ECTRIMS2019. ProfB’s hunch is playing out

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Snooze and You Loose….I am sorry to say this is not our work…we were too slow, but you had the idea here first folks.

We (and others to be fair) have made the idea that memory B cells are an important tartget. If true it says something about CD20-depletion. CD20 antibodies are dosed every 6 months because this is how long it takes for the CD19 B cell population to return. However, memory B cells (CD19+, CD27+) stay depleted for about 2 years so you should not need to dose so much. This will then reduce your risks of infections.

It says if we dose every 6 months for most people we are overdosing for relapsing MS. (Click here)

If this is true the logic of monthly dosing with ofatumumab might have been the wrong idea.

ProfG has proposed that we do the ADIOS trial. This would aim to test the question of whether we need to dose so often

ADIOS (MD CLICK HERE) ADaptIve Ocrelizumab dosing Study (profG CLICK HERE

SO Next Week we have ECTRIMS and here is something I have picked out as a taster

  1. Ocrelizumab depletes memory B cells. Yes we have known that rituximab depletes memory B cells for many months, but we did not know the effect of ocrelizumab. Yep it must have got them as we knew CD19 (which contains the memory B cell subsets) are kept at a nadir. Here is the proof
  2. If you dose people with NMO (neuromyelitis optica), an MS-like demyelinating condition that responds to CD20-depletion, when the memory B cells start to recover rather than dosing according to time and giving druh every 6 months, you can maintain efficacy without disease breakthrough. This was first shown in South Korea and then replicated in France. This new study shows that it works and by optimizing this further you can reduce dosing and eliminate relapses further.
  3. Now for the relevant and interesting bit. If you dose to memory B cell numbers in MS, you can maintain efficacy and reduce the number of doses as found in NMO. So supporting what we suggested and saying that ADIOS should work.
  4. And maybe you do not need to keep dosing because CD20 depletion is like alemtuzumab and it is an immune reconstitution therapy with a long-term effect from a short term treatment. Again something that we have suggested.

Want to see the abstracts?

Abstract 1. Ocrelizumab depletes memory B cells

P686 – Effects of Ocrelizumab treatment in peripheral blood leukocyte subsets of Primary Progressive Multiple Sclerosis patientsJ.I. Fernandez Velasco et al.

Introduction: Ocrelizumab is a humanized anti-CD20 antibody approved for the treatment of primary progressive multiple sclerosis (PPMS).
Objective: To identify changes in leukocyte circulating subsets of PPMS patients after six months of Ocrelizumab treatment.
Patients and methods: Multicenter prospective longitudinal study including 43 PPMS patients who initiated Ocrelizumab treatment. Clinical and epidemiological characteristics of the patients at baseline were age: 50.5 (27-63) years [Median (range)]; EDSS score: 5.5 (2.0-8.0); disease duration: 9.4 (1.4-15.4) years; sex: 18/25 (female/male); presence of gadolinium-enhancing lesions: 28.1% of patients.
Peripheral blood mononuclear cells were obtained before and six months after treatment initiation. Regulatory and effector B and T cells and monocytes were identified by their surface antigen expression and their intracellular cytokine profile by flow cytometry. Wilcoxon matched paired tests were used to assess differences between basal and 6 month samples.
Results: Ocrelizumab treatment induced a decrease of total lymphocyte numbers (p=0.005) due to a drastic reduction of B cells (p< 0.0001) including plasmablasts (p=0.04), naïve (p< 0.0001) and memory (p< 0.0001) subsets. It also decreased B cells producing IL10, IL6, GM-CSF and TNFα (p< 0.0001 in all cases). When exploring other immune cell subsets we also observed a decrease of CD56 bright NK cells (p=0.0003) after Ocrelizumab treatment. By contrast, we detected an increase of total monocyte numbers in peripheral blood (p=0.0004), and particularly, of those expressing the checkpoint molecule PD-L1 (p=0.019). We also found an increase in regulatory CD4+ T cells (Treg, p=0.02). However, no differences were observed in CD4+ or CD8+T cells producing IFN-gamma, TNF-alpha, IL-17 and GM-CSF. In addition, after 6 months of Ocrelizumab treatment, we found clear increases in the ratios between Treg and CD4+ T cells producing TNF-alpha (p=0.0076) and GM-CSF (p=0.02) and between Treg and CD8+ T cells producing TNF-alpha (p=0.0016), GM-CSF (p=0.0099) and IFN-gamma (p=0.0047).
Conclusion: Despite the evident effect played by Ocrelizumab in B cells depletion, we observed a clear effect of this drug in other leucocyte subsets, mainly by increasing regulatory T cells and monocytes. In addition, Ocrelizumab induced a tolerogenic bias in the abnormal immune response by increasing the ratio between regulatory and effector T cells (The T cells don’t want to think it is not T cell driven).

