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Both cladribine and alemtuzumab may effect MS via B-cell depletion.
Neurol Neuroimmunol Neuroinflamm. 2017 Jul; 4(4):e360.NN

Abstract

OBJECTIVE

To understand the efficacy of cladribine (CLAD) treatment in MS through analysis of lymphocyte subsets collected, but not reported, in the pivotal phase III trials of cladribine and alemtuzumab induction therapies.

METHODS

The regulatory submissions of the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) (NCT00213135) cladribine and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data were extracted and statistically analyzed.

RESULTS

Either dose of cladribine (3.5 mg/kg; 5.25 mg/kg) tested in CLARITY reduced the annualized relapse rate to 0.16-0.18 over 96 weeks, and both doses were similarly effective in reducing the risk of MRI lesions and disability. Surprisingly, however, T-cell depletion was rather modest. Cladribine 3.5 mg/kg depleted CD4+ cells by 40%-45% and CD8+ cells by 15%-30%, whereas alemtuzumab suppressed CD4+ cells by 70%-95% and CD8+ cells by 47%-55%. However, either dose of cladribine induced 70%-90% CD19+ B-cell depletion, similar to alemtuzumab (90%). CD19+ cells slowly repopulated to 15%-25% of baseline before cladribine redosing. However, alemtuzumab induced hyperrepopulation of CD19+ B cells 6-12 months after infusion, which probably forms the substrate for B-cell autoimmunities associated with alemtuzumab.

CONCLUSIONS

Cladribine induced only modest depletion of T cells, which may not be consistent with a marked influence on MS, based on previous CD4+ T-cell depletion studies. The therapeutic drug-response relationship with cladribine is more consistent with lasting B-cell depletion and, coupled with the success seen with monoclonal CD20+ depletion, suggests that B-cell suppression could be the major direct mechanism of action.

Authors+Show Affiliations

BartsMS (D.B., S.S.H., C.A.G., C.A., K.S.), Blizard Institute, ITS Research (L.Z.), Queen Mary University of London; and Barts Health NHS Trust (K.S.), Emergency Care & Acute Medicine Neuroscience Clinical Academic Group, London, UK.BartsMS (D.B., S.S.H., C.A.G., C.A., K.S.), Blizard Institute, ITS Research (L.Z.), Queen Mary University of London; and Barts Health NHS Trust (K.S.), Emergency Care & Acute Medicine Neuroscience Clinical Academic Group, London, UK.BartsMS (D.B., S.S.H., C.A.G., C.A., K.S.), Blizard Institute, ITS Research (L.Z.), Queen Mary University of London; and Barts Health NHS Trust (K.S.), Emergency Care & Acute Medicine Neuroscience Clinical Academic Group, London, UK.BartsMS (D.B., S.S.H., C.A.G., C.A., K.S.), Blizard Institute, ITS Research (L.Z.), Queen Mary University of London; and Barts Health NHS Trust (K.S.), Emergency Care & Acute Medicine Neuroscience Clinical Academic Group, London, UK.BartsMS (D.B., S.S.H., C.A.G., C.A., K.S.), Blizard Institute, ITS Research (L.Z.), Queen Mary University of London; and Barts Health NHS Trust (K.S.), Emergency Care & Acute Medicine Neuroscience Clinical Academic Group, London, UK.BartsMS (D.B., S.S.H., C.A.G., C.A., K.S.), Blizard Institute, ITS Research (L.Z.), Queen Mary University of London; and Barts Health NHS Trust (K.S.), Emergency Care & Acute Medicine Neuroscience Clinical Academic Group, London, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28626781

Citation

Baker, David, et al. "Both Cladribine and Alemtuzumab May Effect MS Via B-cell Depletion." Neurology(R) Neuroimmunology & Neuroinflammation, vol. 4, no. 4, 2017, pp. e360.
Baker D, Herrod SS, Alvarez-Gonzalez C, et al. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e360.
Baker, D., Herrod, S. S., Alvarez-Gonzalez, C., Zalewski, L., Albor, C., & Schmierer, K. (2017). Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurology(R) Neuroimmunology & Neuroinflammation, 4(4), e360. https://doi.org/10.1212/NXI.0000000000000360
Baker D, et al. Both Cladribine and Alemtuzumab May Effect MS Via B-cell Depletion. Neurol Neuroimmunol Neuroinflamm. 2017;4(4):e360. PubMed PMID: 28626781.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Both cladribine and alemtuzumab may effect MS via B-cell depletion. AU - Baker,David, AU - Herrod,Samuel S, AU - Alvarez-Gonzalez,Cesar, AU - Zalewski,Lukasz, AU - Albor,Christo, AU - Schmierer,Klaus, Y1 - 2017/06/05/ PY - 2017/01/16/received PY - 2017/04/05/accepted PY - 2017/6/20/entrez PY - 2017/6/20/pubmed PY - 2017/6/20/medline SP - e360 EP - e360 JF - Neurology(R) neuroimmunology & neuroinflammation JO - Neurol Neuroimmunol Neuroinflamm VL - 4 IS - 4 N2 - OBJECTIVE: To understand the efficacy of cladribine (CLAD) treatment in MS through analysis of lymphocyte subsets collected, but not reported, in the pivotal phase III trials of cladribine and alemtuzumab induction therapies. METHODS: The regulatory submissions of the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) (NCT00213135) cladribine and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data were extracted and statistically analyzed. RESULTS: Either dose of cladribine (3.5 mg/kg; 5.25 mg/kg) tested in CLARITY reduced the annualized relapse rate to 0.16-0.18 over 96 weeks, and both doses were similarly effective in reducing the risk of MRI lesions and disability. Surprisingly, however, T-cell depletion was rather modest. Cladribine 3.5 mg/kg depleted CD4+ cells by 40%-45% and CD8+ cells by 15%-30%, whereas alemtuzumab suppressed CD4+ cells by 70%-95% and CD8+ cells by 47%-55%. However, either dose of cladribine induced 70%-90% CD19+ B-cell depletion, similar to alemtuzumab (90%). CD19+ cells slowly repopulated to 15%-25% of baseline before cladribine redosing. However, alemtuzumab induced hyperrepopulation of CD19+ B cells 6-12 months after infusion, which probably forms the substrate for B-cell autoimmunities associated with alemtuzumab. CONCLUSIONS: Cladribine induced only modest depletion of T cells, which may not be consistent with a marked influence on MS, based on previous CD4+ T-cell depletion studies. The therapeutic drug-response relationship with cladribine is more consistent with lasting B-cell depletion and, coupled with the success seen with monoclonal CD20+ depletion, suggests that B-cell suppression could be the major direct mechanism of action. SN - 2332-7812 UR - https://www.unboundmedicine.com/medline/citation/28626781/Both_cladribine_and_alemtuzumab_may_effect_MS_via_B_cell_depletion_ L2 - http://nn.neurology.org/cgi/pmidlookup?view=long&pmid=28626781 DB - PRIME DP - Unbound Medicine ER -
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