An observational study of alemtuzumab following fingolimod for multiple sclerosis

Abstract

Objective:To describe a series of patients with relapsing multiple sclerosis (MS) who experienced significant and unexpected disease activity within the first 12 months after switching from fingolimod to alemtuzumab.Methods:Patients with relapsing MS treated sequentially with fingolimod then alemtuzumab who experienced significant subsequent disease activity were identified by personal communication with 6 different European neuroscience centers.Results:Nine patients were identified. Median disease duration to alemtuzumab treatment was 94 (39–215) months and follow-up from time of first alemtuzumab cycle 20 (14–21) months. Following first alemtuzumab infusion cycle, 8 patients were identified by at least 1 clinical relapse and radiologic disease activity and 1 by significant radiologic disease activity alone.Conclusions:We acknowledge the potential for ascertainment bias; however, these cases may illustrate an important cause of reduced efficacy of alemtuzumab in a vulnerable group of patients with MS most in need of disease control. We suggest that significant and unexpected subsequent disease activity after alemtuzumab induction results from prolonged sequestration of autoreactive lymphocytes following fingolimod withdrawal, allowing these cells to be concealed from the usual biological effect of alemtuzumab. Subsequent lymphocyte egress then provokes disease reactivation. Further animal studies and clinical trials are required to confirm these phenomena and in the meantime careful consideration should be given to mode of action of individual therapies and sequential treatment effects in MS when designing personalized treatment regimens.

Alemtuzumab depletion failure can occur in multiple sclerosis

“…Alternatively it has also been suggested that prior use of fingolimod, to sequester lymphocytes into lymphoid tissue and bone marrow, may block the activity of alemtuzumab and allow more rapid repopulation . Therefore, it is of interest that one of the poor depleters reported here was treated with fingolimod prior to alemtuzumab.…”

“…Two people depleted by < 50% after first administration, although one of these was lymphopenic at baseline. Of note, the individual who was a poor‐depleter (11·1%) had been treated with fingolimod, a risk factor for lack of alemtuzumab activity, before switching to alemtuzumab. However other individuals were identified who depleted very poorly upon the first infusion, but had not used fingolimod previously.…”

“…The failure to adequately report this issue has probably exposed people to the unnecessary risks of the procedures and risks of disease reactivation due to lack of efficacy. Indeed our own experience prompted us to investigate and expose the occurrence of alemtuzumab neutralization. This study indicates that at the individual level NAbs may indeed be very important, and shows that it is critical that lymphocyte‐depleting potential is monitored.…”

Clinical recommendations for the use of ocrelizumab in patients with multiple sclerosis

“…Неврология, нейропсихиатрия, психосоматика. 2019;11(3): [16][17][18][19][20][21][22][23][24][25] К Л И Н И Ч Е С К И Е Р Е К О М Е Н Д А Ц И И Таблица 3. Мониторирование уровня CD19-лимфоцитов в рутинной клинической практике не является обязательным, так как не влияет на график введения препарата.…”

MOG antibodies, cortical encephalitis, and more food for thought studies

“…Willis et al 2 describe 9 patients with relapsing MS treated sequentially with fingolimod and alemtuzumab, who developed substantial and unanticipated disease activity after starting alemtuzumab. In 8 of 9 patients, the disease activity included at least one clinical relapse in the first 12 months after initiating alemtuzumab, and all patients had MRI evidence of new disease activity.…”