Tuesday, 16 December 2014

OffLabel: rituximab

Rituximab is my 6th off-label DMT for treating MS in resource poor environments. #MSBlog #MSResearch #OffLabel

"The sixth in a series of posts to try and help neurologists who treat MS in healthcare environments where they cannot access high-cost innovator DMTs. If you want to know the history of this post please read my post on my visit to South Africa. My position on this has been reinforced by recent trips to South America, Lebanon and India; all regions where personal access to DMTs is largely determined by how wealthy you are. The other five off-label DMTs that I have covered to date are methotrexate, azathioprine, mitoxantrone, cladribine and cyclophosphamide."

"I wasn't going to include rituximab in this list as it not off-patent and is a relatively high-cost drug. However, on my visit to India I have found that a cheap biosimilar (Reditux) is available and the rheumatologists, who use this formulation in India to treat rheumatoid arthritis, are apparently impressed with its effectiveness and its ability to deplete peripheral B cells in a similar fashion to the innovator product."

"I have personally used rituximab in a handful of MSers, who were not eligible for licensed drugs,   with impressive results. Please note in the UK it is frowned upon to prescribe off-label products were licensed products exist for a particular indication and it is illegal for the NHS to support widespread off-label prescribing of a particular product when licensed drugs exist for that indication. This has been discussed previously on this blog in relation to the issue concerning the use of Avastin, instead of Lucentis, as a treatment for macular degeneration."


"Despite the legal restrictions in the EU and elsewhere, I am aware of centres who use Rituximab routinely as part of their MS practice, a few of  these are in Europe. It is also worth noting that Rituximab is coming off patent in 2015 and there are moves by several generic manufacturers to produce rituximab biosimilars. Why? Rituximab is simply a game-changer and is used to treat many autoimmune disease outside of its limited licensed indications for oncology (B cell dyscrasias) and rheumatoid arthritis;it is a good drug and there is an unmet need for it many countries." 


Castillo-Trivino et al. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013 Jul 2;8(7):e66308. doi: 10.1371/journal.pone.0066308. Print 2013.

BACKGROUND: Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.


OBJECTIVES: To evaluate the efficacy and safety of rituximab for MS treatment.

DATA COLLECTION: Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.

MAIN RESULTS: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. 

AUTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.

"What dose of rituximab? I have used a hybrid protocol based on the published RRMS and PPMS protocols of giving 1g of rituximab as an intravenous infusion 2 weeks apart and then giving 1g intravenously 6-monthly up until 18 months. As rituximab causes lysis of B-cells and infusion reaction we pre-treat patients with paracetamol (1 g) and diphenhydramine hydrochloride (50 mg) 30 to 60 minutes before each infusion and as required after that. In MSers rituximab-related infusion reactions tend to mild and well tolerated."

"What do you do after the month 18 infusion? A difficult question. Some people use rituximab as an induction therapy and wait for disease activity to remerge before retreating. Others monitor the peripheral B-cell counts with CD19 as a B-cell surface marker on and retreat when B-cells are detected in the peripheral blood. The latter approach has not worked so well in RA; many RAers relapse before B-cells are detectable in the peripheral blood indicating that peripheral B cells are not the best marker for retreatment. Other neurologists retreat as a maintenance therapy every 12 or 18 months and adjust their retreatment protocol based on whether or not MSers have any breakthrough disease. I prefer the latter approach and have favoured retreating annually with 1g intravenously."

"Are you sure the dose is correct? No I am not. There is anecdotal evidence that we may get away with a lower dose of rituximab, but until we have published evidence for this I would rather err on treating with the published dose of 1g. Some neurologists are using doses of Rituximab as low as 100 mg 6 monthly with apparent efficacy. I have suggested they publish their results in peer-reviewed journals so that we can all assess the robustness of their observations."

"What about MSers living in resource-rich environments? I suggest you wait until the rituximab follow-on compound ocrelizumab comes to market. Ocrelizumab is in late-stage development with two phase 3 RRMS and one PPMS trial. The results of the former are expected late next year. We in the developed world have an obligation to support licensed products."

CoI: multiple

8 comments:

  1. And what about PML risk?

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    1. Re: "And what about PML risk?"

      Low; the majority of PML in patients treated with Rituximab is in patients who have received other chemotherapeutic or immunosuppressive therapies or have malignancies. The estimated risk of developing PML on rituximab monotherapy is than less than 1 in 10,000. The caveat is using rituximab post-natalizumab with carry-over PML. However, even in this situation I suspect the risk of PML is low as rituximab leaves your so called cytotoxic CD8 T-cells intact and these are required to fight and clear PML. This is not the case with alemtuzumab, cladribine, fingolimod, mitoxantrone or other immunosuppressive drugs.

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  2. Supposedly, there are no cases of PML with rituxan in multiple sclerosis out of ~40,000 exposed patients. In one series, there were 4 total cases in rheumatoid arthritis treated with rituxan out of 129,000 exposed, suggesting risk of ~1/25,000; 1 of these 4 cases was with no biologic and minimal immunosuppressive therapy.

    Source: “Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis JAMA Neurology, “09/14/2011 Clifford DB et al.

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    1. Thanks for this. I sat on an PML advisory board several years ago and we reviewed all the PML cases linked to rituximab; we didn't find a single case on monotherapy. The one case referred to here on minimal immunosuppressive therapy had been on steroids. The take home message is that the risk of PML on rituximab is very low; the caveat being carryover PML from natalizumab. I think rituximab, and by inference ocrelizumab and other anti-CD20 therapies, will be a relatively safe drugs to transition onto from natalizumab.

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  3. FYI - For anyone who is looking, I had 1 gram infusion of Rituximab in Peru for MS. The cost of the med was $3,000 USD (Roche brand), and hospitalization with observation 2 day was a few hundred dollars. It is possible.

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  4. I am JCV positive and have a level of 2.38 I was on tysabri for 2 years stopped, and started again for another 2. Got a second opinion went on Gilenya and now going on Rituximab. I need to know if my risk of PML is greater given my long history on tysabri. Please help

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  5. I need to know if I'm at higher risk for PML. My JCV level is 2.38 and I was on tysabri for 2 years stopped, went back on for another 2 then Gilenya. Now going to start Rituximab. Please help

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  6. Jordan hi. im not a doctor. you sd ask your neurologists this question. it is a good question. They may want you to wait a bit for the tysabri to clear out. But im not sure. I hope u can find out. If your ms is agressive, u sd do rituxin. you want to avoid relapses at all costs. even with a small risk of pml. contact Gavin directly above. He really seems to know his stuff. U can do it.

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