What Is The Risk Of PML When Transitioning A Patient From Tysabri to Rituximab?

8/7/2014

Here is My Question:
What is the carryover risk of PML when transitioning a patient from Tysabri to Rituximab? Does that change how you transition?

For example, can you stop Tysabri and then start Rituximab in less than 30days (in an attempt to prevent or reduce likelihood of rebound?) OR because of lingering PML risk do you wait a certain number of days? THANKS (A neuro pharmacist)

Answer:
First, this is great that specialists treating people with MS are starting to ask questions on this site. We want this to be a learning forum for all of us to share and learn, so there is no reason for only those with MS to ask questions here, so thanks for your question!

To answer your question, there is really no single answer for every case. It depends on the individual's risk of a relapse after stopping Tysabri, their JCV antibody index, their prior history of immunosuppression and their duration of Tysabri therapy.

I personally do not wait more than 60 days to treat with Rituximab so as to minimize the risk of relapse after stopping Tysabri, but this wait is often dictated by insurance authorization delays more than anything else. Most relapses after stopping Tysabri occur between 3 and 6 months following the last dose, so treating with Rituximab within 60 days is prudent. You may wait up to 3 months in a person with a lower risk of relapse and a higher risk of PML. You will definitely wait longer if there is any concern of early pre symptomatic PML at the time of stopping Tysabri. I think it is important to repeat another MRI and possibly check CSF before starting Rituximab to make sure there is no new activity suspicious for PML.

These are of course just my thoughts on the matter. Many others in the field wait far longer than 3 months in all cases before using Rituximab after stopping Tysabri.

If you search this site for PML, you will find a lot of information about it. http://www.healthcarejourney.com/apps/search?q=PML

-Rip Kinkel, MD

PLEASE NOTE: The information/opinions on this site should be used as an information resource only. This information does not create any patient-HCP relationship, and should not be used as a substitute for professional diagnosis and treatment. Please consult your health care provider before making any healthcare decisions or for guidance about a specific medical condition.

Brendan W Bauer MD

2/8/2015 02:18:36 pm

Hey Rip, hope all is well. I was one of your former Residents from bright & sunny Cleveland. My question is that I have a JCV granule cell Cerebellar Degeneration that I am treating with Mirtazapine to help & block the receptor, while I am using Mefloquine to help fight the active virus. She received 88 doses of Tysabri & was one of the many who were months away from a wheelchair & literally did a 180 and dropped nearly 3.0 full points on her EDSS. Started getting trunkal ataxia 3 months ago and repeat MRI showed cerebellar vermis degeneration, although not appreciated by radiologist in very small rural Ohio. Spinal tap positive for JCV by PCR and now 2 months into therapy and had IRIS at 6 weeks treated & did very well with ACTHAR injections for 5 days. Due to how well she is doing I am going to repeat her spinal this week and check every 4 weeks until clears. Next question & more important for this site is if one survives and now nearly 70% of Tysabri are, where do we go from here. Do you play it safe and flood the system with decoys with Copaxone or in those who had devastating disease prior to Tysabri can we still use more efficacious drugs like Rituximab since they have different MOA especially when it's from T-Cell to B-cell line and thus allow some T-cytotoxic egress back into the CNS to at least fix how the problem may have started from the Tysabri side of the coin. PML is here to stay. With our success are going to come failures, but these failures of 5 years ago are just setbacks today. When do we have the bigger conversation of we can tell these patients no, but they know way too much about their disease to know when we are being cautious at their expense so we can sleep, when they are the ones living in the body and refuse not to go softly into that good night. I hope this post finds you well and generates some answers on all sides of the fence You are sorely missed by all & I welcome some comments on a very difficult but soon to be more widely discussed topic.

R Kinkel

2/14/2015 02:51:48 am

JCV granule cell neuropathy (JCV GCN) is a unique disorder described by my former colleague at Beth Israel Deaconess Medical Center, Igor Koralnik. Like progressive multifocal leukoencephalopathy (PML) it is most commonly observed in patients with lymphocyte depletion related to HIV infection or other causes. To my knowledge there are only two reported cases in Tysabri treated MS patients, both with exclusive cerebellar degeneration without evidence of typical white matter associated PML. This is in contrast to the HIV literature where JCV GCN often co-exists with typical PML. JCV GCN is associated with a novel mutation in the C terminus of the VP1 protein that does not affect the ability of the virus to replicate but does lead to preferential infection, ability to replicate or both in granule cell neurons instead of astroglial cells. Other potential JCV associated CNS infections could include JCV associated encephalopathy (preferential infection of pyramidal cell neurons) and JCV associated meningitis, both described in HIV but yet to be described in natalizumab treated patients.

I would like to know if you were able to genotype the JCV DNA isolated from the patient’s CSF to make sure it harbors a VP1 terminal deletion, since we now know that the archetypal JCV strain can circulate in the CSF of patients on natalizumab treatment without evidence of PML. It would also be important to know if rearrangements in the TCR region were detected that confer susceptibility to typical PML. Knowing the genotype will allow you to track the clearance of the neurotropic strain in the CSF.

Management of the case going forward is complex with many unanswered questions. Even if the patient demonstrated a strong CD8 response against JCV (associated with a good prognosis) and cleared neurotropic virus from the CSF, it is possible that any lymphocyte deleting drug associated with PML could lead to a recurrence. This would be particular problem with any drug associated with prolonged non-readily reversible lymphocyte depletion. I would be inclined to avoid this drugs until we learn more about the pathogenesis of JCV associated disorders. If I could not control the patient’s MS with glatiramer acetate, interferons or Gilenya (none of which have been directly associated with PML) I would possible try low dose rituximab 100 mg every 6 months, a protocol that we have found very effective in relapsing patients and associated with a more rapid return of CD19 counts prior to pretreatment.

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