2 Depleting memory B cells relates to therapy of an MS-like disease

P1352 – Comparison of two individualized administration schemes of rituximab based on memory B cells monitoring in AQP4 positive disorder P. Durozard et al.

Background: Individualized dosing schedule of rituximab based of memory B-cells count has been demonstrated to be safe and effective for the treatment of patients with AQP4-antibody disorder.
Objective: To compare the efficacy of two different individualized administration schemes of rituximab for the treatment of patients with AQP4-antibody disorder.
Design/Methods: Adult patients with AQP4-antibody disorder treated with rituximabat the Multiple Sclerosis Center of Marseillewere included in a prospective observational study. Patients were treated using an individualized dosing schedule adapted to the biological effect of rituximab monitored by monthly memory B-cells counts. Between January 2012 and August 2016, rituximab re-infusion was performed only when memory B-cells reached 0.05% of the peripheral blood mononuclear cells (“original scheme”). Because relapses occurred after 6 months in several patients, we decided in August 2016 to optimize the protocol. Before 6 months, patients were re-treated if memory B-cells reached the threshold of 0.05%. At 6 months, patients were re-treated regardless of the level of memory B-cells if memory B-cells had not reemerged before (“optimized scheme”). Annual relapse rates were compared between the two administration schemes. Only data of patients treated during at least one year using one of the two schemes were included in the analysis.
Results: Fifteen patients were treated using the “original scheme” during at least one year (mean duration: 28 months (13 – 55)). In these patients mean annual relapse rate was 0.35 (0-1.6). Twenty-nine patients were treated using the “optimized scheme” during at least one year (mean duration 22 months (13 – 25)). In these patients mean annual relapse rate was 0.04 (0-0.7). In patients first treated with the “original scheme” and secondly with the “optimized scheme” (n=15) relapse rate decreased from 0.35 (0-1.6) to 0 (p< 0.001).
Conclusions: Compared to the non-individualized classical 6 months rituximab administration scheme, the present individualized “optimized scheme” enables to detect rapid reemergence of memory B-cells before 6 months without the risk of relapse after 6 months inherent to the individualized “original scheme”.

3.Now the interesting bit. Why is this interesting? Well our Italian Chums have got off their bums and done it, lso I have to say well done to my Dance Partner….last seen by me gyrating in a bar (What happened in Athens, stays in Athens:-). If you dose to memory B cell numbers in MS, you can maintain efficacy and reduce the number of doses.Just like in NMO.

P971 – Tailoring B-cells depleting therapy in MS according to memory B-cells monitoring: a pilot study G. Novi et al.

