Contributions
Abstract: P1141
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: In CLARITY and CLARITY Extension, lymphopenia was the most common adverse event, consistent with the mechanism of action of cladribine tablets (CT). Absolute lymphocyte counts (ALC) were shown to recover towards the normal range over time in these studies.
Objective: To evaluate the effect of CT on innate immune cell counts.
Methods: Data from patients randomised to CT 3.5 mg/kg (CT 3.5; cumulative dose over 2 years) in CLARITY or CLARITY Extension (N=685) were pooled to provide long-term follow-up data. Data from patients randomised to placebo in CLARITY and followed up in PREMIERE are also reported (N=435). Neutropenia was graded by Common Terminology Criteria for Adverse Events v3.0.
Results: At baseline (start of CLARITY or CLARITY Extension), median (Q1-Q3) neutrophil counts were 4.19×109/L (3.30-5.31) for CT 3.5 and 4.20×109/L (3.41-5.35) for placebo. At the end of Year 1 (48 weeks), median neutrophil counts were 3.80×109/L (2.91-4.94) and 4.24×109/L (3.28-5.50) for CT 3.5 and placebo, respectively. At the end of Year 2 (96 weeks), neutrophil counts were 3.71×109/L (2.90-4.70) and 4.30×109/L (3.32-5.46) in CT 3.5 and placebo patients, respectively. At the end of Years 3 and 4 (144 and 192 weeks), neutrophils in the CT 3.5 group (with no further treatment) plateaued at 3.60×109/L. In the placebo group, median neutrophils were 4.28×109/L (3.30-5.25) and 3.46×109/L (2.49-5.80) at the end of Years 3 and 4, respectively. Following CT 3.5 treatment, neutrophil counts remained within the normal range (>2.03x109/L ) over the 2 treatment years and beyond, and ≤6 (< 2% ) patients treated with CT 3.5 reported Grade 3 or 4 neutropenia at any single time point. Baseline median (Q1-Q3) monocyte counts were 0.40×109/L (0.30-0.50) for CT 3.5 and 0.42×109/L (0.31-0.53) for placebo. At the end of Year 1 (48 weeks), the monocyte count was 0.36×109/L (0.27-0.45) for CT 3.5 and 0.42×109/L (0.34-0.53) for placebo. At the end of Years 2, 3 and 4, monocytes in the CT 3.5 group were 0.34×109/L (0.28-0.45), 0.36×109/L (0.28-0.48), and 0.36×109/L (0.26¬-0.44), respectively. In the placebo group, monocytes were 0.41×109/L (0.30-0.51), 0.40×109/L (0.32-0.50) and 0.42×109/L (0.32-0.55) at the end of Years 2, 3 and 4, respectively.
Conclusions: These data, together with the previously-reported data on ALC, support the concept that CT selectivity reduces adaptive immune cell counts, and that the impact on the innate immune system is relatively minor.
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).
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.
FD: is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Darmstadt, Germany.
CH: is an employee of Merck KGaA, Darmstadt, Germany.
GG: has received speaker honoraria and consulting fees from Abbvie, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec FivePrime, GlaxoSmithKline, GW Pharma, Merck,, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood.
Abstract: P1141
Type: Poster
Abstract Category: Therapy - disease modifying - 26 Immunomodulation/Immunosuppression
Background: In CLARITY and CLARITY Extension, lymphopenia was the most common adverse event, consistent with the mechanism of action of cladribine tablets (CT). Absolute lymphocyte counts (ALC) were shown to recover towards the normal range over time in these studies.
Objective: To evaluate the effect of CT on innate immune cell counts.
Methods: Data from patients randomised to CT 3.5 mg/kg (CT 3.5; cumulative dose over 2 years) in CLARITY or CLARITY Extension (N=685) were pooled to provide long-term follow-up data. Data from patients randomised to placebo in CLARITY and followed up in PREMIERE are also reported (N=435). Neutropenia was graded by Common Terminology Criteria for Adverse Events v3.0.
Results: At baseline (start of CLARITY or CLARITY Extension), median (Q1-Q3) neutrophil counts were 4.19×109/L (3.30-5.31) for CT 3.5 and 4.20×109/L (3.41-5.35) for placebo. At the end of Year 1 (48 weeks), median neutrophil counts were 3.80×109/L (2.91-4.94) and 4.24×109/L (3.28-5.50) for CT 3.5 and placebo, respectively. At the end of Year 2 (96 weeks), neutrophil counts were 3.71×109/L (2.90-4.70) and 4.30×109/L (3.32-5.46) in CT 3.5 and placebo patients, respectively. At the end of Years 3 and 4 (144 and 192 weeks), neutrophils in the CT 3.5 group (with no further treatment) plateaued at 3.60×109/L. In the placebo group, median neutrophils were 4.28×109/L (3.30-5.25) and 3.46×109/L (2.49-5.80) at the end of Years 3 and 4, respectively. Following CT 3.5 treatment, neutrophil counts remained within the normal range (>2.03x109/L ) over the 2 treatment years and beyond, and ≤6 (< 2% ) patients treated with CT 3.5 reported Grade 3 or 4 neutropenia at any single time point. Baseline median (Q1-Q3) monocyte counts were 0.40×109/L (0.30-0.50) for CT 3.5 and 0.42×109/L (0.31-0.53) for placebo. At the end of Year 1 (48 weeks), the monocyte count was 0.36×109/L (0.27-0.45) for CT 3.5 and 0.42×109/L (0.34-0.53) for placebo. At the end of Years 2, 3 and 4, monocytes in the CT 3.5 group were 0.34×109/L (0.28-0.45), 0.36×109/L (0.28-0.48), and 0.36×109/L (0.26¬-0.44), respectively. In the placebo group, monocytes were 0.41×109/L (0.30-0.51), 0.40×109/L (0.32-0.50) and 0.42×109/L (0.32-0.55) at the end of Years 2, 3 and 4, respectively.
Conclusions: These data, together with the previously-reported data on ALC, support the concept that CT selectivity reduces adaptive immune cell counts, and that the impact on the innate immune system is relatively minor.
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).
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.
FD: is an employee of EMD Serono, Inc., Billerica, USA, a business of Merck KGaA, Darmstadt, Germany.
CH: is an employee of Merck KGaA, Darmstadt, Germany.
GG: has received speaker honoraria and consulting fees from Abbvie, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec FivePrime, GlaxoSmithKline, GW Pharma, Merck,, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck, Novartis, and Ironwood.