as did alem trials which was not double blinded)

  • Such a beast. Don't understand that T2-free, how can it be 69% at year 2 and then go up to 70% at year 3? Has somebody died or dropped out? And second question: To me it looks that the 1/3 of patients getting lesions, that this might happen right after giving the drug? So, once you have passed year 2, there won't be anymore activity? Perhaps this shows that the damage actually needs quite some time to manifest, leading again back to the EBV-story? Anyhow, seeing this data, I don't believe it is ethical to not offer this drug to anybody diagnosed. Forcing patients to fail on the other drugs before offering this, equally unethical…

    • This fluctuation in T2 lesions outside of the core study is within the standard error and suggests that pretty much the effect on MRI lesion load with not only Alemtuzumab but other mabs. Of course there are always non-responders and these are them. They tend to have highly active disease outset and more likely to rebound with induction protocols (my opinion, not evidenced based!).
      I agree with your last point ‘Time is brain’.

    • This post and replies is that Alemtuzumab and myeloablative HSCT are highly effective and that Time is Brain are so cruelly thwarted here in the UK, and not solely in regards to those PwMS who so sadly fail on either treatment.
      No! It's the point about medical ethics made by Anon. I remember when one neuro described the escalation approach, with no mention of induction, saying to him that I was sorry but I felt compelled to say that it is perverse. To wait until someone has gotten worse before providing more effective treatment is simply perverse!
      MS needs to is perceived to be one disease and hit it hard and hit it early is the treatment model. Sometimes though I get depressed thinking that only Bart's is promoting this, with little support from elsewhere, and that too little progress has been made in regards to having this approach universally adopted.
      Oh, and I have to mention the other key requirement: early and accurate diagnosis. I've become rather fond of saying on this blog but it's true a) I wasn't diagnosed for 4 years after my first relapse despite MRIs and seeing an orthopaedic surgeon. b) I wasn't given any DMT for a year after diagnosis and had another relapse in that year. C) perverse but true, I was glad of the relapse within six months of diagnosis and the NHS delay at the time because it meant that I clearly met the criteria for highly active MS and could therefore request to have Alemtuzumab.
      Lucky to have the NHS and to have access to DMTs and very lucky to have responded to Alemtuzumab, but the extent of the unethical and perverse is still breathtaking!

    • Dear Doc Gnanapavan,

      You didn't directly answer my question. An example: Did you mean to say that if you find new T2 lesions in year 1 in a particular patient, but the lesions are not anymore there in year 2, that you wouldn't have to loo look again at the images of year 1 and correct the analysis? Or could it be that the lesions disappeared? Or do you say that the particular lesions is on the border of being detectable (noise), so one year yes this other year not, basically random?

    • The fluctuations you see outside of the core study (year three onwards as in the above poster) are random. It is though that we can miss 40% of lesions on MRI, it will also depend on where the slices are taken on the images, so depending on how you go into the scanner the images understandably are not exactly matched.

  • Can someone update on third dose alemtuzumab which has now been approved
    If someone has relapses and sees worsening of symptoms since having two courses are they eligible for a third dose?

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