Background: Phase II and III clinical trials revealed the potent suppressive activity on MRI activity and ARR of CD20 directed antibodies in MS. However, no studies to dissect the optimal infusion regimen (i.e.: the minimum drug dosage associated with maximum re-infusion interval that maintains maximum efficacy) have been performed. Infusion regimens with higher infusion intervals and lower drug dosage might maintain the same efficacy than current (fixed-dose) treatment schedule.
Objectives: To evaluate rituximab (RTX) efficacy using a memory B-cell based reinfusion regimen, with a variable reinfusion cut-off, according to year of treatment. MS activity was assessed as clinical disease activity (annualized relapse rate – ARR) or MRI activity (new Gd+ enhancing lesion or new/enlarging T2 lesions).
Methods: This is an observational, retrospective bicentric study including patients with MS treated with RTX in 2 Italian MS units. All patients were treated with rituximab induction (two-1g-infusion 15 day apart), followed by maintenance infusion at the dosage of 375 mg/m2, according to memory B-cells repopulation. Predefined cut-off values for reinfusion (percentage of memory B cells among peripheral blood PBMC) were: 0.05% for the first two years of treatment, with subsequent doubling for each year of treatment (maximum cutoff at year 6 of 1.6%).
Results: 101 patients were included in the analysis, 32 patients had a relapsing remitting phenotype, while 69 had a progressive phenotype (40 secondary progressive and 29 primary progressive).
Mean FU was 1.75 years (range 0.29-6.56).
ARR was 0.67 (95% Confidence Interval (CI): 0.53-0.85) in the year before RTX start and decreased to 0.02 (95%CI 0.004-0.04) during the whole FU.
Proportion of patient with MS activity (i.e.: relapse or MRI activity) was 73.3% in the year before RTX start and decreased to 15.5% and 3.70% in the two years after RTX initiation.
Annualized RTX infusion rate was 1.70 (95%CI:1.45-1.99), 1.41 (95%CI:1.09-1.80), 0.97 (95%CI:0.62-1.43) and 0.85 (95%CI:0.36-1.64) for the first four years after RTX initiation, respectively.
Conclusions: Results of this study show that memory B cells based RTX reinfusion protocol is able to reduce mean number of RTX reinfusion (and drug dosage) with persistent reduction of disease activity. A memory B cells threshold for disease activity recrudescence could be possibly identified with longer follow-up (and higher reinfusion cut-off).

See the French study above to maybe get the insight.

Good stuff.

4. A long term effect from a short term treatment

P607 – Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; No evidence of rebound disease activityA. Juto, K et al. .

Introduction: Rituximab (RTX) and other anti-CD20 therapies are increasingly used as disease modifying treatments (DMTs) in MS. However, data on reasons to interrupt treatment, alternative DMTs after anti-CD20 therapy and potential rebound disease activity is limited.
Objectives: To determine the rate and cause of RTX treatment interruptions and responses to subsequent DMTs in a large single centre cohort.
Methods: A retrospective observational study of all relapsing-remitting MS (RRMS) patients having received at least one dose of RTX at the Karolinska University Hospital from 2009 to 2018 and having either stopped treatment or had more than one year since last RTX infusion, as identified in the Swedish MS registry with additional data derived from clinical charts.
Results: As of February 2018, we identified 809 patients ever treated with RTX out of 1514 RRMS patients with current or previous DMT, 92 (11%) had terminated RTX; 26 (28%) stopped RTX due to adverse events, 27 (29%) due to pregnancy, 9 (10%) due to stable disease, 23 (25%) for other reasons, and the remaining 7 (8%) due to lack of effect. Of these 92 patients, 34 later restarted RTX, 27 switched DMT, 24 remained without DMT and 7 were lost to follow up. In the group terminating RTX due to lack of effect (n=7), 3 started ofatumumab, 3 had autologous hematopoietic stem cell transplantation and 1 was lost to follow up.
Notably, excluding patients stopping RTX due to lack of effect, only 3 patients had relapses and 4 had new T2 lesions after RTX discontinuation (one of which had both). Gadolinium was administered in 78% of follow up magnetic resonance imaging (MRI) with no enhancing lesions found (mean MRI follow up from RTX discontinuation 29 months, range 7-92 months, n=77).
Conclusions: Findings are consistent with a low rate of RTX interruptions, with adverse events as most frequent reason. A small proportion of patients switched due to breakthrough disease in context of incomplete B-lymphocyte depletion. Signs of ongoing disease activity in the remaining group was low regardless of if a new DMT was started. These findings are consistent with a long acting effect of RTX in RRMS and absence of rebound disease activity phenomena

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16 comments

  • There were 6 deaths associated with infections in the RA phase III trial.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3911947/

    There were 5 deaths associated with serious infections in the Lupus phase III trial.

    http://onlinelibrary.wiley.com/store/10.1002/art.38037/asset/art38037.pdf;jsessionid=56D0FF7FEB5443ABC4858427023012B0.f02t02?v=1&t=iii4zymg&s=224ccbcb77fc96b8b1d4954e810ec703381232a4

    HOW MANY MORE DEATHS of MS participants in the trial would be reported if patients on Ocrelizumab were followed for 5 years?

