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Comparative Study
. 2025 Aug 6;272(9):559.
doi: 10.1007/s00415-025-13300-z.

Real-world comparison of lymphopenia profiles in S1P receptor modulators for multiple sclerosis: a multicenter retrospective study

Giorgia Teresa Maniscalco  1   2 , Maddalena Sparaco  3 , Maria Di Gregorio  4 , Giuseppina Cafasso  5 , Elisabetta Signoriello  3 , Felice Romano  6 , Rosa Iodice  7 , Roberta Fantozzi  8 , Paolo Bellantonio  8 , Aurora Zanghi  9 , Leonardo Sinisi  10 , Alessandro D'Ambrosio  11 , Vincenzo Busillo  12 , Valentina Scarano  5 , Rocco Capuano  4 , Luigi Lavorgna  11 , Michela Williams  2 , Antonio De Martino  1 , Maria Elena Di Battista  1 , Daniele Di Giulio Cesare  1 , Giacomo Lus  3 , Emanuele Cassano  13 , Paola Sofia Di Filippo  9 , Grazia Sibilia  10 , Gianmarco Abbadessa  3 , Vincenzo Andreone  1 , Simona Bonavita  14
Affiliations
Comparative Study

Real-world comparison of lymphopenia profiles in S1P receptor modulators for multiple sclerosis: a multicenter retrospective study

Giorgia Teresa Maniscalco et al. J Neurol. .

Abstract

Introduction: Sphingosine-1-phosphate (S1P) receptor modulators, regulating the S1P/S1PR pathway, lead to lymphocyte sequestration in lymphoid organs, which results in peripheral lymphopenia. This study evaluates the degree of lymphopenia induced by S1P modulators in people with Multiple Sclerosis (MS): Ozanimod, Siponimod, Ponesimod, and Fingolimod.

Methods: We conducted a retrospective multicenter study across thirteen MS centers in Italy, including 191 MS patients (mean age 46.4 years; 61.3% women). Of these, 28.8% received Siponimod, 26.2% Ozanimod, 24.1% Fingolimod, and 20.9% Ponesimod. Lymphocyte counts were measured at baseline (T0), one month (T1), three months (T3), and six months (T6) post-treatment. Lymphopenia grades range from 0 (≥ 1.0 × 10^9 cells/L) to 4 (< 0.2 × 10^9 cells/L), according to Common Terminology Criteria for Adverse Events.

Results: At T1, Ozanimod showed a significantly higher mean lymphocyte count than Siponimod and Fingolimod (p < 0.001), Ponesimod higher mean lymphocyte count than Siponimod (p = 0.006). The differences persisted between Ozanimod than Siponimod and Fingolimod at T3 (p = 0.01 and p = 0.04), and between Ponesimod and Siponimod at T6 (p = 0.03). Severe lymphopenia cases were significantly higher in Siponimod than in Ponesimod and Ozanimod, at T1 (p = 0.001 and p = 0.0001). The differences remained significant between Ozanimod and Siponimod, at T3 (p = 0.001), and between Ponesimod and Siponimod, Fingolimod and Ozanimod, at T6 (p = 0.001). Grade 4 lymphopenia was observed in Ozanimod and Siponimod at T3.

Conclusion: This is the first real-world, head-to-head observational study comparing lymphopenia among different S1P modulators. Our results might assist in therapy choice depending on patients baseline hematological characteristics.

Keywords: Lymphopenia; Multiple sclerosis; Sphingosine-1-phosphate receptor modulators.

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Conflict of interest statement

Declarations. Conflicts of interest: The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Trend of lymphocyte counts at the four timepoints
Fig. 2
Fig. 2
Combined percentage of cases presenting severe lymphopenia (Grade 3 + Grade 4) attributed to different S1P modulators at timepoints T1, T3, and T6
Fig. 3
Fig. 3
Percentage of cases with grade 3 and grade 4 lymphopenia separately reported across different S1P modulators at timepoints T1, T3, and T6
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