Contributions
Abstract: P667
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: ORACLE-MS demonstrated the efficacy of cladribine tablets 3.5mg/kg (cumulative dose over 2 years) in patients with early multiple sclerosis (MS). Evaluation of lymphocyte subtypes from patients in the cladribine tablets 3.5 mg/kg arm of the study showed that a transient ~82% median reduction in CD19+ B cell count occurred by week 13 with reconstitution from week 24 to 48. CD4+ and CD8+ T cells were also reduced (median reductions between ~40 and ~55%). Because of the durable clinical effects of cladribine tablets, the influence on cells with regulatory immune function is also of interest.
Objective: To examine effects on central and effector memory CD4+ T cells and naturally occurring regulatory CD4+ T cells (nTregs) after the first administration of cladribine tablets in the ORACLE-MS study.
Methods: Peripheral blood T lymphocytes were immunophenotyped at baseline, and weeks 5, 13, 24 and 48 in patients treated with cladribine tablets at week 1 and week 5 in ORACLE-MS (3.5 mg/kg group; n=41) using T lymphocyte surface markers. Absolute numbers and proportions of central memory (CD4+RO+CCR7+), effector memory (CD4+RO+CCR7-), Th1-type (CD4+CXCR3+) and nTregs (CD4+CD25+CD127-), including naïve-like nTregs (CD4+CD25+CD127-RA[HI]+) and memory-like nTregs (CD4+CD25+CD127-RA-) were measured.
Results: Greatest median reductions from baseline in absolute cell numbers occurred at week 13 for effector memory cells (-54%) and week 24 for central memory (-63%) and Th1-type cells (-51%) with similar or slightly increased levels of these CD4+ cell subtypes at week 48. Over time, there was a reduction (~5%) in the proportion of the central memory cells in total CD4+ cells, but no change in proportion for effector memory and Th1-type cells. Absolute numbers of nTregs (-48%), naïve-like nTregs (-67%) and memory-like nTregs (-42%) were decreased at week 48. The proportions of nTregs and naïve-like nTregs in total CD4+ cells were not changed. Memory-like nTregs slightly increased up to 48 weeks after treatment with cladribine tablets (median increase from baseline in the proportion of memory-like nTregs was 11% at week 48).
Conclusion: The first administration of cladribine tablets has a comparable magnitude of effect on CD4+ T cell subpopulations, with no dramatic shifts in their proportions. Further investigation is ongoing to explore the implications for the mechanism of action of cladribine tablets in MS and the effects of retreatment in the second year.
Disclosure: This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW).
OS: serves on the editorial boards of JAMA Neurology, Multiple Sclerosis Journal, and Therapeutic Advances in Neurological Disorders. He has served on data monitoring committees for Pfizer and TG Therapeutics without monetary compensation. He has advised Genzyme and Novartis, and has participated in a Teva-sponsored meeting. He currently receives grant support from Teva Pharmaceuticals and Opexa Therapeutics. He is funded by a Merit Review grant (federal award document number (FAIN) I01BX001674) from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development.
PS-S: has served on advisory boards for Biogen, Merck, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck Serono, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck, Teva, Novartis, Roche, and Genzyme.
TL: has received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, Teva Neuroscience.
YH, DD and UB: are employees of EMD Serono, USA.
Abstract: P667
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: ORACLE-MS demonstrated the efficacy of cladribine tablets 3.5mg/kg (cumulative dose over 2 years) in patients with early multiple sclerosis (MS). Evaluation of lymphocyte subtypes from patients in the cladribine tablets 3.5 mg/kg arm of the study showed that a transient ~82% median reduction in CD19+ B cell count occurred by week 13 with reconstitution from week 24 to 48. CD4+ and CD8+ T cells were also reduced (median reductions between ~40 and ~55%). Because of the durable clinical effects of cladribine tablets, the influence on cells with regulatory immune function is also of interest.
Objective: To examine effects on central and effector memory CD4+ T cells and naturally occurring regulatory CD4+ T cells (nTregs) after the first administration of cladribine tablets in the ORACLE-MS study.
Methods: Peripheral blood T lymphocytes were immunophenotyped at baseline, and weeks 5, 13, 24 and 48 in patients treated with cladribine tablets at week 1 and week 5 in ORACLE-MS (3.5 mg/kg group; n=41) using T lymphocyte surface markers. Absolute numbers and proportions of central memory (CD4+RO+CCR7+), effector memory (CD4+RO+CCR7-), Th1-type (CD4+CXCR3+) and nTregs (CD4+CD25+CD127-), including naïve-like nTregs (CD4+CD25+CD127-RA[HI]+) and memory-like nTregs (CD4+CD25+CD127-RA-) were measured.
Results: Greatest median reductions from baseline in absolute cell numbers occurred at week 13 for effector memory cells (-54%) and week 24 for central memory (-63%) and Th1-type cells (-51%) with similar or slightly increased levels of these CD4+ cell subtypes at week 48. Over time, there was a reduction (~5%) in the proportion of the central memory cells in total CD4+ cells, but no change in proportion for effector memory and Th1-type cells. Absolute numbers of nTregs (-48%), naïve-like nTregs (-67%) and memory-like nTregs (-42%) were decreased at week 48. The proportions of nTregs and naïve-like nTregs in total CD4+ cells were not changed. Memory-like nTregs slightly increased up to 48 weeks after treatment with cladribine tablets (median increase from baseline in the proportion of memory-like nTregs was 11% at week 48).
Conclusion: The first administration of cladribine tablets has a comparable magnitude of effect on CD4+ T cell subpopulations, with no dramatic shifts in their proportions. Further investigation is ongoing to explore the implications for the mechanism of action of cladribine tablets in MS and the effects of retreatment in the second year.
Disclosure: This study was sponsored by EMD Serono Inc, a business of Merck KGaA, Darmstadt, Germany (in the USA), and Merck Serono SA, Geneva, an affiliate of Merck KGaA Darmstadt, Germany (ROW).
OS: serves on the editorial boards of JAMA Neurology, Multiple Sclerosis Journal, and Therapeutic Advances in Neurological Disorders. He has served on data monitoring committees for Pfizer and TG Therapeutics without monetary compensation. He has advised Genzyme and Novartis, and has participated in a Teva-sponsored meeting. He currently receives grant support from Teva Pharmaceuticals and Opexa Therapeutics. He is funded by a Merit Review grant (federal award document number (FAIN) I01BX001674) from the United States (U.S.) Department of Veterans Affairs, Biomedical Laboratory Research and Development.
PS-S: has served on advisory boards for Biogen, Merck, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck Serono, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck, Teva, Novartis, Roche, and Genzyme.
TL: has received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, Teva Neuroscience.
YH, DD and UB: are employees of EMD Serono, USA.