The most common questions about rituximab

These questions are collected from the Swedish Facebook group with 372 group members Jan 2018 and US Facebook group 1.9K group members May 2018

Posted in COMBAT-MS 2018-10-25

1. Mechanisms: How does the drug work?

A. What is the target of rituximab? Some says B cells and others anti-CD20. Would be happy if someone can explain so that I understand.

Anders Svenningsson:

All circulating B cells (also called B lymphocytes) have a molecule on its surface that is named CD20 (CD: “Cluster of Differentiation”). The CD20 molecule sits almost exclusively on B cells and is therefore considered a “marker” for B cells. Rituximab is an antibody that specifically detect and attach to the CD20 molecule (hence “anti-CD20) and while doing so initiate a series of immunological reactions that destroy the B cell it is sitting on. So rituximab targets B cells by binding to the B cell-specific surface molecule CD20.

B. Is rituximab a cancer therapy?

Anders Svenningsson:

It may be a cancer therapy if it is the B cells that have transformed to cancer. That occurs in a cancer form called lymphoma, for which rituximab is a cancer therapy. But this is the only cancer that can be treated with rituximab, i.e. it is not a “general” cytotoxic drug that is used to treat many cancers.

C. Some says that MS is caused by EBV and that this virus infect B cells. Is this why Rituxan works? Because it clears all the infected B cells?

Anders Svenningsson:

This is a very interesting theory that I have given a lot of thoughts but we have still not had the time to look deeper into this question, but I hope we will be able to study that theory in the future. However, it is unlikely that this is the main mechanism since autoimmunity when developed involves a lot of other cells than B cells, which are not infected by EBV. We will definitely have this question in mind while planning future studies.

D. Can my rheumatism become better by Rituximab?

Anders Svenningsson:

If your rheumatism is of a type that fulfills the standard criteria of Rheumatoid Arthritis it can definitely improve by rituximab.

2. B-Cells/Repopulation

A. When a patient repopulates do the B-Cells come back non-autoimmune?

Anders Svenningsson:

We do not know the answer of this question but we will try to study that in our upcoming projects. One has to look at the immune system as a team where the B cell population is one of the players. So even if the repopulating B cells are less autoreactive there may be other cell types (mainly T cells) that retain their autoimmune potential.

B. Why do some patients repopulate faster than others?

Anders Svenningsson:

Several factors appear to influence this phenomenon. Age is clearly one of them, young individuals repopulate faster than older. That may indicate need for lower doses or longer infusion intervals over time. Another factor is dose of rituximab, the higher dose, the longer time to repopulation. Also the immue system can react against the drug and form anti-drug antibodies (ADA) that at high level can reduce the effect of the drug. These can be measured and patients that have develop ADA can regain a good effect if they are switched to another anti-CD20 drug.  In addition there are probably genetic factors and possibly how active inflammation the patient have but this is still poorly understood.

C. Why do we have to repopulate at all?

Anders Svenningsson:

With high probability there will be higher risks with long-term treatment if the B-cells are continuously depleted year after year. The risks will likely involve sensitivity to infections, maybe severe opportunistic infections and possibly malignancies as well. We are presently performing studies regarding how much repopulation of B cells that still gives a good protection for disease activity. Clinical experience indicates that the repopulation that occurs within one year will not result in a significant risk of disease reactivation.

D. What are the long-term effects of having no B Cells?

Anders Svenningsson:

This is a very important question that we don’t know the answer to. It is fair to assume that the risk for infections increase and that is why we now perform studies to see if we can allow some level of repopulation without disease reactivation. However, rituximab have been used for over a decade for treating Rheumatoid Arthritis and from follow-up studies of these patients there are no indications of increased infections or cancer over time.

E. How can I relapse if my B-Cells are at zero?  (does that mean it isn't working?)

Anders Svenningsson:

It is important to verify such a relapse with MRI and possibly cerebrospinal fluid analysis (to detect increased levels of Neurofilaments). If a relapse seems confirmed and you still have no measurable B cells in the circulation I would regard the treatment as insufficient for you and consider to change to another treatment. With the genetic variability between people it is expected that there will be some people with rare genetic variants that do not respond as well to the rituximab treatment. There is still no treatment that in 100% cure MS (autologous hematopoietic stem cell transplantation is the closest to that). An alternative can be to repeat a higher dose rituximab since we know that even if there are no measurable B cells in the circulation there are still B cells left in lymph nodes. Therefore, an additional and higher dose has some chance to be effective. It is important to point out that our knowledge regarding the relation between B cells in the circulation and effect on autoimmune disease is poorly understood. Rheumatologists rarely measure B cells when they use rituximab for that reason.

