Thursday, 28 August 2014

ClinicSpeak: When to say no to alemtuzumab treatment?

When good intentions turn sour; tipping the risk:benefit scales the wrong way #ClinicSpeak #MSBlog #MSResearch

“When I was a much younger MSologist I recall having to formulate mitoxantrone treatment guidelines for MSers with highly-active MS. At the time we had two competing protocols the monthly Edan protocol, for 6 months, for highly-active MSers who had failed the injectables therapies and the 3 monthly Hartung protocol, for 2 years, for MSers who have active disease with more advanced MS. MSers who were being considered for the 2-year protocol tended to have more advanced MS and tended to be on the cusp of developing secondary progressive MS. One patient taught me how delicately balanced therapeutic decisions can be when using risky therapies such as mitoxantrone in patients with more advanced MS. This particular patient had had a severe spinal relapse and needed a urinary catheter; the intention was this catheter was short-term and would be removed once he had recovered from his relapse. Because his MS was so active I went ahead and prescribed mitoxantrone, which was a mistake. A week later he was admitted urgently to his local hospital with neutropenic (low white blood cell counts) sepsis from a urinary tract infection. He ended up in intensive care unit with septicaemia and septic shock and almost died.”



“The lesson I learned from this unfortunate patient was the urinary catheter had tipped the risk:benefit scale the wrong way. A similar thing may be happening with alemtuzumab. A large number of neurologists that I am meeting across Europe are telling me that they are using Alemtuzumab third-line in patients with advanced MS who sound to me as being on the cusp of  having SPMS. We need to be careful using alemtuzumab in this population. Firstly, the Cambridge group showed almost a decade ago that alemtuzumab is unlikely to make much difference in SPMS, which is why the drug was developed in early RRMS. The baseline criteria for both phase 3 studies targeted early MS (see slide 14 below); disease duration for both studies was low. This is why the European Medicine Agency has given alemtuzumab a liberal 1st-line license; in their opinion the risk:benefit ratio in this population is favourable. At present we don’t know what the risk:benefit ratio is in patients who have had symptomatic MS for more than 10 years and are in the early secondary progressive phase. What we need is controlled phase 3 clinical trials in this phase of the disease to define the benefit:risk ratio. The aim of this study would be to see if alemtuzumab slowed the rate of progression or if there was at therapeutic lag and that MSers did well later on.”

“Why is this issue important? Because a large number of MSers with advanced disease, and/or SPMS, are seeking my opinion regarding alemtuzumab treatment and are going way disappointed, and frustrated, because I won’t agree to treat them with alemtuzumab. In the same way as urinary catheters became a contra-indication to mitoxantrone treatment, clinically progressive MS is a relative contra-indication to alemtuzumab treatment. We simply don’t have data to define whether or not the risks associated with alemtuzumab treatment, the burden of monthly blood & urinary monitoring and the cost of treatment justify the undefined benefits. This is why MSers with advanced MS or SPMS seeking my opinion regarding alemtuzumab treatment need to realise that until I have data to the contrary I will say no to alemtuzumab treatment in this phase of the disease.”





“The following is the paper from Cambridge showing a differential response to alemtuzumab based on disease duration and MS stage.”

Coles et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol. 2006 Jan;253(1):98-108.

Background: From 1991-2002, we treated 58 MSers using the humanised monoclonal antibody, Alemtuzumab, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed.

Results: In both the relapsing-remitting (RR) and secondary progressive (SP) stages of the illness, Alemtuzumab reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of SPMSers, treated with Alemtuzumab 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differentially affected depending on the phase of the disease. SPMSers showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in MSers with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, RRMSers showed an impressive reduction in disability at 6 months after Alemtuzumab (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on-going inflammation in these MSers with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment. 

Conclusion: We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long-term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Alemtuzumab and IFN-beta in the treatment of drug-na├»ve MSers with early, active RRMS.

CoI: multiple

14 comments:

  1. I don't think mitoxantrone-urinary catheter and alemtuzumab-SPML are similar.

    The urinary catheter made mitoxantrone treatment more risky. The benefit was presumably the same.
    SPML does not make alemtuzumab treatment more risky. The risks are the same as for RRMS. It's the benefit that is uncertain

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    1. Not sure I agree with you; it's about the ratio between the risks and the benefits.

