Assessing Sustained B-Cell Depletion and Disease Activity in a French Multiple Sclerosis Cohort Treated by Long-Term IV Anti-CD20 Antibody Therapy

Infectious Diseases Neurology Biochemistry Medical Imaging Life Sciences Immunology Medicine
multiple sclerosis anti-CD20 B-cell depletion disease activity long-term therapy adverse events immunotherapy

Long-term Intravenous Anti-CD20 Antibody Therapy Assessment in a French Multiple Sclerosis Cohort

Background and Research Motivation

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease affecting the central nervous system, leading to varying degrees of physical and cognitive impairment. Recent Phase II and III clinical trials of selective intravenous (IV) B-cell depleting therapies (BCDTs) targeting the CD20 antigen on B lymphocytes have significantly transformed the treatment landscape for relapsing MS (RMS) and active progressive MS (PMS). However, there is limited research on how sustained B-cell depletion from long-term BCDT affects clinical and radiological stability.

While some studies have explored reduced BCD doses or extended dosing intervals, whether sustained B-cell depletion accurately predicts disease activity in MS patients remains unclear. Moreover, long-term anti-CD20 therapy carries risks of severe infections, including hypogammaglobulinemia and lymphocytopenia. To address these issues, this study aims to evaluate the efficacy and safety of long-term IV anti-CD20 antibody therapy in MS patients.

Study Source and Methodology Overview

This study was conducted at the MS expert center of Lille University Hospital (CHU of Lille), with data collected between January 2014 and September 2021. The paper, authored by Sean A. Freeman and his team, was published in Neurotherapeutics (2023, Vol. 20).

The study is a single-center retrospective cohort analysis involving 192 MS patients who underwent BCDT for over one year and completed at least three treatment cycles. Patients included relapsing (RMS, 62.5%), secondary progressive (SPMS, 17.7%), and primary progressive (PPMS, 19.8%) MS phenotypes. The study focused on: - Achieving no evidence of disease activity (NEDA-3) and minimal evidence of disease activity (MEDA) statuses. - Maintenance of sustained B-cell depletion. - The incidence and influencing factors of severe adverse events (SAEs).

Clinical and radiological data were evaluated using brain and spinal cord MRI scans and the Expanded Disability Status Scale (EDSS). Data were collected before each BCDT treatment cycle.

Study Process and Experimental Design

1. Patient Grouping and Treatment Plans

Patients were categorized based on their MS phenotypes, with treatment plans including: - Fixed-dose regimens of ocrelizumab or rituximab administered every six months at 600 mg. - Documentation of patient histories and pre-treatment disease activity (including MRI activity and annual relapse rates).

2. Data Collection and Analysis

Data collection included: - B-cell depletion status: Confirmed by CD19+ cell proportion. - Immunoglobulin (Ig) levels: Monitoring IgA, IgG, and IgM dynamics. - Lymphocyte subsets: Quantities of CD4+ and CD8+ T-cells and NK cells. - SAE data: Documenting severe infections requiring hospitalization.

3. Statistical Analysis

Statistical methods included the Mann-Whitney U test, Fisher exact test, and Bonferroni correction to adjust for multiple comparisons.

Key Findings

1. Achievement of NEDA-3 and MEDA Status

  • At 18 months, 84.2% of patients achieved NEDA-3, and 96.9% achieved MEDA.
  • Most patients failed to achieve NEDA-3 at 12 months, primarily due to new lesions visible on MRI.

2. Sustained B-Cell Depletion and Disease Activity

  • At 18 months, 85.8% of patients maintained sustained depletion of CD19+ B-cells. However, sustained depletion did not significantly predict clinical or radiological stability.

3. Immunoglobulin Level Dynamics

  • IgM levels began to decrease six months into BCDT and remained low throughout treatment.
  • IgG levels significantly decreased after 30 months, while IgA levels dropped at 42 months.

4. SAE Incidence and Risk Factors

  • SAE rates were low (4.04/100 patient-years), with urinary tract infections (42.8%) and pneumonia being the most common.
  • SAEs primarily occurred in patients with extended BCDT cycles, suggesting a cumulative effect.

5. Effects of Prior Lymphocytopenia-Inducing Treatments (LIT)

  • Patients with prior LIT exhibited lower T-cell counts before and during early BCDT cycles.
  • These patients also showed a higher proportion of IgG hypogammaglobulinemia at 30 months.

Study Conclusions

This study demonstrates that long-term anti-CD20 antibody therapy enables high rates of disease control (NEDA-3 and MEDA statuses), particularly after 18 months of treatment. However, sustained B-cell depletion status alone does not predict disease control. The study also confirms that long-term BCDT is associated with significant IgG hypogammaglobulinemia and that SAE risks increase with prolonged treatment duration.

The findings suggest the possibility of adjusting BCDT strategies after 18 months to balance disease control and adverse event risks. Future studies on personalized treatment strategies should focus on the dynamics of B-cell subpopulations and the reconstitution rates of memory B-cells.

Research Implications

This study provides valuable insights for optimizing long-term BCDT in MS patients, emphasizing the importance of monitoring biomarkers such as Ig levels and lymphocyte subsets. These findings may inform future personalized treatment protocols, minimizing risks while maintaining therapeutic efficacy.