Monday, 18 December 2017

Alemtuzumab stops working. I wonder why?

Alemtuzumab can stop working. Is it because CD4 T cells are no longer depleted or is it because they have neutralizing antibodies?

In some people this occurs, and could be more of a problem after the the second infusion cycle. 

Whats more, some people do not deplete in the first place.

What information do we need to know from the manufacturer?
Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses.
Rolla S, De Mercanti SF, Bardina V, Horakova D, Habek M, Adamec I, Cocco E, Annovazzi P, Vladic A, Novelli F, Durelli L, Clerico M. J Neuroimmunol. 2017 Dec 15;313:89-91.

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab.

This is an interesting one because it has been shown that neither T cells numbers, nor CD19+ B cell numbers for that matter, correlate with disease activity. 

In this report they show that on first dose, there is marked lymphocyte depletion that is present 6 months after the first infusion. However there is no obvious depletion 6 months after the second or subsequent infusions and when disease activity re-appears. The percentage CD4 positive value does not change in two non-responders.

However, there is the problem if there are 50% CD4 cells at baseline and 50% 6 months later, but the number of cells have dropped by 50% then the number of cells are 25% of the number present at the start and so there is depletion.

Now the next problem. Immature/Mature B cells are good space fillers and means the B cell compartment is back to normal by 3 to 6 months and this complicates understanding about what's going on when you use percentages compared to absolute numbers.

So the authors were a bit stumped on how to explain this effect. 

There was an apparent lack of depletion after second or more courses. Perhaps this is the first report of people developing neutralizing antibodies to block function as a consequence of the first infusion. 

This may be consistent with the lack of effect.

The idea was not even mentioned and perhaps this is because they were not mentioned in the pivotal trials, so nobody knows about them, unless they have read our paper 


or the fine print in the FDA reports. 

Neutralizing antibodies can stop the drug working. 

If only they had been measured, we could have an idea if this was the case.  

Indeed, we have found this when we interrogated the MS CARE 1 trial.

Dubuisson N, Baker D, Kang AS, Pryce G, Marta M, Visser LH, Hofmann WE, Gnanapavan S, Giovannoni G, Schmierer K. Alemtuzumab depletion failure can occur in multiple sclerosis. Immunology 2017;DOI: 10.1111/imm.12879


SUMMARY
Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Whilst these anti-drug responses have been reported to be of no significance, we hypothesised that they will affect the depleting-capacity and treatment-response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population-level there was lack of influence of “ever-positive” alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and side-effects during the two year trial. This was not surprising as no one prior to first-infusion, and only 0.6% of people prior to the second-infusion had pre-infusion, neutralizing antibodies (Nabs). However, at the individual-level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, suggests that problems may occur in people requiring addition alemtuzumab-cycles. In addition, we also identified individuals, following ‘post-marketing’ alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Thus, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete-poorly, probably due to biological-response variation and NAbs and this may lead to treatment failure. Monitoring depletion following infusion and assessment of neutralizing response prior to re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure.


In the MS-CARE trials, it was evident that neutralizing antibodies generate quickly. They were there within one month of first infusion, but they may not have caused too much of a problem because they disappear within 12 months.  But by 24 months over 30% of people have an existing neutralizing antibody response. Meaning that one will have more concern for the antibody not depleting as well on third cycle.

Binding antibodies have been reported, although they are reported to be of minimal importance.

Neutralizing antibodies have not been mentioned in the pivotal phase II and phase III trials and were even called inhibitory antibodies in the (European Medicines Agency) report. 

If antibodies were not a potential problem then the Cambridge group would not have done a trial to get rid of these antibodies (click).

Alemtuzumab was the first humanised antibody which was designed to get rid of  neutralizing antibodies, but in reality it is not that great at stopping these and about 80% of PwMS taking alemtuzumab get anti-alemtuzumab antibodies.

Actually one wonders, if this dictated the dosing schedule of alemtuzumab, of two cycles and only dosing the additional cycles at the year end rather than after disease reactivation, to allow antibodies to disappear before the next dose. After two treatment cycles there is a greater chance of the drug not working

Has this issue been hidden all along? 
(One for the conspiracy theorists)

Is this important. Based on the trial data only 5 people had pre-existing neutralising antibodies before the second cycle. 

We could work out the MS-CARE 1 response because the EMA had provided data of the maximum and minimum and the medium response and there were only three people affected. There were also categoriesed in relation to the amount of antibody produced. One person had a higher level of neutralizing antibodies and 1 out of 3 people clearly did not deplete well or did not deplete at all. We could not say what they were before. We did ask but we were not given the raw data.

