Rituximab post-alemtuzumab to prevent secondary autoimmunity
The whack-a-mole paper is a hypothesis begging for a randomised controlled trial.
At the CMSC meeting in Denver last week, I was asked by a US-based neurologist if I use rituximab in combination with alemtuzumab to prevent secondary autoimmunity. He referred to old blog posts of mine on derisking alemtuzumab (19-Nov-2014, 03-Dec-2016, 19-June-2017) and to the more recent whack-a-mole strategy of Eliot Frohman’s group (see paper 1 below). The Frohman whack-a-mole paper is not a study but an early experience of 10 patients managed this way. In short, if this was a study, it would be massively underpowered, and the follow-up is too short to draw any conclusions. In my opinion, the whack-a-mole paper is a hypothesis begging for a randomised controlled trial.
We tried to get funding for two trials to prevent secondary autoimmunity after alemtuzumab. David Baker (The Mouse Doctor) and I approached Genzyme in 2014 to do an alemtuzumab-rituximab study. Genzyme did due diligence on our proposal and thought the science behind the hypothesis needed more data, and they considered it too risky. We then went back to Genzyme with a proposal to do an alemtuzumab-teriflunomide trial, which, although a safer combination, was not supported for financial reasons. I think teriflunomide’s and alemtuzumab’s patent lives were too short, and it did not make sense for Genzyme to support this.
The immune system uses many mechanisms in place to prevent autoimmunity. When you learn how the immune system works, it is pretty surprising that autoimmunity is so uncommon. The immunologists tell us that there must be a series of underlying biological processes causing secondary autoimmunity. If we can determine these, we can intervene and prevent this complication.
This is what Professor Joanne Jones and Reverend Professor Coles attempted to do in Cambridge. Because the immune system reboots itself from peripheral memory cells post-alemtuzumab, it is more likely to result in an aberrant autoimmune response. They did a trial to encourage rebooting of the immune system using more naïve cells from the thymus using a hormone called, Palifermin that stimulates the thymus to produce more naïve T-cells. The study was called the Cam-Thy study. Contrary to animal studies, palifermin reduced thymic output in their study subjects, and there was no difference in the rate of autoimmunity between the group who received palifermin and those who did not.
Interestingly, when you compare cladribine, another immune reconstitution therapy (IRT), with alemtuzumab, you can’t help but notice that the B-cell reconstitution profiles are very different. With alemtuzumab, B-cells come back very quickly and overshoot their baseline values. We hypothesised that if you changed the shape of the B cell reconstitution with a small dose of the B cell-depleting antibody such as rituximab, you might be able to prevent this secondary autoimmunity. We proposed using a small dose of rituximab, i.e. 10-20mg, just enough to delay B cell reconstitution by 4-6 months.
The good news is the Australians have managed to get a trial funded and have called it the RAMBLE study (Reducing the frequency of Autoimmune adverse events in the treatment of Multiple sclerosis with alemtuzumab using B-celLdEpletion: a phase II/III, randomised, placebo-controlled clinical trial; ). In this study, they are randomising patients to receive rituximab 100 mg per m2 at weeks 10, 30, 62 and 82 or placebo. This study is still recruiting (ACTRN12621001502820). As it is a 4-year study, the results will only be known in about 5-6 years. If you are interested, you can download the RAMBLE protocol here.
So my answer is no, we don’t use rituximab to prevent secondary autoimmunity post-alemtuzumab. We need to wait for the results of the RAMBLE study before adopting this practice. Rituximab is still considered a high-cost drug on the NHS, and this indication would be off-label. Using rituximab with alemtuzumab would require us to submit a business case to NHS England and/or our formulary committee. Based on previous experiences with other business cases, NHS England will almost certainly say no because the rationale is speculative and evidence base so anaemic.
Another issue is prescribing off-label; any clinician prescribing off-label puts themselves at risk medicolegally. In the event of a severe or serious adverse event or death, which would potentially occur with this combination, it would put them at risk of sanction by the GMC. The days of the lone wolf or maverick consultant doing research under the guise of clinical practice are probably over, particularly in relation to a disease such as MS with several licenced therapies.
As appealing as it may seem to jump the gun and start using rituximab with alemtuzumab to prevent secondary autoimmunity, we must wait for the tried and tested scientific method to deliver the evidence. There are many examples from the past when the early adoption of a treatment, which seems rational, has proved ineffective and, worse, has caused harm.
Paper 1
Objective: To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%-50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.
Methods: In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50-150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.
Results: Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed.
Conclusions: An anti-CD20 "whack-a-mole" B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.
Classification of evidence: This study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.
Paper 2
Background: The lymphocyte-depleting antibody alemtuzumab is a highly effective treatment of relapsing-remitting multiple sclerosis (RRMS); however 50% of patients develop novel autoimmunity post-treatment. Most at risk are individuals who reconstitute their T-cell pool by proliferating residual cells, rather than producing new T-cells in the thymus; raising the possibility that autoimmunity might be prevented by increasing thymopoiesis. Keratinocyte growth factor (palifermin) promotes thymopoiesis in non-human primates.
Methods: Following a dose-tolerability sub-study, individuals with RRMS (duration ≤10 years; expanded disability status scale ≤5·0; with ≥2 relapses in the previous 2 years) were randomised to placebo or 180mcg/kg/day palifermin, given for 3 days immediately prior to and after each cycle of alemtuzumab, with repeat doses at M1 and M3. The interim primary endpoint was naïve CD4+ T-cell count at M6. Exploratory endpoints included: number of recent thymic-emigrants (RTEs) and signal-joint T-cell receptor excision circles (sjTRECs)/mL of blood. The trial primary endpoint was incidence of autoimmunity at M30.
Findings: At M6, individuals receiving palifermin had fewer naïve CD4+T-cells (2.229x107/L vs. 7.733x107/L; p=0.007), RTEs (16% vs. 34%) and sjTRECs/mL (1100 vs. 3396), leading to protocol-defined termination of recruitment. No difference was observed in the rate of autoimmunity between the two groups.
Conclusion: In contrast to animal studies, palifermin reduced thymopoiesis in our patients. These results offer a note of caution to those using palifermin to promote thymopoiesis in other settings, particularly in the oncology/haematology setting where alemtuzumab is often used as part of the conditioning regime.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional, who will be able to help you.
Every time I try to write, I have very good points and important things to say, but my body always feels otherwise and manages to erase everything I took hours to write. And it’s too difficult and time-consuming to redo everything since most of it was a kind of stream of consciousness endeavor. It’s tragic and very sad because my thoughts., I believe , are important in the conversation, and especially germane to this subject
Hi Prof G.
I understand many of these issues, and the vital importance of empirical research. But it also takes quite a bit of time, and many of us pwMS don’t have years and years of time to wait for clinical trials to play out. This is not a complaint, it’s just a fact. I was Dx'd (diagnosed) with multiple sclerosis in 2002, and I was originally hopeful that science and technology in the new millennium would have concrete answers quite soo. But after