    • Both of those trials had background lymphocyte inhibitory drugs. RA had methotrexate, Lupus had Mycophenolate mofetil or cyclophosphamide followed by azathioprine. Not that same compared with MS patients.

      • This was NMO yes RA generally has methotrexate, but in the literature there are at least 5 other conditions where this has been done. Proof is is in the pudding. There is enough info to think it is worth doing

        • Methotrexate its bad 🙁
          Methotrexate chemotherapy induces persistent tri-glial dysregulation that underlies chemotherapy-related cognitive impairment

          Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation and a persistent deficit in myelination. OPCs from chemotherapy-naïve mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent upon inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-induced neurological dysfunction. These therapeutic strategies will depend on understanding microglial repopulation dynamics following colony-stimulating factor 1 receptor-mediated depletion. On-going work investigating microglia repopulation after CSF1R inhibition following chemotherapy will be discussed.

          http://www.glia2019.eu/default.asp?s=detailedprogramabstracts

  • A noobie question to start with, to bring us all up to speed:

    If MS is 1 disease (as we are reminded ever so often), and SMPS/PPMS are nothing but later stages, how come Ocrel works in Phase 1 (RRMS) and Phase 3 (PPMS) and not phase II?

    On the same token, how is Siponimod being licensed for Phase II and not Phase III?

    Thanks

    • Pharma have created.three disease ocrelizumab has not been tested in phase II and as for siponimod it will work in phase II and.if they design the trial right they can show an activity in phase I.

      If they do an ocrelizumab trial where there is limited inflammatory activity it will struggle to show an effect on EDSS just like the others

      • Sorry, not sure i follow here:

        “Pharma have created.three disease ocrelizumab has not been tested in phase II “. So Roche is willingly missing out on the SPMS market share that is exponentially larger than PPMS?

        “If they do an ocrelizumab trial where there is limited inflammatory activity it will struggle to show an effect on EDSS just like the others”
        Isn’t PPMS a limited inflammatory stage?

        Or possibly the counter argument has substance (until proof of the contrary), that Phase II and III are biologically different.

  • I am a patient on ocrelizumab. I can’t tell you scientifically what it’s doing but what I can tell you is it helps me feel better and at 5 months post infusion I start to feel worse. By 6 months I feel so lousy I’ve moved my infusions up from 26 to 24 weeks. If you told me I’d have to wait longer you’d have one very unhappy patient. And I know I’m not alone in this, in fact it’s so common many patients have dubbed it the “crap gap”. Perhaps the science will prove you can wait but then how do you tell a patient they have to feel worse for a bit? And how do you explain this very common patient experience when it’s time for another infusion?

    • If you view the way it is done in NMO, it can be more than 6 months for some but likewise less than six months for others…it is personalised. Now if you can link your “crap gap” to you B cells then you have a biomarker so some people repopulate quickly others do not and take years. The “crap gap” as you say happens with other agents for example I know 0f someone who used to refer to their natalizumab as coke…because at about 3 weeks they knew it was time for their next fix at four weeks.

      • Yes! I have often referred to it as knowing it’s time for another fix. I still would love to understand WHY depleting B cells makes old symptoms better too – and why those symptoms start to come back as B cells repopulate. I can tell you that my B cell count is still at O at the 6 month mark but given how I feel I suspect there is the beginnings of repopulation that the blood tests are not yet sensitive enough to detect. Really appreciating this discussion.

    • I was on rituximab for more than 3 years. I never experienced this “crap gap,” but social media groups are quite chatty about its existence, and I absolutely believe it is real. I too would love to know the why someday.

      • What would it mean if CD19 and cd20 levels went from zero to 12 with a reference of ( 3-30) % in a 10 week time frame on ocrevus?
        Context: had ocrevus in May and then in August cd19 and cd20 were close to zero, then 10 weeks later the numbers are at 12?
        Thanks.

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