However this raises some important questions:

How many people receiving third or more courses of antibody deplete well and how many deplete poorly?

What is the level of pre-existing neutralizing antibodies (titre) that stops alemtuzuamb from depleting?

The manufacturers of the drug must know these answersas the phase III extension data has a number of people receiving three or more courses and about 30% would have pre-existing neutralizing antibodies before treatment cycle 3. (Read the paper above).

The manufacturers had made a poster of people switching from alemtuzumab to fingolimod to say it was OK (Click here). 

The poster shows the lymphocyte levels in 13 people of which 6 had three or more infusion cycles. Of these 6 people there were two people (a third) who stopped depleting on cycle 3. Was this due to neutralising antibodies? One can only guess. 

I should say you would expect that any protein treatment will cause neutralizing antibodies and for most people I am sure treatment will work. However, it would be valuable to know just how likely it is for you to be the person, where it will stop working. 

Also in CD52 is down-regulated to make CD52 negative cells cells following alemtuzumab. Does this influence activity?

Importantly we found there are some people where the drug does not appear to work at all. So there is no depletion in the first place, so someone is paying £28,000 or more for something that does not appear to work.

What is the cause

We have not found people who do not express CD52 (the target for alemtuzumab) having looked in a data base of 60,000 people. There were also no loss of function variants.

However, there are genetic variations that block IgG1 antibodies from depleting properly. If this is the problem what would the effect on ocrelizumab be, maybe the same.

If you are one of those unlucky people who don't deplete on first infusion and are willing to help us try find a  reason, get your neurologist to contact us.  

Why bring this up? 
Because it is about your safety or the safety of your pwMS.

CoI. We are authors ProfG, NDG, DrK multiple

30 comments:

  1. You really have a grudge against Alemtuzumab! The majority of patients do very well. There is a very low conversion to SPMS. Brain atrophy figures look very good etc. etc. There will always be some recipients who don't do as well (for various reasons). Not sure what your end game is by keep chipping away with these posts or the posts on the very rare side-effects. 10 years ago I got on an Alemtuzumab trial as (i) I did not want to transition into SPMS and (ii) I wanted to put MS to the back of my mind so I could get on with my life (through NEDA and no more MS drugs). Alemtuzumab delivered for me. Why don't you provide some balance in you reports rather than just scare mongering or making out there has been a conspiracy (data cover-up etc.). Or, come up with a more effective and safer drug (please don't refer to oral Cladribine in an effort to boost the share price and the value of your holdings).

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    1. No holdings re Cladribine, no share price boosting. The aim of providing an at least equally effective but with a safer side-effect profile is front and centre, as always.
      Alemtuzumab is the gift that literally keeps on giving (publication wise and it's now clear side-effect wise too), it's undoubtedly effective in a majority of cases but not all as this paper demonstrates (and why that is the case).

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  2. When you say non-depleters. Do you mean those who have non zero lymphocyte count at day 5 of the first course of Alemtuzumab? Or o you mean those who deplete to zero at day 5 but have normal lymphocyte counts say at month2 ? To me both these groups will be non-responders as immune would not have to rebalance or modify due to rapid re-population! Besides the bloods done after alemtuzumab count aggregate values and not by subpopulation type such as cd4. So how can you correlate white cell types and determine non responders before treatment?

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    1. People with no evidence of significant depletion but you make a good point without immunophenotyping you can't make a call as you don't know what is filling the space.

      The point for the non depletes is not to catch them before but to monitor and possibly change treatment of they don't respond.
      You can't screen for the problem until you know what the solution is. You won't look for the problem if you don't know it exists.

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    2. MD, Do you ever see pwMS with no significant lymphocyte depletion but have responded well to Alemtuzumab?

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    3. Thanks MD. Was trying to get my self included in your study. fortunately I went zero at month 0. Not sure it's working for me at month 3.

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    4. MD do yo ever see...

      I don't see pwMS I'm not a Doctor, but in terms of lack of depletion we have two people. I dont know their clinical profile, but suspect they a a disease time bomb ticking. I heard of one more when speaking to a neuro last week. Is there rapid repopulation within a month not sure. I suspect non depleters will not get infusion reactions. But as person above said we need differential blood counts. I would lie to see CD27 B memory cell numbers.

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    5. Zero at month three not working at 3 month.

      (a) We know there is space filling by new B cells coming out of bone marrow, you may be repopulating with B cells. So maybe ask for CD4 test They normally do for about 36 months.