Posted in COMBAT-MS 2019-03-08

3. How efficient is the treatment?

A. Is there any statistic on the frequency of reduced number of relapses at clinics using Rituxan?

Anders Svenningsson:

There is a lot of data from Swedish MS centres showing that the relapse frequency is extremely low for patients treated with rituximab. We have published that in a couple of studies already, but presently running a controlled trial with relapses as endpoint. In all, it is far below 1 relapse per every 10 years on average which is as good as any of the highly active treatments on the market. Only autologous stem cell transplantation beats it regarding efficacy, in my opinion.

B. Can one after some years of treatment with Rituxian have a slowdown of MS disease (that is what my doctor is telling me)?

Anders Svenningsson:

If you mean with slowdown that the disease activity is turning less active permanently it is probably true, but still too early to say if it has “stopped” to be active. With time the disease becomes less active by itself to be almost completely inactive by the age of 55-60. So these two mechanisms might work in concert to reduce risk for further relapses over time.

C. Is it right to give Rituxan to patient when the disease is not so active anymore?

Anders Svenningsson:

I would say it is a matter of age. Around 55-60 (maybe youger!) the combination of a prolonged treatment effect and natural cessation of disease activity makes treatment of very low value, but you still retain the risks. So I would say as a rule of thumb that if you are over 50 and have had a not so active disease anytime it might be worth trying discontinuing all therapies. Of course keep yearly MRI controls.

D. What is the risk of having a relapse while on Rituximab?

Anders Svenningsson:

See above. Much less risk than one relapse per 10 years for one individual, most likely it is closer to 1 every 20 years…

E. Does Rituxan have a better effect than Tysabri (natlizumab)?

Anders Svenningsson:

I would from clinical experience say “no”. Tysabri is exceedingly effective that is hard to beat, but I think rituximab is equally effective. I wanted to do a comparative study between the two drugs some years ago, but realized that we should never get a “winner”. So, the difference between the two drugs does not lie within efficacy but rather convenience (1 infusion per moth vs 1 infusion per 6 or 12 months) and safety (primarily the risk of PML and herpes infections for Tysabri vs probably slightly higher risk of other infections for Rituximab). It is up to the discussion between the doctor and the patient to decide which “profile” fits the best in each individual case.

4. What dose interval should be used and why?

A. After three years on the drug and if the disease is stable you shift to 1 time per year, at least this is how they do it at Danderyd hospital, right?

Anders Svenningsson:

Yes, that is the normal procedure we use and it is as well used regularly in Umeå where I started to use this treatment in 2008.

B. Do all hospitals follow these treatment regimens?

Anders Svenningsson:

I am not sure if all do, but this protocol becomes more and more common since we do not see a clear tendency of recurrence of the disease from doing so and we surely increase safety by it. To get the “final” answer to this question, we are now in Sweden running a large trial (RIDOSE-MS) where we randomize between treatment every 6 and treatment every 12 months after initial 1 – 3 years of treatment every 6 month. It is a long trial of totally 4 years (thus end by year 2023), but it will eventually tell us very well which regimen is giving the best benefit vs risk ratio.

C. For how long do one stay on once a year infusions (my neurologist does not give me any clear answers)?

Anders Svenningsson:

I understand he or she doesn’t because none of us know that for sure yet. It might be a decision made of several parameters where our age definitely is one of those. The key question we do not have the answer to yet is whether the repeatedly depleted memory B cells eventually have “lost their memory” for the disease and thus you could say if you would be immunologically “cured”. Even that might be individual, so we really would need a specific way to measure the individual response to whatever autoantigen that is most relevant in order to safely quit treatment permanently. In a practical sense, one could use different algorithms out of which this one is quite practical (completely pragmatic from my own practice): After 3 years (this might be possible to shorten by the way) 6 monthly interval, increase the interval by 6 months every other infusion. Ex, after the 7:th infusion (3-year time-point), go on with intervals of 12, 12, 18, 18, 24, 24 months and so on. If you have had no recurrence of the disease by 50-55 years of age you could probably quit permanently. Remember, this is my practical approach that is not tested scientifically, but builds on real-world experience on using the drug for over 10 years. It might be modified in the future.

D. If you stop Rituximab treatment, will you be without disease modifying treatment then? And if so, are there any studies supporting this? How is it going to be monitored?

