What is your risk of developing PML on fingolimod?

The following update on PML risk on fingolimod was released to us by Novartis. 

Will this new data lead to a change in practice? 

PML under fingolimod therapy not attributed to previous natalizumab treatment is very rare and the risk is estimated to be less than 1:10,000 patients.

19 confirmed PML cases in >225,000 fingolimod-treated patients (>508,000 patient-years) as of the 30th of November 2017.

The estimated risk (95% CI) is 0.084 (0.051; 0.131)/1,000 patients and the incidence rate (95% CI) is 3.74 (2.25; 5.84)/100,000 patient-years exposure.)

• Two cases had confounding medical conditions (1 previous cancer and 1 ulcerative colitis/immunosuppressive therapy).
• One patient had previous NTZ exposure for 10 months (3 years and 9 months before PML diagnosis).
• In one patient, PML occurred during 3 months of NTZ exposure, after 4.5 years of fingolimod treatment; this patient also had a history of recent exposure to steroids.
• Demographics: age range from 34 to 71 years, with a female preponderance (14 of 19 cases) and a diverse geographic distribution.
• Fingolimod exposure ranged from 18 to 84 months. 18 of the 19 patients had fingolimod ranging between 29 and 84 months while one had received fingolimod for 18 months.
• There was no pattern of sustained grade 4 lymphopenia (defined as absolute lymphocyte count ≤200 cells/µL and based on the reported absolute lymphocyte count values in 15 of 19 cases).
• JCV DNA PCR test was positive in all cases.

In the past, there has been no clear correlation between opportunistic infection risk and lymphocyte counts on fingolimod. As a result of this, the FDA did not mandate the monitoring of lymphocyte counts in pwMS on fingolimod in routine clinical practice. In comparison, the EMA implemented the same requirements that were part of the fingolimod trial programme; i.e. dose interruption was done if the total, or absolute, lymphocyte count dropped below 200. The latter is quite common in people with MS on fingolimod. To reconcile the differences between the FDA and EMA we suggested a half-way house mark and to only interrupt fingolimod dosing if the counts dropped below 100. 

Only the minority of PML cases (~20%) on fingolimod had counts below 200. Does this mean we now have to change this recommendation? I think it would seem reasonable to go back to the 200 cut-off as recommended by the EMA. 

Does this mean that the FDA will now have to change their recommendations? I am sure they will. The FDA is a data-driven organization and are likely to respond to this new information. 

Unfortunately, fingolimod does not move from the list of DMTs that can't be derisked regarding immunosuppression and opportunistic infections, to the list of DMTs that can potentially be de-risked. The majority of opportunistic infections still occur in pwMS with lymphocyte counts above 200. 

NOTE: If you are on fingolimod and your lymphocyte count is below 200 please speak to your neurologist or clinical nurse specialist. If you don't know your lymphocyte count you should find out. As we can't derisk fingolimod you must be please remain vigilant of any new symptoms, this includes neurological and systemic symptoms, that could suggest an opportunistic infection. 

ProfG    

PML warning on Cladribine by MHRA.

There has been a warning about the development of PML after the use of cladribine for the treatment of haematological problems issued by the MHRA. Therefore please be vigilant. 


So far this is associated with the use of the generic cladribine, probably in cancer, rather than oral variant in MS. It says there have been three cases.

Lipomed who make the generic version have issued this warning.

Cladribine dhpc-01-12 from BartsMSBlog

• Dosing in hairy cell leukemia is 10mg for 5 days = 50mg
• Dosing in Non-Hodgkins lymphoma and chronic lymphocytic leukemia = 35mg monthly to a maximum of 6 cycles = 210mg
• Dosing in multiple sclerosis. Dose used at QMUL = 30mg and up to 30mg one month later depending on lymphopenia. The mavenclad equivalent dose is about (25mg + 25mg a month apart) 50mg 

We can see the cases reported a few years ago

A case of PML was reported in someone (81 years old) with HCL who got pentostatin (a chemotherapeutic drug) 2 years later and 3 years later developed PML. Their T cell counts were extremely low at 67 and 28 cells/mm*3. Therefore severe lymphopenia seems to be a problem.

