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