Sunday, 20 September 2015

ClinicSpeak: is rebound activity post-natalizumab real or not?

We take rebound post-natalizumab very seriously. #MSBlog #MSReasearch #ClinicSpeak

"Earlier this week I saw an unfortunate young woman with a spinal cord relapse post-natalizumab. She had rapidly-evolving severe MS and had done very well on natalizumab (NEDA) for ~2 years. Despite being JCV seronegative her neurologist switched her to DMF (Tecfidera) on the grounds that he was worried about her being on natalizumab long-term. This young lady was very anxious and concerned about whether or not she would make a full recovery from the relapse. I suspect she will make a good recovery as she is young and was fully functional prior to the relapse; i.e. she has good functional reserve. As the relapse was impacting on her mobility and she had bothersome sensory symptoms I treated her with high-dose oral steroids (500 mg methylprednisolone x 5 days). This is another relapse that could have been prevented."

“I have recently been taken to task on whether or not rebound of MS disease activity post-natalizumab is a real phenomenon, or simply a ‘statistical artefact’. One commentator used the oft-quoted paper below (O'Connor et al.) and refers to the conclusion as evidence that rebound does not occur: ‘a rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted’. The problem with this statement is that it assumes, and defines, rebound as disease activity beyond placebo-treated levels. I personally disagree with this statement and prefer to define rebound according to the English definition of the word."


rebound (verb) = recover in value, amount, or strength after a decrease or decline

"In the context of natalizumab withdrawal rebound is simple the occurrence of disease activity when the mode of action of the drug wears off. Whether or not this is more, or less, than some arbitrary figure is irrelevant. One lesion in a strategic location is potentially enough to cause a devastating relapse and can even cause death. This is why we go to a lot of trouble to prevent rebound when stopping natalizumab. In the study below comparing the level of activity to that which occurred in the placebo treated group is fraught with difficulties. Firstly, the placebo treated figures are from an earlier epoch. We know that disease activity regresses to the mean; i.e. goes down with time making this comparison difficult."


"Any analysis that looks at rebound should not include the initial 3 months post-natalizumab when the drug is still on board and working. As you can see from the slide show that there is very little rebound activity in months 1, 2 and 3. However, in month 4, 5 and 6 and beyond there is a clear signal of rebound disease activity. Rebound coincides with desaturation of the VLA-4 antigen on the surface of lymphocytes and their retrafficking into the brain and spinal cord. You would anticipate a similar thing with fingolimod; fingolimod traps disease causing lymphocytes in lymph nodes. When fingolimod is stopped and washed out of the system these lymphocytes migrate from the lymph nodes and retraffick to the brain and spinal cord and trigger focal inflammatory events. The difference between fingolimod and natalizumab is the timing; on stopping treatment fingolimod levels drop earlier than natalizumab and hence you would expect rebound to occur earlier, which has been the observation to date. The observation that most DMTs, with the exception of fingolimod, are not effective in preventing post-natalizumab rebound is interesting. I suspect this is due to fingolimod's mode of action; trapping lymphocytes in lymph nodes prevents reconstitution of immune surveillance to the central nervous system and prevents rebound. However, for fingolimod to prevent rebound it needs to be started before natalizumab has time be cleared from the system. This is why we start it within 4 weeks of the last natalizumab infusion."

"I hope I have convinced you; rebound is not a statistical artifact but a real phenomenon with consequences. If you don't believe me read the literature or come and meet some of my patients who have suffered the consequences of rebound."

Rebound:

O'Connor et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011 May 31;76(22):1858-65.

BACKGROUND: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies.

OBJECTIVES: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS.

METHODS: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumabdosing that occurred in February 2005. 

RESULTS: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted.

CONCLUSIONS: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.

Preventing rebound:

Kappos et al. Switching from natalizumab to fingolimod: A randomized, placebo-controlled study in RRMS. Neurology. 2015 Jul 7;85(1):29-39. 

OBJECTIVE: To investigate the effect of different natalizumab washout (WO) periods on recurrence of MRI and clinical disease activity in patients switching from natalizumab to fingolimod.

METHODS: In this multicenter, double-blind, placebo-controlled trial (TOFINGO), patients with relapsing-remitting multiple sclerosis (RRMS) were randomized 1:1:1 to 8-, 12-, or 16-week WO followed by fingolimod treatment over 32 weeks from last natalizumab infusion (LNI). Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24.

