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