Today I give thanks…
Many Americans will sit down to watch the football today… Not realising the football is really on tomorrow (friday =World Cup:-)
As the Americans tuck into their turkey, nut roast or what-ever floats their boat, for Thanksgiving, where thanks is given for natural things that they can kill and eat:-). I can only dream of tucking into Christmas pud…a bit of cheese, a slice of turkey and some festive cheer.
However, Christmas has arrived and I have been sent a present from Sweden.
Sometimes you have an idea, you open your big gob and then get a good intellectual kicking as people rush off to prove you and your idea are wrong.
Now one should not think that people proving you wrong is a bad thing, because this is a scientific process. You don’t try to prove stuff you try to disprove it….if you succeed the idea is wrong, but if you fail you try again to disprove it. So far I don’t think the idea has been disproved and this is why I am happy
So a few years ago we made the comment that all MS drugs inhibit the memory B cell response and importantly alemtuzumab and cladribine do the same thing as CD20 depleting antibodies. Therefore, do you need to dose CD20 B cell depleting antibodies every 6 months? Alternatively can you dose for a year (like alemtuzumab and cladribine) and then do a “watch and wait” like alemtuzumab and cladribine as MS is inhibited..
I got the phase II extension data and suggested that you could dose less frequently and still get benefit from ocrelizumab and we also reported that when memory cells are depleted they stay depleted for a long, long time suggesting that you may not have to dose as frequently thus potentially avoiding risk of serious infections and perhaps allowing a drug-free pregnancy. This was retrospective evidence from looking at past studies, but can we do a study looking forward to see we can do the same thing. This is what we call a prospective study.
We planned it with other groups around the UK and then came along COVID-19 and some people started extended dosing intervals (dosing interval longer than 6 months) to increase vaccination potential and avoid COVID-19 risks, meaning it was going to difficult to get people to recruit to studies loking at standard or extened dosingintervals. It is not in the interest of pharma to do these studies after all turkeys don’t vote for Thanksgiving/Christmas. But remember sooner or later you are going to have agents that inhibit progressive MS and pharma will charge top dollar. Anti-inflammatory drugs will come out of patent and you will want them in addition to the protection repair agents. So having an immunomodulator that you dont have to take all the time has merits. So having IRTs (Immune reconstitution therapy) would be useful and I think anti-CD20 depleters are IRTS. The data isn’t clear cut but today we have more evidence.
In Sweden they use a lot of rituximab and here they examine the effect of extending the dosing interval from the standard 6 months to 18 months, in people who were showing a response to rituximab. They looked at people treated at less than 8 month intervals, 8-12 month intervals, 12-18month intervals and more than 18 months intervals and did not find significant differences, so an 18 month delay still gives disease control. B cells repopulated by 12 months, telling me that ocrelizumab is probably a bit more effective and at the dose used as it takes about 14-16 months for ocrelizumab. Memory B cells were depleted for 16 months so again further supporting the data we had teased out from data we had obtained from ocrelizumab trials. This study goes further an indicates that the class switched memory B cells, take 24 months to repopulate
There was no indication that when cells come back, disease comes back and again this doesn’t surprise me there as the cells that come back are not the same as was there before. Imaging also did not show marked differences from extending the interval between doses. Remember there may be some disease breakthrough with treatment with alemtuzumab (~40-50%) so you may expect a few people to relapse.
The study suggests that ” relapse risk remains low with extended infusion intervals of rituximab, so maybe it is as much or an IRT as alemtuzumab and cladribine..
Starvaggi Cucuzza C, Longinetti E, Ruffin N, Evertsson B, Kockum I, Jagodic M, Al Nimer F, Frisell T, Piehl F. Sustained Low Relapse Rate With Highly Variable B-Cell Repopulation Dynamics With Extended Rituximab Dosing Intervals in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022 Nov 21;10(1):e200056.
Background and Objectives B cell–depleting therapies are highly effective in relapsing-remitting multiple sclerosis (RRMS) but are associated with increased infection risk and blunted humoral vaccination responses. Extension of dosing intervals may mitigate such negative effects, but its consequences on MS disease activity are yet to be ascertained. The objective of this study was to determine clinical and neuroradiologic disease activity, as well as B-cell repopulation dynamics, after implementation of extended rituximab dosing in RRMS.
Methods We conducted a prospective observational study in a specialized-care, single-center setting, including patients with RRMS participating in the COMBAT-MS and MultipleMS observational drug trials, who had received at least 2 courses of rituximab (median follow-up 4.2 years, range 0.1–8.9 years). Using Cox regression, hazard ratios (HRs) of clinical relapse and/or contrast-enhancing lesions on MRI were calculated in relation to time since last dose of rituximab.
Results A total of 3,904 dose intervals were accumulated in 718 patients and stratified into 4 intervals: <8, ≥8 to 12, ≥12 to 18, and ≥18 months. We identified 24 relapses of which 20 occurred within 8 months since previous infusion and 4 with intervals over 8 months. HRs for relapse when comparing ≥8 to 12, ≥12 to 18, and ≥18 months with <8 months since last dose were 0.28 (95% CI 0.04–2.10), 0.38 (95% CI 0.05–2.94), and 0.89 (95% CI 0.20–4.04), respectively, and thus nonsignificant. Neuroradiologic outcomes mirrored relapse rates. Dynamics of total B-cell reconstitution varied considerably, but median total B-cell counts reached lower level of normal after 12 months and median memory B-cell counts after 16 months.
Discussion In this prospective cohort of rituximab-treated patients with RRMS exposed to extended dosing intervals, we could not detect a relation between clinical or neuroradiologic disease activity and time since last infusion. Total B- and memory B-cell repopulation kinetics varied considerably. These findings, relevant for assessing risk-mitigation strategies with anti-CD20 therapies in RRMS, suggest that relapse risk remains low with extended infusion intervals. Further studies are needed to investigate the relation between B-cell repopulation dynamics and adverse event risks associated with B-cell depletion.