RESULTS: Of 142 enrolled and randomized patients, 112 (78.9%) completed the study (8 weeks, n = 41/50; 12 weeks, n = 31/42; 16 weeks, n = 40/50). Number (95% confidence interval [CI]) of active (new/newly enlarged T2) lesions from LNI through 8 weeks of fingolimod treatment (primary outcome) was similar in the 8-week (2.1 [1.7-2.6]) and 12-week WO groups (1.7 [1.3-2.2]) and higher in the 16-week WO group (8.2 [7.3-9.1]). During the WO period only, the number (95% CI) of active lesions increased with increasing WO duration (8 weeks, 0.4 [0.2-0.6]; 12 weeks, 2.1 [1.6-2.6]; 16 weeks, 3.6 [3.0-4.2]). Over the 24 weeks from LNI, gadolinium-enhancing T1 lesion counts were lower in the 8-week WO group (14.1 [5.67-22.53]) than in the 12-week (21.3 [1.41-41.19]) or 16-week (18.5 [8.40-28.60]) WO groups. More patients were relapse-free in the 8-week (88%) and 12-week (91%) WO groups than the 16-week WO group (84%). Sixty-eight percent of patients experienced adverse events (mostly mild/moderate), with similar incidence across groups. No unusually severe relapses or opportunistic infections occurred.

CONCLUSIONS: Initiating fingolimod therapy 8-12 weeks after natalizumab discontinuation is associated with a lower risk of MRI and clinical disease reactivation than initiation after 16-week WO.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS switching from natalizumab to fingolimod, shorter natalizumab WO periods are associated with less MRI disease activity than are longer WO periods.


CoI: multiple

19 comments:

  1. So called Multiple Sclerosis (MS) is an unproven autoimmune THEORY based solely on symptoms. Many feel and know so called MS is a mechanical issue no drug treatment or therapy can solely rectify !

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  2. I made the comment on the previous post, suggesting that post-natalizumab rebound might be a statistical artifact. If rebound is only defined as a return to pre-natalizumab disease activity, then I agree, rebound is real: all of the evidence suggests that it is. But there are two things to note:

    -By this definition, every non-induction treatment is associated with rebound activity after cessation of treatment. If post-interferon disease activity returns to pre-interferon disease activity (which it does), then there is post-interferon rebound. There is nothing distinctive about post-natalizumab rebound.

    -In the previous post, you were using post-natalizumab rebound as evidence for a theory of the disease: that there is a pathogen in the CNS which is being attacked by the immune system. If rebound is only defined as a return to pre-treatment disease activity, then it provides no evidence for this disease mechanism. Rebound would also be predicted by an autoimmune theory of MS, no pathogen is needed.

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    1. Re: "By this definition, every non-induction treatment is associated with rebound activity after cessation of treatment."

      That is correct. But about 1 in 10 patients the rebound post-natalizumab (and probably fingolimod) is pseudotumoral (massive lesions) or malignant (15+ active lesions). Almost all MSologists talk about these cases amongst ourselves and many have now been published in the literature. You rarely see this when other maintenance treatments are stopped. There is something special about anti-trafficking therapies; this is why we take the issue so seriously and try and prevent it. I have two patients who had been left pretty disabled from rebound. One from a frontal pseudotumoral lesion; he has a major personality change and disinhibited behaviour. He is simply not the same person he was prior to the relapse. The second is a young woman who had a cervical cord lesion; she now has permanent bladder dysfunction and walking difficulties. Tragically for her and her husband she came off natalizumab to start a family; they have now decided to not have a family. Discussing data is fine, but there are real and personal consequences to rebound.

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    2. What does the 1 in 10 figure represent? The probability of having a malignant relapse, among all patients who stop natalizumab? Or the probability of having a malignant relapse, among patients who have post-natalizumab rebound?

      If it's the latter probability, maybe that's right, that's a difficult quantity to estimate due to data sparsity. But if it's the former probability, that's a very strong claim, and not one that I've seen supported in the literature. I understand that there are some small case series which are compatible with this figure. But these case series were published precisely because they were exceptional, and this figure hasn't been borne out in later studies.

