Saturday, 16 August 2014

ClinicSpeak: secondary autoimmunity post-alemtuzumab

Secondary autoimmunity occurs in ~50% of MSers treated with alemtuzumab. #ClinicSpeak #MSBlog #MSResearch

"The following post is in response to yesterday's ClinicSpeak post on natalizumab vs. alemtuzumab and the question about secondary autoimmunity post-alemtuzumab."

"The abstract below summarises the long-term follow-up of the alemtuzumab-treated MSers in Cambridge. Overall they do very well; 60% of MSers had a stabilization or improvement in their disability. 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."

The following are some excerpts from the paper in relation to secondary autoimmunity:

....Clinical autoimmune disease developed in 41 patients (48%, omitting one patient with pre-existing thyroid disease); a further 12 (14%) patients developed sustained novel autoantibodies (9 anti-nuclear antibodies and 3 anti-thyroid peroxidase antibodies) with no evidence of associated clinical disease....

..... This occurred a median of 16 months since last treatment ... 

.... Autoimmunity was not associated with the number of alemtuzumab treatment cycles administered....

..... Thyroid autoimmunity developed in 41% of whom 63% had hyperthyroidism (Graves’ disease); 1 patient had transient thyroiditis, and 34% developed primary hypothyroidism with positive antithyroid peroxidase antibodies... 

... Most patients were treated medically; three with Graves’ disease also required radio-iodine treatment..... 

..... Three patients (3.5%) developed immune thrombocytopenic purpura (ITP).... 

..... Asymptomatic autoimmune neutropenia developed in a single patient 3 months after her second alemtuzumab cycle....

..... One patient developed autoimmune haemolytic anaemia, which was detected on full blood count monitoring.. 

.... One patient developed Goodpasture’s disease requiring renal  transplantation.... 

"In addition to these cases I am aware of a patient developing bullous skin disease (bullous pemphigoid) post-alemtuzumab. Based on the spectrum of secondary autoimmune diseases that are seen in the bone marrow transplant setting, I predict that we will see thrombotic thrombocytopenic purpura (TTP), which is also a severe potentially life-threatening antibody mediated autoimmune disease of clotting, myasthenia gravis and others; however, these will be very rare."

"In conclusion, although secondary autoimmunity post alemtuzumab is common, the majority will be related to the thyroid and relatively easy  to manage. The rarer potentially life-threatening autoimmune diseases will be detected with screening and if treated early should be a manageable risk. Please let me know if you need any other information."

ITP

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. The long term study results are nearly the same as the extension study for Copaxone:

    http://www.ncbi.nlm.nih.gov/pubmed/20106943

    The only difference is the wonder drug Alemtuzumab gives you a 50% chance for secondary autoimmunity. I see why this is being marketed as a "highly effective" therapy (not).

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    1. One very important thing to note is that paper describes open label usage of glatiramer acetate, which means patients were self-selecting onto or away from the medications. In the extreme, it's possible that everyone with a naturally worse disease progression moved off the drug to find more effective medications and everyone with naturally slow disease progression stayed on Copaxone since they weren't getting worse. I believe Copaxone probably did modify the disease course, but the question is was it responsible for 10% of the benefit? 90%? We unfortunately do not know.

      However, alemtuzumab is being tested in true randomized placebo trials (to my knowledge), which makes the results significantly stronger.

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    2. The alemtuzumab long term data are based on observational results they are not placebo controlled. It would be problematic as well as unethical to have a longterm placebo controlled trial.

      The Copaxone paper is an extension trial of the original pivotal trial looking at those who were on Copaxone for 15 years continuously. This dose not guarantee that the patients were truly on a single agent (Copaxone) for the whole time.

      Likewise, in the alemtuzumab observational data, there is no guarantee that the subjects did not seek other treatments for the length of the study (7 years on average).

      Delete
  2. Thank you, this is a nice summary.
    It is almost like hypothetical trading of MS ( choose 1 or 2 options :-) for Graves, hypothyroidism, ITP, GBM antibody mediated disease or ANA ( sustained ANA = possibility of SLE further down the line or maybe nothing - like in patients on TNF alpha inhibitors who get ANA, but usually without any more trouble).

    Hmmmm...
    On the positive side... maybe a remission, maybe not... then re-treatment. And we don't know if it will stop conversion to progressive MS, although we hope it will.

    This is getting seriously difficult.

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    1. Re: "And we don't know if it will stop conversion to progressive MS, although we hope it will."

      Only 4 of 87 subjects (5%) developed secondary progressive MS. Based on the baseline characteristics and disease duration one who have expected 40-50% of the MSers in this study to have become SP in this time frame.

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  3. I have a conflict of interest as received my first infusion of Alemtuzumab 7 years ago and the second 6 years ago. No relapses since 1st infusion. Did get Graves but take tiny thyroxine tablet every day. Had highly active RRMS and told that if I had not received the treatment would have become very disabled. Very disabled to me = suicide. So Alemtuzumab kept me a live. Secondary autoimmunity needs to be put in context - can it be detected early? Can it be treated effectively? MS is one of the worse so called autoimune disease if left untreated - we need to keep this in mind. Remember the average reduction in life years with MS is 10! The long term Alemtuzumab results are impressive, but I'd like to know the outcomes for the 40 per cent who didn't improve or stabilise. How bad did they get?

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    1. Re: "The long term Alemtuzumab results are impressive, but I'd like to know the outcomes for the 40 per cent who didn't improve or stabilise. How bad did they get?"

      They haven't done that badly either. Only 4 of 87 subjects (5%) developed secondary progressive MS. Based on the baseline characteristics and disease duration one who have expected 40-50% of the MSers in this study to have become SP in this time frame.

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  4. "..... Three patients (3.5%) developed immune thrombocytopenic purpura (ITP).... "

    is this 3.5% of all patients or 3.5% of patients who developed secondary auto-immunity ? My understanding is this is a serious and potentially fatal condition.

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    1. Re: "is this 3.5% of all patients or 3.5% of patients who developed secondary auto-immunity ? My understanding is this is a serious and potentially fatal condition."

      48% developed secondary autoimmunity, of which 3.5% developed ITP. Yes, ITP is a potentially fatal condition, which is why we do monthly monitoring to detect it.

      Delete
  5. What about PML risk in alemtuzumab treatment?

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    1. Re: "What about PML risk in alemtuzumab treatment?"

      PML post-alemtuzumab for treating MS will be a low risk.Why? The immune system reconstitutes itself and is able to fight new and old viral infections. Alemtuzumab does not affect immune surveillance.

      In the cancer field there are a number of reports of PML in patients who have been treated with alemtuzumab. However, this situation is very different. The types of cancers are the risk fact, in particular chronic lymphoid leukaemia.

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    2. also the dosage of alemtuzumab in cancer patients is much higher than that used in MSers

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  6. Thank you very much for responding so quickly. Thyroid issues really shouldn't be much of consideration for anyone, however mild or bad their ms. For those of us who are relatively well and whose disease course thus far has been 'mild' the possibility of one of the rarer and more unpleasant autoimmunities is a serious concern. Do we stick to a safer but less effective treatment and live with the sword of Damocles hanging over us or do we plump for the most effective treatment and hope we're not one of the unlucky ones? The prospect of remission (a better word than cure maybe), perhaps even with a bit of recovery as a sweetener is so very, very tantalising. Wish there were more reliable prognostic factors to help us choose. Thank you once again for your blog, it is invaluable.

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