Anders Svenningsson:

Please see my answers above, which basically deal with this question. Formal studies have yet not been performed regarding stopping treatment. Being “without” treatment could be a good thing to be if you do not need treatment and possibly repeated treatments with rituximab will make your disease milder so you don’t need treatment any longer (OBS! Hypothesis!). If you are above 50 years of age the need for treatment is going down rapidly and in this category of individuals I cannot remember any recurrence of disease activity when we have stopped treatment. It is important that you are followed continuously with yearly MRI scans, however, since we never know for sure in the individual case.

E. Do they take into account individual variations when they prolong the intervals?

Anders Svenningsson:

Yes, we do. Someone with initially low disease activity and small number of brain lesions could be increasing intervals earlier.

F. I want to know why some doctors say that the treatment is for three years and other says that there is no limit for how long you can be treated.

Anders Svenningsson:

Do not know what they mean when saying that it is a “3-year treatment” and that’s it. Possibly if you are above 50 years of age it would make sense to me. Otherwise I would advocate an individual approach on that issue, but in any case taper off the treatment somewhere between 50 and 60 years of age, no longer than that is needed.

G. Why do doctors have different protocols?

Anders Svenningsson:

I think that is because the treatment has not been licensed for MS by a company, which otherwise prescribe specific protocols in the product label. But it is not at all unique that treatment schedules are individualized in medicine and in many ways that is ideal. You never have “one-dose-for-everybody” when it comes to hypertension or diabetes therapy. We need to be better in measuring disease activity in real time in MS to do that systematically, but you could definitely see the changing protocols of rituximab as a way to adapt the treatment after the need for treatment, which I think is quite exciting.

H. Why do some get 2 infusions back to back in 2 weeks and others start with 1 and then go 6 months?

Anders Svenningsson:

It is an old protocol inherited from rheumatology that was used more in the beginning of rituximab treatment for MS. We found it unnecessary high and have successively lowered the dose to make the treatment safer.

I. How long can you stay on rituximab treatment?

Anders Svenningsson:

I think you will find the answer to that question above. As a rule of thumb, until the age between 50 and 60 years, depending on individual factors. It will not be needed any longer as far as we can conclude from what we know about the disease and the drug today.

J. Is there a set time and when one can say that you are close to being cured?

Anders Svenningsson:

I wish I could have an answer to this thrilling question. The day we can measure the relevant autoimmune phenomenon and we see that it has disappeared and not come back for many years without treatment, then I would say “cured”. A “wholly grain” for MS treatment is to get rid of all signs of inflammation in the cerebrospinal fluid (CSF), that could be an intermediate goal. More than half of very inflammatory active patients that will be treated early with autologous bone marrow transplantation will lose every sign of inflammation, including in the CSF. I think those individuals are cured.

K. What is the longest time that someone has been on rituximab for MS?

Anders Svenningsson:

I would say almost 10 years, but in those cases the intervals have been successively increased so I need to do some deeper checking what the infusion scheme actually look like for those persons.

L. What is next if I fail on rituximab?

Anders Svenningsson:

It completely depends on why you fail. If it is because you have developed anti-drug antibodies (ADA), Ocrevus or ofatumumab will work fine to switch to. If it is because of other side effects, Tysabri would be a good alternative if you are anti-JCV antibodies are negative, otherwise possibly Lemtrada or Mavenclad. If it is because of hypogamma or a lot of infections, it is trickier -  if you are JCV+, the one safe alternative would be Copaxone. The most unlikely reason would be return of disease activity and no ADA and if that would happen I would consider autologous bone marrow transplantation. In my practice, it has never occurred, however… (with hundreds of patients for many years on rituximab).

5. About using drugs off-label:

A. How close are we to recommending Rituxan as MS treatment?

Anders Svenningsson:

Oh, that is a tricky question where Big Pharma is doing everything they can to prevent that, and regulatory authorities in my opinion are weak and more sensitive to the economic rules set up to protect pharma than to the best need for patients and society of effective medication for reasonable prices. We work actively on the matter in Sweden, but are not there yet. Hopefully something will start to happen this year.

We can of course informally “recommend” the treatment between doctors and that is what is happening in practice from gaining more and more positive experience of the drug. More formal “official” recommendations in, for example, national guidelines provided by national authorities has been prevented from aggressive actions performed by Big Pharma companies.

B. What will be the consequences when Ocrevus (ocerlizumab) is approved?

Anders Svenningsson:

That will vary a lot from place to place. In Sweden, it will be used in very little amount for obvious reasons and in the USA, I think it will depend on individual doctors and insurance policies.