Saturday, 24 May 2014

Alemtuzumab: long-term follow-up for up to 12 years

Long-term follow-up of alemtuzumab-treated MSers. Is it as good as it says on the vial? #MSBlog #MSResearch

"The abstract below summarises the long-term follow-up of the alemtuzumab-treated MSers in Cambridge. Please note these MSers had highly-active disease and were treated as part of an open-label compassionate use programme. On average this group of MSers would be expected to do poorly and would almost certainly end-up on natalizumab treatment in the current NHS environment. It is remarkable that just over half of the treated MSers were rendered NEDA after two courses. Please note that some of this cohort have reached 12 years of follow-up; this is too early to say whether or not they been cured of their disease. 48% of MSers needed more than two courses. Only one MSer required 5 cycles of treatment; this suggests that almost all MSers treated with alemtuzumab respond to this treatment given sufficient cycles of alemtuzumab. We will need to wait to see if the open-label extension study of the phase 2 & 3 programme confirms these results."

"Overall 60% of MSers had a stabilization or improvement in their disability. It will be important to find out what happens to markers of disease activity that reflect deeper layers of the iceberg; those beneath the water. Has the rate of brain atrophy in this group been normalised? Do they have normal spinal fluid neurofilament levels? Are the cognitively stable? What has happened to their quality of life? I would be very interested to know in those that have been followed up for 10 years or more and have NEDA if they have lost their oligoclonal IgG bands in their CSF."


"Please note that almost 50% of treated MSers developed secondary autoimmunity as a consequence of alemtuzumab treatment; a stark reminder that a decision to be treated with alemtuzumab needs to be taken seriously and that you need to highly motivated and adherent with the strict monitoring programme to detect these complications."

Epub: Tuohy et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2014 May 21. pii: jnnp-2014-307721. doi: 10.1136/jnnp-2014-307721.

OBJECTIVES: Alemtuzumab is a newly licensed treatment of active relapsing-remitting multiple sclerosis (RRMS) in Europe, which in phase II and III studies demonstrated superior efficacy over β-interferon in reducing disability progression over 2-3 years. In this observational cohort study, we sought to describe our longer-term experience of the efficacy and safety of alemtuzumab in active RRMS.

METHODS: Clinical and laboratory data including serial Expanded Disability Status Scale (EDSS) assessments, from all 87 MSers treated with alemtuzumab on investigator-led studies in Cambridge, UK, from 1999 to 2012, were collected. The occurrence of adverse events including secondary autoimmunity, malignancy and death, and pregnancy outcomes was recorded. Baseline variables including age, disease duration and relapse rate were compared in univariate and logistic regression analyses between groups with different disability outcomes.

RESULTS: Over a median 7-year follow-up (range 33-144 months), most MSers (52%) required just two cycles of alemtuzumab. In the remaining MSers, relapses triggered re-treatment to a total of three cycles (36%), four cycles (8%) or five cycles (1%). Using a 6-month sustained accumulation of disability definition, 59/87 (67.8%) of MSers had an improved or unchanged disability compared with baseline. By an area under the curve analysis, 52/87 (59.8%) MSers had an overall improvement or stabilisation of disability. Higher baseline relapse rate was associated with worse long-term disability outcomes, with trends for longer disease duration and older age at first treatment. Secondary autoimmunity was the most frequent adverse event occurring in 41/86 (47.7%) MSers, most commonly involving the thyroid gland.

CONCLUSIONS: Alemtuzumab is associated with disease stabilisation in the majority of MSers with highly active RRMS over an average seven-year follow-up. No new safety concerns arose over this extended follow-up.

CoI: multiple

13 comments:

  1. Impressive results given these were MSers with highly acive disease. I would have like to have seen info on the number who became SPMS and more info on those who got worse i.e. How much worse did they get.

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    1. Re: "number who became SPMS"

      'Four alemtuzumab-treated patients (5%) fulfilled the definition of secondary progression.'

      In the pre-DMT era the median time to onset of SPMS was ~10.8 years from disease onset (London Ontario Data). The average disease duration on entry to this study was 36 months and average follow-up of 86.1 months on study; i.e. at the end of the observation period the average disease duration was 122.1 months or over 10 years. In the pre-DMT era more than 50% of these subjects should have been in the secondary progressive phase of the disease at 10 years, not 5%. The 50% is a conservative estimate as the MSers in this study had highly-active MS and would on average have had a poorer prognosis.

      Please note that there is no comparison group hence comparing them with a natural history cohort is probably not appropriate, but is the best we have.

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    2. Baased on presentations made I know that Dr Coles had a more contemporary comparison group. The referees appeared not accept it in the publication and he mentioned that the progressors tended to start treatment later and had more aggressive disease.

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  2. "I would be very interested to know in those that have been followed up for 10 years or more and have NEDA if they have lost their oligoclonal IgG bands in their CSF."

    Even those who undergo HSCT do not lose their ologoclonal bands. This is thought to be because these bands are caused by long lived b cells which cannot be eliminated with even the most aggressive immunosuppressive therapy.

    The reality is that if you have NEDA but still have ologoclonal bands after an immune system reset, something else happened to your immune system other than eliminating auto reactive components of the immune system. Restoration of Treg function is probably responsible for this as has been indicated after HSCT therapy.

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    1. So you reason that Alem does nothing for the B-cells? I thought it eliminates both T-cells and B-cells? Please clarify.

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    2. In a study we have published looking in the short-term (3 years) OCBs did not disappear post-alemtuzumab. But after 10 years of treatment is a different question. Interestingly, a large proportion of MSers treated with natalizumab lose their OCBs so it looks as if long-lived B cells and plasma cells may not be so long-lived.

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    3. Regarding B cells. Yes, alemtuzumab depletes B cells and they rebound very quickly. The cells that come back may not be the same cells that were present before alemtuzumab.

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  3. Prof G,
    Did they assess MRI activity in this follow-up? What is proportion of activity-free patients?
    Thanks.

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  4. Re: "Did they assess MRI activity in this follow-up? "

    Yes, but not in all subjects. The MRI data was not included in this paper. I suspect they will discuss that in a future publication.

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    Replies
    1. I got the full text already but thanks anyway.
      The progression charts are not so impressive ... do you still think that those people have flat-lined?
      For my naive eyes looks like they are not..

      Regards.

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    2. Hm.. but Sustained improvers looks like they do... but they are less than 52%..

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    3. Remember to add the stable to the improvers

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  5. Prof G,

    do you think around 50% will turn out to be the true rate of auto-immunity from alemtuzumab?

    Is there anything to suggest that this was a higher rate over the same time perior as in the phase 3 alemtuzumab studies?

    If it was a higher rate, is there a reason? Did this group have more active disease, for instance, and somehow that group gets more auto-immunity?

    thanks as always.

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