In a multicenter retrospective cohort study, we aimed to evaluate the incidence of lymphopenia following the initiation of siponimod treatment in clinical practice, as well as the factors predisposing to and the clinical relevance of lymphopenia events. The study involved data collected from the medical records of 129 patients with multiple sclerosis (MS) from 15 tertiary hospitals in Spain, all of whom had initiated treatment with siponimod and were followed for at least 3 months, with at least one lymphocyte count evaluation per patient.
Results showed that 121 out of 129 patients (93.6%) reported lymphopenia events. Of these, 110 patients (85.3%) experienced grade ≤ 3 lymphopenia, and 11 patients (8.5%) had grade 4 lymphopenia. These rates are higher than those reported in the pivotal clinical trial, where 73.3% of patients experienced grade ≤ 3 lymphopenia and 3.3% experienced grade 4 lymphopenia. Interestingly, the study had an unexpectedly high proportion of male patients (72.9%), which could have led to an underestimation of the actual risk magnitude in the broader population.
The findings from this study indicate that the incidence and severity of lymphopenia following the initiation of siponimod treatment were higher than those observed in prior clinical trials. This raises concerns about the treatment management of MS patients in clinical practice. The results suggest a need for larger studies to better characterize the risk of lymphopenia events and to identify potential risk factors. It is crucial to investigate whether factors such as an insufficient washout period, residual lymphopenia from prior therapies, or individual characteristics (such as sex or genetic factors) could contribute to the observed differences.
Additionally, it is important to assess the clinical consequences of lymphopenia in the current clinical landscape. Specifically, further research is needed to determine whether lymphopenia poses an increased risk for severe infections or affects the response to vaccination, similar to what has been observed with anti-CD20 therapies and their association with COVID-19 and vaccine responses. Finally, it is important to understand how prior therapies frequently used in clinical practice might influence the incidence of lymphopenia during siponimod treatment.