Wednesday, 1 February 2017

What maybe the long term effect of alemtuzumab in MS...lets look at arthritis

What happens in the long-term after alemtuzumab. The simple answer is that we do not know?


Based on the long-term Cambridge data there are a few people that have converted to SPMS, and according to ProfC from Cambridge these people tended to be those who started DMT later in their disease course and those that showed less responsive to treatment.

CAMPATH-1H was tried in a miriad of conditions before the two Cs from Cambridge tried it in MS.

In this report, the study looks at the bloods 20 years after alemtuzumab and it is clear that the cells numbers in the bloods do not revert back to normal. The immune output of cells relates to bone marrow and thymic output and with age these drop. Compared with controls the alemtuzumab cohort had significantly reduced CD4+ and CD8+ central memory T-cells, CD5+ B cells, naïve B cells and CD19+CD24hiCD38hi transitional (putative regulatory) B cells.

Compilation of the primary causes of death from the entire cohort from 1994 to 2015 showed overall 37 of the original 53 patients who received alemtuzumab had died. The predominant causes of death were cardiovascular/atherosclerotic (n = 12), infection (n = 11), and malignancy (n = 8). Other causes were non-malignant gastrointestinal tract perforation (n = 2), pulmonary fibrosis (n = 1), dementia (n = 1), upper gastrointestinal bleed (n = 1) and primary sclerosing cholangitis (n = 1).

It is evident that once you have alemtuzumab your white cell profile changes for ever. This in part because as you age your thymus where T cells are educated, atrophies. So once you deplete after this the immune machinery is not working the same as it was before. In the animals too, after imune depletion the  cell levels dont return in the same way. However this is also part of the re-booting process, that helps alemtuzumab switch off MS

Immune reconstitution 20 years after treatment with alemtuzumab in a rheumatoid arthritis cohort: implications for lymphocyte depleting therapies.Cooles FA, Anderson AE, Drayton T, Harry RA, Diboll J, Munro L, Thalayasingham N, Östör AJ, Isaacs JD. Arthritis Res Ther. 2016 0;18(1):302

BACKGROUND:Alemtuzumab, an anti-CD52 monoclonal antibody, was administered to patients with RA between 1991 and 1994. We have followed a cohort of recipients since that time and previously reported significant delays in immune reconstitution. Here we report >20 years of follow-up data from this unique cohort.
METHOD:Surviving alemtuzumab recipients were age, sex and disease duration matched with RA controls. Updated mortality and morbidity data were collected for alemtuzumab recipients. For both groups antigenic responses were assessed following influenza, Pneumovax II and combined diphtheria/tetanus/poliovirus vaccines. Circulating cytokines and lymphocyte subsets were also quantified.
RESULTS:Of 16 surviving alemtuzumab recipients, 13 were recruited: 9 recipients underwent a full clinical assessment and 4 had case notes review only. Since our last review 10 patients had died from causes of death consistent with long-standing RA, and no suggestion of compromised immune function. Compared with controls the alemtuzumab cohort had significantly reduced CD4+ and CD8+ central memory T-cells, CD5+ B cells, naïve B cells and CD19+CD24hiCD38hi transitional (putative regulatory) B cells. Nonetheless vaccine responses were comparable between groups. There were significantly higher serum IL-15 and IFN-γ levels in the alemtuzumab cohort. IL-15 levels were inversely associated wth CD4+ total memory and central memory T cells.
CONCLUSION: After 20 years the immune system of alemtuzumab recipients continues to show differences from disease controls. Nonetheless mortality and morbidity data, alongside vaccination responses, do not suggest clinical immune compromise. As lymphodepleting therapies, including alemtuzumab, continue to be administered this work is important with regard to long-term immune monitoring and stages of immune recovery.

14 comments:

  1. > overall 37 of the original 53 patients who received alemtuzumab had died
    > malignancy (n = 8)

    soo nice

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  2. If we look at the long term alemtuzumab data published from the Cardiff group (Willis et AL) the occurance of a cancer was 10 percent.

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  3. Cancer causes 25% of all deaths in the UK. In this study, 8 deaths from malignancy out of 37 is 22%, slightly lower than the national stats, so not too bad, really!

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    1. Thanks for this input, we need to keep the stats in prespective

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    2. but aren't people 20 years after taking lemtrada slightly younger than the 25% stat (i suspect) loaded with people who die from cancer in the old age?

      if we are going to compare, than surely it's nice to compare apples with apples :)

      76% of women diagnosed with breast cancer in aus are diagnosed at 50 plus... 5.2% at ages 30 to 39 and less than 1% at ages 20 to 29.... (this was great comfort when my partner was diagnosed at age 31 lol... initially misdiagnosed by her then breast surgeon on account of it being unlikely at her age lol)

      speaking of which, anyone know how old were the people diagnosed with breast cancers in the ocrelzumab studies?

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  4. Does this long term compromised immune function put JC virus patients at a higher risk of PML?

    Emily

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    1. There is no evidence of increased risk of PML of people taking alemtuzumab, indeed as the drug is out of your system pretty quickly there is nothing to stop you immune system fighting viruses. CD8 cells return to normal within about 6 months so they can fight virus

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  5. how is this theoretically different to continued immunosuppression associated with ongoing (for an undefined period of time) rituximab and ocrelizumab treatments?

    i know the concept of induction v maintenance treatment... but can you tell what's 'better' safety wise? 'reconstituted" system post induction treatment or ongoing immuno suppression associated with non induction therapy such as rituximab or ocrelizumab?

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  6. Although the horse had bolted - have already had my first course of Alemtuzumab infusions, I am increasingly keen to see the guest post answering the 23 questions listed by ProfG at the beginning of Dec '16, especially in view of the above conclusion, and the opening statement that we don't know what happens long term after Alemtuzumab.
    Any chance the guest might also address the potential strategies for the prevention of secondary autoimmunity post Alemtuzumab, such as the question of the overshoot of B cells.

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    1. We will try and address the issue of secondary autoimmunity cause and potential treatment soon

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  7. Thanks for the reply. Alongside the reassurance from MD2 in December, and ProfG saying the questions he'd raised will be addressed, it gives me some additional peace-of-mind. As mentioned before, I thought I'd made an informed decision to have Alemtuzumab, but from my on-going access to the Blog, I've got so much more appreciation of just how complex the world of MS and DMTs is! Having as much as possible clarified and pinned down will, I feel, enhance my capacity to engage with the next stages of this new world I occupy.

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  8. What was the dosing like for RA with alemtuzumab? Was it similar to that that's given for MS?

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    1. It didn't say the cancer dose is higher than the MS dose

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