      Some patients have malignant relapses post-natalizumab. But the critical question is, what would have been the rate of malignant relapses in this population if they had never taken natalizumab? Patients taking natalizumab are selected for especially severe disease activity. Among this population, how often did you see such relapses pre-2004? One in every 20 patient years? The figure would need to be considerably lower than this (maybe even smaller than one in 100?) to be clearly incompatible with the observed malignant relapse rate post-natalizumab.

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    3. data sparsity is the name of the game,incredibly useful to Biojen Idec. How many deaths are going unrecorded ? I have one, 20 weeks post cessation of Tysabri due to infection. How many more ? keep it real like the good Doc says. People can't get off this shite alive.

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    4. sorry we massively screwed up

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  3. Same commenter. I've been thinking about this more, and as someone who's actually taking natalizumab, I can tell you: it does matter whether rebound means an increase of disease activity, or just a return in disease activity. This is particularly true for people who start natalizumab with low ARR and low EDSS. Suppose that I was contraindicated for fingolimod (or that it was unavailable for some other reason), and was contemplating whether to start natalizumab, knowing that I would eventually need to stop it. I might be willing to return to my pre-natalizumab disease activity, but not to a disease level which may be greatly increased.

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    1. RE: "increase of disease activity, or just a return in disease activity."

      I am not sure this is a quantitative issue, but a qualitative issue. What you should be concerned about is where the disease activity occurs. Optic nerve = visual loss; Spinal cord = paralysis, bladder, bowel and sexual dysfunction; Cortex = cognition etc.; Brainstem = double vision, incoordination, swallowing problems, etc.

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    2. Re: "What you should be concerned about is where the disease activity occurs."

      I agree. Is there any evidence that natalizumab cessation changes the distribution on lesion location? That would be very interesting if true. If not, then the question is still the quantitative one, does stopping natalizumab increase disease activity over the pre-natalizumab baseline?

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    3. Re: "Is there any evidence that natalizumab cessation changes the distribution on lesion location?"

      Not sure as a lot of lesions are microscopic. Our one patient had a low lesion load (< 10) and when she had rebound she had about 80 active lesions. I refer to scan as looking like a Christmas Tree; lit up with lights.

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    4. How many patients have you taken off natalizumab without immediately transitioning to a comparably effective treatment? How many of those patients have had a rebound effect? Did you ever see Christmas Tree MRIs pre-2004? Sorry to keep banging on about this, but I'm genuinely curious about your clinical experiences with rapidly evolving severe MS pre-2004.

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  4. Rebound post-natalizumab is so predictable that one Pharma company is now using this to do a clinical trial. In fact, stopping natalizumab is such a good predictor of relapse that it allows you to do smaller trials than recruiting study subjects from the general MS population and waiting for them to become active. In the TOFINGO study over 60% of MSers became active after a 16 week washout.

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    Replies
    1. What do you do when a person has a diagnosis of SPMS and wants to come off Tysabri
      (JC-, 33 infusions)? Since there is no current medication for SPMS. Just treat with steroids?
      I'm scared , death or disability from PML, or death and disability from MS. I wish I had never started the poison.

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    2. I believe there are postings on this blog about stopping Tysabri with a reasonably safe transition to a different, efficacious DMT. Cross fingers re Ocreluzimab, Biotin, etc.

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  5. Prof Giovannoni, you have developed a "strategy" for monitoring the state of patients under Natalizumab. Are the consequences of stopping fingolimod in equal proportions, and whether there are similar rules, at least in your clinic, for follow-up of patients on fingolimod.

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    Replies
    1. Re: "Are the consequences of stopping fingolimod in equal proportions..."

      The answer is probably yes, but as we don't have much experience yet with fingolimod there are fewer publications.

      1: De Masi R, Accoto S, Orlando S, De Blasi V, Pasca S, Scarpello R, Spagnolo L,
      Idolo A, De Donno A. Dramatic recovery of steroid-refractory relapsed multiple
      sclerosis following Fingolimod discontinuation using selective immune adsorption.
      BMC Neurol. 2015 Jul 31;15:125. doi: 10.1186/s12883-015-0377-2. PubMed PMID:
      26227815; PubMed Central PMCID: PMC4521477.