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  2. Prof G:

    You mention 10 years as a cutoff point for prescribing Alemtuzumab. Is your decision based on the length of time someone had MS, or just the stage (i.e. clearly identifiable SPMS)? For example, if someone had been diagnosed 12 years ago and just now had a severe relapse, would you prescribe Alemtuzumab?

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    1. The 10 year cut-off is based on disease duration of the CARE-MS 2 study; i.e. all MSers had to be treated within 10 years of disease onset. This is only a guide; the point I am making is the evidence that alemtuzumab has any meaningful effect in MSers with longer disease duration and advanced disability is poor. I am aware that MSers who find themselves in this situation disappointed that they can't be treated, but the risks are not insignificant of being treated with this agent.

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    2. Does that mean your basing your decisions on statistics? I understand not prescribing if disability is poor, but putting a time limit on disease onset seems cruel. This only make me more sceptical about the efficacy of the treatment. Can you imagine what would happen if someone had cancer for a few years and was denied treatment because they had it for too long?

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    3. Re: "Does that mean your basing your decisions on statistics?"

      No;I state that this is only a guide. What the 10 years tells you is we don't have an evidence-base beyond this.

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    4. Your answer to M's question is confusing, are you saying that will prescribe or not?

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    5. Yes, I will prescribe alemtuzumab according to the license for adult patients with active relapsing-remitting MS. WHat I am saying is I won't be prescribing it for people with more advanced MS, i,e, with SPMS. I will however, be asking Genzyme to consider doing a trial in this group of MSers. The survey above is clear in that respondents agree data is needed regarding this groups of MSers.

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  3. Could you say whether trials and prescribing guidance use time since onset or time since diagnosis? They are often different and time of onset is not always clear. Thank you.

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  4. So what do you estimate the percentge of SPMSers that benefit from alemtuzumab? I would say if it is even as low as 10% it might be worth a try if there is nothing in their future but further decline.

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  5. "Do you have any suggestions on how to manage the expectations of SPMSers who want alemtuzumab treatment, but can't have it under the NHS?"

    Here's a stab at an over-simplified analogy. Sometimes when there are problems with a computer, a 'reboot' can help. This flushes out the computer's 'memory' (RAM) and allows its operating system (e.g. Windows, MacOS) to be started up again from scratch.

    Similarly, alemtuzumab 'reboots' the immune system by flushing out white blood cells - simultaneously deleting the 'memory' that resides within the immune system, e.g. that myelin is something that should be attacked. The immune system can then relearn more or less from scratch, with the hope that it will no longer attack myelin following its 'reboot' This doesn't come without risks - the immune system's memory is what allows it to respond quickly to infections that it has seen before, and how it arranges itself on 'startup' is what allows it to refrain from attacking the body's own tissues.

    However, there are some computer problems that a reboot won't fix, for example physical damage to hard drive sectors that will only get worse as the hard drive is used. Likewise, in SPMS the physical damage to the CNS has less of an inflammatory component than in RRMS, and has progressed to the extent that 'rebooting' the immune system is unlikely to yield the benefits that is can in earlier stages of the disease.

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    1. Excellent explanation Heather

      Question to the docs:
      When a CNS has the equivalent of 'physical damage to hard disk sectors'

      Is it possible that the brain will get worse or more worn out if you use the damaged areas?
      Could it be wiser to avoid stressing or overusing the CNS

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  6. Is there a standardised definition of what constitutes 'active' rrms? As in if someone's MS is x in xx months/years ... I ask because in my opinion I have active MS - at least 1 relapse a year for the last 14 years (no dmt or other meds) however I have no EDDS score, and on the surface seem to recover quickly and effectively, but as we know that is far from the reality of MS, my MRIs tell a different story. So in a cost-benefit analysis, for me it would seem a good risk to take but I'm not sure my neurologist would agree so I wonder how much of the decision to treat is objective or subjective.

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    1. This a good point as "Active MS" can mean access to Lemtrada so it is going to be in the definition

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