In another case (67 years old) reported 6 months after the last dose of cladribine had 160 CD4+ cells/mm3 and 360 CD8+ cells/mm3 but had been down to 100 lymphocytes cells/mm3).

The dosing schedule in use for oral cladribine aims to reduce the chances of severe lymphopenia <500 cells/mms (<200 CD4 T cells) = grade 3 lymphopenia, <200 cells/mm3 (<50cells/mm3) = grade 4 lymphopenia

In the warning it says "If PML is suspected, stop cladribine treatment immediately and ensure the patient receives specialist investigation"

However, as cladribine give long term depletion, if PML occurs it may be problematical.

At the heart of the use at QMUL, is careful monitoring to ensure that persistent lymphopenia does not occur. 

If you are taking mavenclad monitoring occurs to ensure that lymphopenia is reduced.

However, persistent lymphopenia is going to be a problem for any treatment. But which cell type deals with PML the best...I guess CD8. 

Will PML occur in MS after Cladribine?

This is quite possible, it has occurred with most MS drugs

DrK's Brain Attack trial

Time is Brain, even in MS! 

How quickly should we treat MS? 

DrK makes the case for treating everyone as quickly as possible. Do you agree? Can you help us convince Biogen about the case for a Brain Attack Trial?

When we were at the ECF meeting in Baveno DrK came up with a very important trial design to maximise the protection of the brain in MS. We all know that 'Time is Brain' and most MSologists will have patients who have had catastrophic relapses whilst waiting for a diagnostic workup and/or DMTs. We also know that MS activity tends to be clustered, i.e. one of the best predictors of a relapse is a recent relapse. Instead of putting patients with possible early symptomatic MS at risk from having to wait why don't we to treat them all with natalizumab to protect their brains and spinal cords? This is analogous to treating stroke.

Why natalizumab? It is one of our most effective DMTs, it works very quickly, it is given as an IV infusion, hence there is no problem with adherence and is very safe for up to 12 months. It is also relatively safe in pregnancy. During this 12 month period, the neurologist and the patient can then decide what strategy they want to pursue in the long-term. This could be to continue natalizumab long-term or to switch to another DMT, or in the case of an alternative diagnosis the drug can be stopped.

To make the Brain Attack Trial a reality we would have to get Biogen to ask the EMA to license natalizumab as a 1st-line treatment. This may require data. Hence we are proposing that Biogen sponsor a 'Brain Attack Trial'. This would become even more important if you can derisk the PML problem associated with natalizumab. Imagine if we can reduce the risk of PML to zero? Who wouldn't want to start on natalizumab as a first-line therapy? Natalizumab will become the one and only platform therapy. The problem with this is that Biogen has other DMTs in the MS space and the Brain Attack Trial will potentially result in natalizumab cannibalizing their other DMT market. How bold is Biogen?

I can't resist a business anecdote. Sony invented the Walkman, which transformed the way we listen to music. Sony then developed a digital version of the Walkman, i.e. their version of iPod. This was done a decade before Apple launched the iPod. However, Sony blinked and you should never blink in business. The issue was that Sony also produced content via Sony Music and other record labels (e.g. Columbia Records) and as a result of this Sony Executives decided it was too risky to launch the digital Walkman and decided to keep it under wraps and mothball it. Sony was worried that a digital Walkman would fuel digital piracy and cannibalize the music industry. Fast-forward a decade an Apple launches the iPod, which transforms the music industry, kills the Sony Walkman, revitalises Apple and the rest is history. 

Sony was the one company, outside of Apple, Steve Jobs admired and feared most. Have you compared the recent fortunes of Apple and Sony? Joseph Schumpeter, the famous economist, calls this creative destruction. 

The moral of this story is that if Biogen doesn't do this study another company will and Biogen will run the risk of becoming the Sony of the MS world; first admired, then envied and finally irrelevant.

ProfG