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.
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.
ProfG
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Why nobody tried the obvious idea of using 5-ht2a antagonists as preventive measure in those, who s at high risk?Say quentiapine… I saw it in a list of potentially remyelinating agents so this potentially could be win/win