      2: Cavone L, Felici R, Lapucci A, Buonvicino D, Pratesi S, Muzzi M, Hakiki B,
      Maggi L, Peruzzi B, Caporale R, Annunziato F, Amato MP, Chiarugi A. Dysregulation
      of sphingosine 1 phosphate receptor-1 (S1P1) signaling and regulatory
      lymphocyte-dependent immunosuppression in a model of post-fingolimod MS rebound.
      Brain Behav Immun. 2015 Jun 27. pii: S0889-1591(15)00172-5. doi:
      10.1016/j.bbi.2015.06.019. [Epub ahead of print] PubMed PMID: 26130058.


      3: Berger B, Baumgartner A, Rauer S, Mader I, Luetzen N, Farenkopf U, Stich O.
      Severe disease reactivation in four patients with relapsing-remitting multiple
      sclerosis after fingolimod cessation. J Neuroimmunol. 2015 May 15;282:118-22.
      doi: 10.1016/j.jneuroim.2015.03.022. Epub 2015 Apr 7. PubMed PMID: 25903738.


      4: Alroughani R, Almulla A, Lamdhade S, Thussu A. Multiple sclerosis reactivation
      postfingolimod cessation: is it IRIS? BMJ Case Rep. 2014 Oct 15;2014. pii:
      bcr2014206314. doi: 10.1136/bcr-2014-206314. PubMed PMID: 25320259.


      5: La Mantia L, Prone V, Marazzi MR, Erminio C, Protti A. Multiple sclerosis
      rebound after fingolimod discontinuation for lymphopenia. Neurol Sci. 2014
      Sep;35(9):1485-6. doi: 10.1007/s10072-014-1800-y. Epub 2014 Apr 23. PubMed PMID:
      24756193.


      6: Sempere AP, Berenguer-Ruiz L, Feliu-Rey E. Rebound of disease activity during
      pregnancy after withdrawal of fingolimod. Eur J Neurol. 2013 Aug;20(8):e109-10.
      doi: 10.1111/ene.12195. PubMed PMID: 23829238.


      7: Beran RG, Hegazi Y, Schwartz RS, Cordato DJ. Rebound exacerbation multiple
      sclerosis following cessation of oral treatment. Mult Scler Relat Disord. 2013
      Jul;2(3):252-5. doi: 10.1016/j.msard.2012.11.001. Epub 2012 Dec 21. PubMed PMID:
      25877732.


      8: Piscolla E, Hakiki B, Pastò L, Razzolini L, Portaccio E, Amato MP. Rebound
      after Fingolimod suspension in a pediatric-onset multiple sclerosis patient. J
      Neurol. 2013 Jun;260(6):1675-7. doi: 10.1007/s00415-013-6933-z. Epub 2013 May 5.
      PubMed PMID: 23645219.


      9: Gross CM, Baumgartner A, Rauer S, Stich O. Multiple sclerosis rebound
      following herpes zoster infection and suspension of fingolimod. Neurology. 2012
      Nov 6;79(19):2006-7. doi: 10.1212/WNL.0b013e3182735d24. Epub 2012 Oct 3. PubMed
      PMID: 23035074.


      10: Hakiki B, Portaccio E, Giannini M, Razzolini L, Pastò L, Amato MP. Withdrawal
      of fingolimod treatment for relapsing-remitting multiple sclerosis: report of six
      cases. Mult Scler. 2012 Nov;18(11):1636-9. doi: 10.1177/1352458512454773. Epub
      2012 Jul 24. PubMed PMID: 22829326.


      11: Havla JB, Pellkofer HL, Meinl I, Gerdes LA, Hohlfeld R, Kümpfel T. Rebound of
      disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol.
      2012 Feb;69(2):262-4. doi: 10.1001/archneurol.2011.1057. PubMed PMID: 22332194.

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    2. Is it possible to prevent rebound after stopping fingolimod? Fingo helps with post-Tysabri rebound, what would help with post-fingo rebound?

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  6. Where do you get a 500mg oral methylprednisolone? I 5ink in the US the highest dose is 40mg. That would be a lot of pills.

    ReplyDelete
    Replies
    1. Re: "Where do you get a 500mg oral methylprednisolone?"

      We prescribe the 5 x 100mg tablets. http://www.medicines.org.uk/guides/Methylprednisolone/anaemia%20(all%20types)

      Delete

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