Wednesday, 6 April 2016

ResearchSpeak: failure of intrathecal anti-CD20 in progressive MS

Can we modify the intrathecal B cell and plasma cell biology? #ResearchSpeak #MSReseach #MSBlog

"The trial below which tested the intrathecal at administration of rituximab (anti-CD20) in progressive MS did not have the desired outcome; CSF biomarkers of tissue damage were unchanged. Why? The problem with the lumbar sac, into which  the rituximab was injected, is that it is actually a dead end, or cul de sac, and the spinal fluid in this compartment is destined to be flushed out of the CNS into the periphery. Therefore very little rituximab if any would get to the brain to target the B cell follicles. If you want to give intrathecal drugs we really need to give them intraventricularly to allow them to circulate to where we want them to go; i.e. into the sulci and around the veins (Virchow-Robin spaces)."


"In collaboration with a group in St Petersburg, Russia, we showed that administering intrathecal rituximab was similar to giving a dose intravenously; it had a greater impact on peripheral blood B cells that it did on B-cells in the spinal fluid. Based on these findings I wouldn't draw too many conclusions about the lack of efficacy of intrathecal anti-CD20 therapy. It is clear that giving it intravenously is sufficient for efficacy in the relapsing phase of the disease. Whether this strategy will be sufficient in the clinically apparent progressive phase of the disease is another story. I suspect we will need dual therapy, i.e. an anti-CD20 and a neuroprotective. Please note there is very little evidence that anti-CD20 clears the CNS of the plasma cell response and the OCBs (oligoclonal bands). The evidence that the OCBs in MS are part of the pathogenesis of MS and if we really want to make a difference to MS in the long-term we need to clear them for the brain, spinal cord and CSF. For the latter we will need a whole new approach to the treatment of MS. We are however, on the case, we are exploring various different treatment options to target the intrathecal plasma cell response."


Komori et al. Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis Ann Clin Transl Neurol. 2016 Feb 1;3(3):166-79.

OBJECTIVE: Inaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low-Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?

METHODS: Patients aged 18-65 years were randomly assigned to rituximab or placebo. Protocol-stipulated interim analysis quantified the efficacy of B-cell depletion.

RESULTS: The efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B-cell-related CSF biomarkers (sCD21 and B-cell activating factor) changed only in the active-treatment arm. While CSF B cells were killed robustly (median -79.71%, P = 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, P < 0.0001). Consequently, the T-cell-specific CSF biomarker sCD27 decreased slightly (-10.97%, P = 0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56(dim) NK cells contribute to decreased efficacy of rituximab in the CNS.

INTERPRETATION: Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS-inflammation targeting monoclonal antibodies.

CoI: multiple

18 comments:

  1. Thank you for the post. Interesting topic but raises lots of questions for me. How long does it take for b cell follicles to develop? Is it their development that triggers/signifies the transition between relapsing and progressive disease? Perhaps this is why current DMTs are ineffective in progressive disease i.e. is it too late once follicles have developed as DMTs have no effect on them? And finally, what is the real evidence that OCBs are involved in the pathogenesis of MS? Why are they seen in other disease too?

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  2. I think it is already evident that only treatment with immunosuppressants will not take positive effects in progressive forms of MS. More than urgent need Neuroprotective ongoing studies evaluating potential neuroprotective associated with potent immunomodulatory/immunosuppressants.

    The clinical trial Proximus has managed to close the ideal number of participants?

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  3. "I suspect we will need dual therapy, i.e. an anti-CD20 and a neuroprotective."

    Something approaching useless in PPMS which may have severe health consequences + a neuroprotective? I'd rather opt for just the neuroprotective - or something else, working on progression in some other (truly effective) way. And I'll hope that the anti-CD20 element is not compulsory!

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  4. Any chance that intraventricular administration would even be a possibility of testing?

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    1. Could we convince you to have a hole drilled in you skull and a needle passed through you brain to get into the ventricles. You baulk at the thought of a lumbar puncture would you do this? When ProfG states the problems of the intrathecal route I ask should why this have been done.

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  5. Prof G,

    Any chance you could do a blog post addressing this - brain infection linked to Alemtuzumab for MS. Why would a history of anorexia have contributed?

    http://www.medpagetoday.com/clinical-context/MultipleSclerosis/57171?xid=nl_mpt_DHE_2016-04-06&eun=g975687d0r

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    1. This a case of a bacterial infection after alemtuzumab Nocardia farcinica and adds to the list of infections that can develop. This is a hazard for alemtuzumab as it depletes your immune system and its job is to protect you from infection.

      If you are anorexic you will be underweight, but when Alemtuzumab is administered its dose is not adjusted by weight you get your 12mg infusion I believe, so if you are 100kg and overweight that is 0.12mg/kg but if you are only 50kg then it is 0.24mg/kg so twice as much drug, so it may be more depleting or hang around for longer.

      This could be the problem for laquinimod being developed the 0.6mg dose dose looks safe but heart attacks occurred at 1.2mg dose so if you were anorexic you could be effectively getting a 1.2mg dose when on 0.6mg because you are small or underweight. This issue may kill the development it is already dead for RRMS will PPMS follow.

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    2. Oh... I had mild hopes for laquinimod, I'm not anorexic, but have no "extra baggage" at 54kg... Could be dodgy then.

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    3. Could something like this also happen with all immunosuppressive drugs or is this unique to lemtrada?

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    4. Thanks MD,
      Why not adjust the dose to body weight?
      So the 'history' of anorexia didn't impact the case, it's more to do with body weight *at the time* of receiving Lemtrada?

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    5. Anorexia can lead to a weakened immune system due to low nutrient levels, so it may have had an impact, though it isn't made clear when the patient was anorexic (ie historical or concurrent with treatment).
      As MD says body weight also impacts on the dose received.

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    6. I'm 50kg and that is borderline underweight for my height, I am not anorexic, but have no padding or spare tyre. I am trying hard to gain weight to help decrease the risk of getting infections and thinking of changing DMT.

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    7. I plucked 50kg out of the air to compare with the 100kg which I plucked out of the air to make calculations easy . The average human is about 70kg half of 70kg would be 35kg. Anorexia is BMI of below 17.5 so if you are 50kg you have normal weight if you are below 5 foot 5 inches (165cm)to be anorexic you would be about 5 foot 8 inches.

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    8. Why not adjust to weight they could do but it means fiddling with the packed product

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  6. it appears cladribine enters the CSF at 20-25% of plasma levels (this is through intact BBB), probably much higher through compromised BBB...so what effect does cladribine have on CNS-resident B cells (particularly the plasma cells)? Is this why it has the durable 4-5 year effect or is it the simple reboot and repopulation patterns in the periphery that do the trick?

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    1. I suspect that it can enter the CNS in significant amounts is important. That it is effective in depleting plasma cells in the periphery suggests it should be equally effective in de-pleting those that might be resident in the CNS.

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    2. We saw this potential too and we are on the case.

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