Data has suggested that patients with multiple sclerosis who have withdrawn from treatment with fingolimod (Gilenya, Novartis) can safely be treated effectively with alemtuzumab (Lemtrada, Sanofi Genzyme) or rituximab (Rituxan, Genentech/Biogen).
Francisco C. Pérez-Miralles, MD, PhD
Treating patients with relapsing multiple sclerosis (MS) who have withdrawn from fingolimod (Gilenya, Novartis) is both safe and effective with alemtuzumab (Lemtrada, Sanofi Genzyme) or rituximab (Rituxan, Genentech/Biogen).1
Previous research has suggested that therapies such as alemtuzumab would be less effective following fingolimod treatment due to the dynamics of lymphocyte repopulation post-withdrawal.2 This analysis has shown that after roughly 30 months, the annualized relapse rate (AAR) was significantly reduced from baseline with both alemtuzumab and rituximab (P <.001 for both), without significant differences between the 2 groups.
At baseline, the alemtuzumab group had an AAR of 1.29 and the rituximab group had an AAR of 1.24. After 28.8 months of follow-up, their respective AARs were 0.004 and 0.02.
The investigators, including coauthor Francisco C. Pérez-Miralles, MD, PhD, a clinical neurologist at Hospital Universitari i Politècnic la Fe in Valencia, Spain, noted that the baseline characteristics were similar between the 2 groups, “except to the median of [previously] received treatments and the mean disease duration from the first relapse to the new treatment, being both greater for rituximab.” Although, these differences are due to rituximab’s status as an off-label treatment for MS, thus the investigators pointed out that on-label treatments may have been prioritized, thus delaying the start of the drug.
Ultimately, the observational, retrospective study assessed 55 patients with a minimal follow-up of 6 months after fingolimod withdrawal. Of those, 28 patients were administered alemtuzumab and 27 patients were administered rituximab. In total, 90.9% of patients (n = 50) had active disease during the year prior to their treatment with either rituximab or alemtuzumab. In the remaining 5 patients, fingolimod withdrawal was due to adverse effects (AEs).
Of the 55 total patients with relapsing MS included, baseline lymphoctye counts (P = .3) and washout period (P = .9) were not different between patients who had inflammatory activity (n = 11; baseline lymphocyte count, 1056 [range, 680 to 1310]; washout period, 38 days [range, 15 to 70]) after alemtuzumab or rituximab and those who did not (n = 44; baseline lymphocyte count, 1310 [range, 782 to 1630]; washout period, 38 days [range, 20.5 to 58.5]).
Expanded Disability Status Scale (EDSS) scores were reduced from 2.8 to 2.0 in the alemtuzumab group and 3.5 to 2.5 in the rituximab group (P <.001 for both), without differences. In the alemtuzumab group, 82% (n = 28) of patients achieved no evidence of disease activity (NEDA) criteria, while 69.2% (n = 26) of patients in the rituximab group did so, with no differences between groups (P = .3).
As for safety and tolerability, symptoms related to the infusion were the most frequent AEs in both groups, occurring in 57.1% (n = 16) of those in the alemtuzumab group and 29.2% (n = 7) in the rituximab group. The specific symptoms which were most frequent were headache and cutaneous rash.
There was 1 withdrawal in the alemtuzumab group due to confirmed disability progression 2 years after the last infusion. That patient received a diagnosis of secondary-progressive multiple sclerosis (SPMS) was performed and compassionate treatment with rituximab was initiated. Comparatively, 6 patients in the rituximab group withdrew treatment: 2 due to suboptimal response, 2 due to AEs (1 for serum sickness and 1 for persistent pruritus), and 1 due to a safety concern after a diagnosis of breast cancer.
“We are conscious that our study has several limitations, mainly the retrospective design, the limited patient numbers, and the short follow-up time after the first course of alemtuzumab,” Pérez-Miralles and colleagues wrote.
They acknowledge that although confirmatory findings in a randomized trial would be advisable, the cost and difficulty of doing so are quite high. However, they also noted that real-life data studies can add novel information regarding the safety and lymphocyte repopulation dynamics, as well as aid in the design of future studies comparing the efficacy of high-efficacy drugs, thus “evidence from observational studies is paramount,” they wrote.
“Despite our limitations, in the absence of interventional, randomized studies, we conclude that treating RRMS patients with alemtuzumab or rituximab after fingolimod withdrawal is effective and safe,” they concluded.
This finding comes just months after the FDA issued a safety alert related to the halting of therapy with fingolimod, stating that the condition can become much worse when treatment is stopped in comparison to while it was being taken or when it was first started. This worsening, the agency warned, is rare but may lead to permanent disability. The FDA recommended that health care professionals inform their patients before starting treatment about the potential risk of a severe increase in disability after stopping fingolimod.3
1. Alcalá C, Gascón F, Pérez-Miralles F, Domínguez JA, Gil-Perotín S, Casanova B. Treatment with alemtuzumab or rituximab after fingolimod withdrawal in relapsing-remitting multiple sclerosis is effective and safe. J Neurol. Published online January 19, 2019.
2. Willis M, Pearson O, Illes Z et al (2017) An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2017;4(2).
3. FDA. Gilenya (fingolimod): Drug Safety Communication - Severe Worsening of Multiple Sclerosis After Stopping the Medicine. FDA website. Published November 20, 2018. fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm626264.htm. Accessed January 29, 2019.