      (b) many agents take time to work and it could be that disease activity was destined before treatment started and it was too late to stop activity but will stop new activity.

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    6. So I am guessing Alemtuzumab works very different to DMF. As there are pwMS who are responders to DMF but have a consistently normal lymphocyte range level.

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    7. Yes do have different mechanisms, but I have been saying they all work the same way but nonones listening:-(

      By depleting a specific subset of cells, however their depletion can easily be masked by a seemingly normal number of cells.

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    8. Thanks. The subset of cells to look out for would be CD4 and Normal range for CD4 is 31-60 is this correct? For DMF and Alemtuzumab. My CD4 level has been 36 on DMF.

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    9. For PML I am guessing CD8 are most important as they are common in lesion.

      The Normal range of CD4 is 500-1,500 cells mm3, below <50 is grade 4 lymphopenia so 34 is very low I am afraid.

      DMF inducs lymphopenia is about 5% of people

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    10. CD4 42 % 31-60
      CD4 (abs) 990 10 6/L 410-1590
      CD8 20 % 13-41
      CD8 (abs) 478 10 6/L 190-1140

      This isn't low or is it?

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    11. Sorry for misunderstanding
      I try not to talk about percentages as it is meaningless

      If you have 500 cells per mm3 and there are 500 non CD4 the percent is 50% if you have 500 per mm3 and there are 1000 non CD4 cells then it is 33%. Same number of CD4 cells in both cases.

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  3. Prof G's twitter today refers to CladriIbine and PML cases. As Cladribine pushers, why not focus on this emerging risk rather than dissing your competition?

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    1. The report (3 casesin leukaemia) you were referring to. Problem seems to be prolonged lymphopaenia, Dr K has a strategy to remedy this.
      https://www.gov.uk/drug-safety-update/cladribine-litak-leustat-for-leukaemia-reports-of-progressive-multifocal-encephalopathy-pml-stop-treatment-if-pml-suspected

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    2. I focus on a paper I have written. When I write a paper on problems with cladribine,I will post on that.

      We have the Alemtuzumab data and I am interpreting it for you.

      I will look at profG tweet when I have time

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  4. If the company was really trying so hard to hide this data, why would they have funded your study?

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    1. They did not fund our study, we received no funding for this piece of work

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  5. So are you saying there is no point in getting Alemtuzumab to treat RRMS? I am 23, recently diagnosed and I was hopeful it would give me a 'few good years'...

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    1. Absolutely not saying this, this may be the best option in UK as it has a liberal licence and so wide availability. As you can see by the first commenter some people do very well on this drug, but its use often comes with baggage and you need to be aware and prepared for it

      Delete
  6. Would you class tripping as relapse? This is great article. Directly relevant. Barts at its best.

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    1. I trip all the time, but I would ask has this become a frequent occurrence that wasn't there before. I don't know my neuro anatomy to know where picking you feet up is controlled maybe one of the neuros can answer.

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  7. I have a very interesting case of Alemtuzumab failure.

    I had a total depletion of lymphocites after phase 1 of alemt, 0.0

    two months later I was having a new relapse, and the MRI shown a old lesion was way bigger (and active).

    Three months after that relapse I had another relapse, another MRI, and 3 new lesions, even though my lymphocytes were at 0.3.

    A massive failure. Now I'm going to have aHSCT, I've been told that's my only option. Before Alemtuzumab I also failed with avonex and tecfidera. Every MRI I had shown new lesions.

    What scares me a lot, is that even though alemtuzumab didn't work at al, my lynphopenia is severe. After 16 months, my lymphocite levels are at 0.5 and PML is my worst nightmare.

    My neuro told me that to not to recover normal level of lymphocites is common after lemtrada, and having steroids every two/three months does not help, but being below 0.5 is way too low.

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  8. As someone who received the second round of infusions last month, and is desperately hoping it will be as successful as for Anon Monday 18th, I was really touched by your post Victor - please accept my best wishes for AHSCT!

    Another good post MD - had got the message before receiving Alemtuzumab that it's highly effective, most do well on it and that it comes with nasty side effects. Thanks to you, now know that we go on to develop neutralising antibodies. Feel more informed to discuss treatment options with my neuro, when the time comes.
    Good luck with your efforts to try and determine why some fail on it straightaway. None of us, fortunate enough to have access to DMTs, would wish to undergo treatment when there's the prospect of it being a waste of time! The knowledge of who is fully eligible and who need to be given alternatives will be so beneficial!

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  9. What's not clear is the definition of poor depletion. I was just about 0 for both infusions, but not 0.0. Could it be classified as poor depletion or not?

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