The Lasting Imprint of Past Therapies: How Prior Drug Exposure Shapes T-Cell Dynamics in Ocrelizumab-Treated MS Patients

< Multiple sclerosis (MS) is a complex immune-mediated demyelinating disorder of the central nervous system, driven by complex immune dysregulation. Over the past two decades, disease-modifying therapies (DMTs) have revolutionized MS care, targeting different immune pathways to limit relapses and progression. Among them, ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, has emerged as a key option for both relapsing-remitting MS (RRMS) and primary progressive MS (PPMS).

OCR’s main mechanism is depletion of CD20+ B cells, yet clinical trials also suggested modest reductions in T-cell subsets. This raised questions: Does OCR directly deplete T cells, or are observed changes a lingering effect of previous DMTs? Doriana Landi and colleagues (2022) tackled this question in a multicenter retrospective study, exploring how prior exposure to different drugs influences lymphocyte dynamics after OCR initiation.

Study Design in Brief
Cohort: 161 MS patients from 5 Italian centers, starting OCR between 2019–2020.

Groups:

Naïve (no prior DMT; n=40)

Fingolimod (FTY) switchers (n=52)

Other DMT switchers (dimethyl fumarate [DMF], glatiramer acetate, interferons, teriflunomide; n=69)

Follow-up: Lymphocyte subsets measured at baseline, 6 months, and 12 months.

Endpoints: Mean counts of total lymphocytes, CD3+, CD4+, CD8+, CD20+, and NK cells; prevalence of lymphocytopenia.

Key Findings
1. Ocrelizumab selectively depletes B cells
As expected, OCR almost completely depleted CD20+ B cells within 6 months, persisting through 12 months. This confirms its selectivity and consistency with trial data.

2. T-cell reduction is not uniform and depends on treatment history
Across the whole cohort, CD3+, CD4+, and CD8+ T-cell counts were largely stable over 12 months, with only minor transient reductions.

However, patients previously treated with fingolimod had significantly lower baseline T-cell values — especially CD3+ and CD4+ subsets — which persisted throughout follow-up.

Those switching from DMF also showed prolonged T-cell reductions, though less severe than FTY.

This suggests OCR itself exerts only modest pressure on T cells; most depletion stems from carryover effects of prior therapies, particularly fingolimod and DM.

3. Lingering lymphocytopenia is common after fingolimod
FTY group: Highest rates of lymphocytopenia across timepoints.

Logistic regression confirmed FTY pre-exposure significantly increased odds of total, CD3+, CD4+, and CD20+ lymphopenia at baseline, and of total/CD4+ lymphopenia at 6 and 12 months.

Importantly, the length of washout or treatment duration did not predict recovery — highlighting that immune reconstitution after FTY can be unexpectedly slow.

4. Clinical implications: a “double hit” on immune cells
OCR efficiently eliminates B cells. When layered onto prior FTY- or DMF-induced T-cell depletion, patients face dual suppression of B and T subsets. This could theoretically elevate infection or malignancy risk, though this study did not observe major opportunistic infections during its limited follow-up.

Why Does This Matter?
This study underscores the importance of treatment sequencing in MS. Unlike a “reset button,” switching to OCR does not erase the immunologic footprint of prior drugs. Instead, the immune system carries over suppressed T-cell pools, especially after S1P modulators like fingolimod.

For clinicians, this means:

Risk stratification: Patients switching from FTY or DMF may need closer infection surveillance.

Washout caution: Standard intervals (e.g., ~2 months after FTY) may be insufficient for immune recovery.

Personalized sequencing: Treatment choice should weigh not just the next drug’s efficacy, but the lingering biological consequences of the last. Limitations
The study was retrospective, lacked centralized lab assays, and had limited follow-up. It did not directly link lymphopenia to clinical outcomes (e.g., infections, cancer risk). Larger, prospective studies are needed to determine the true clinical impact of prolonged T-cell depletion after switching.

Conclusion
Landi et al. (2022) demonstrate that ocrelizumab-induced T-cell changes are largely shaped by prior DMT exposure rather than OCR itself. Fingolimod leaves a particularly strong immunologic shadow, with prolonged CD4+ lymphopenia even months after discontinuation.

As the MS> therapeutic landscape expands, understanding these immune dynamics is vital. Sequencing therapies without accounting for carryover effects could inadvertently heighten risks, while a careful, biology-informed approach may optimize both efficacy and safety in the long run.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Landi D, Grimaldi A, Bovis F, et al. Influence of Previous Disease-Modifying Drug Exposure on T-Lymphocyte Dynamic in Patients With Multiple Sclerosis Treated With Ocrelizumab. Neurol Neuroimmunol Neuroinflamm. 2022;9(3):e1157. doi:10.1212/NXI.0000000000001157