Contributions
Abstract: P654
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Alemtuzumab is a humanised anti-CD52 monoclonal antibody that depletes circulating T and B lymphocytes. Following depletion, a distinctive pattern of T- and B-cell repopulation begins within weeks, potentially leading to a rebalancing of the immune system. Alemtuzumab demonstrated greater improvements in efficacy outcomes over SC IFNB-1a in patients with active relapsing-remitting MS (RRMS) who were treatment-naïve (CARE-MS I; NCT00530348) or had an inadequate response (≥1 relapse) to prior therapy at baseline (CARE-MS II; NCT00548405) over 2 years. An extension study (NCT00930553) has shown durable efficacy through 5 years in the absence of continuous treatment.
Goal: To evaluate the pattern of T- and B-cell depletion and repopulation in patients receiving only 2 courses of alemtuzumab and those receiving 1 or 2 retreatments.
Methods: In CARE-MS I and II, patients received 2 courses of alemtuzumab 12 mg (5 days at Month 0; 3 days at Month 12). Patients completing the studies could enter the extension, with as-needed alemtuzumab retreatment for relapse or MRI activity. Blood counts were tested monthly; lymphocytes were phenotyped by flow cytometry.
Results: In patients who received only the original 2 courses of alemtuzumab, mean CD4+, CD8+ and CD19+ counts at the start of Course 2 were 0.28, 0.24 and 0.34 x 109/L, respectively. Both T and B lymphocytes were depleted after the second course of alemtuzumab (N=369), reaching their lowest levels at 1 month after Course 2 (mean CD4+: 0.05; mean CD8+: 0.06; mean CD19+: 0.03 x 109/L). CD19+ counts repopulated quickly and reached the lower limit of normal (LLN; 0.1 x 109/L) by 3 months. T cells repopulated more slowly; CD8+ counts reached LLN (0.2 x 109/L) by about 6 months, and CD4+ counts reached LLN (0.5 x 109/L) at Month 24. Once reaching plateau (CD19+, 15 months; CD8+, 30 months; CD4+, 24 months), cell counts were stable through 48 months and remained above LLN. Depletion and repopulation of T and B cells were similar after 1 or 2 alemtuzumab retreatments (Course 3: n=79; Course 4: n=10).
Conclusions: The distinct pattern of lymphocyte repopulation began within weeks after alemtuzumab treatment, with T- and B-cell counts remaining stable through 48 months after reaching plateau. This pattern remained unchanged with retreatment. These effects may explain the durable efficacy of alemtuzumab in the absence of continuous treatment.
Disclosure:
Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.
ANB: Consulting fees/participated in clinical trials (Bayer, Biogen, Merck Serono, Novartis, Sanofi Aventis, Sanofi Genzyme, and Teva).
EH: Honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi Genzyme, and Teva) and support from Ministry of Education of Czech Republic, project PRVOUK-P26/LF1/4.
JK: Consulting and/or speaker fees (Bayer, Bio CSL, Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme) and principal investigator with funds to institution.
VL: Honoraria for consulting and speaking at symposia (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva, with approval by the HR-Department, Cologne General Hospital, University of Cologne).
KWS: Consulting and/or speaking fees (Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Synthon).
BS: Nothing to disclose.
PV: Consulting and/or speaking fees, and research support (Almirall, Bayer, Biogen, GlaxoSmithKline, Merck Serono, Novartis, Sanofi Genzyme, and Teva).
DHM and EC: Employees of Sanofi Genzyme.
SW: Consulting and/or speaking fees or principal investigator (Alkermes, Bayer, Biogen, EMD Serono, Sanofi Genzyme, and Teva).
Abstract: P654
Type: Poster
Abstract Category: Therapy - disease modifying - Immunomodulation/Immunosuppression
Background: Alemtuzumab is a humanised anti-CD52 monoclonal antibody that depletes circulating T and B lymphocytes. Following depletion, a distinctive pattern of T- and B-cell repopulation begins within weeks, potentially leading to a rebalancing of the immune system. Alemtuzumab demonstrated greater improvements in efficacy outcomes over SC IFNB-1a in patients with active relapsing-remitting MS (RRMS) who were treatment-naïve (CARE-MS I; NCT00530348) or had an inadequate response (≥1 relapse) to prior therapy at baseline (CARE-MS II; NCT00548405) over 2 years. An extension study (NCT00930553) has shown durable efficacy through 5 years in the absence of continuous treatment.
Goal: To evaluate the pattern of T- and B-cell depletion and repopulation in patients receiving only 2 courses of alemtuzumab and those receiving 1 or 2 retreatments.
Methods: In CARE-MS I and II, patients received 2 courses of alemtuzumab 12 mg (5 days at Month 0; 3 days at Month 12). Patients completing the studies could enter the extension, with as-needed alemtuzumab retreatment for relapse or MRI activity. Blood counts were tested monthly; lymphocytes were phenotyped by flow cytometry.
Results: In patients who received only the original 2 courses of alemtuzumab, mean CD4+, CD8+ and CD19+ counts at the start of Course 2 were 0.28, 0.24 and 0.34 x 109/L, respectively. Both T and B lymphocytes were depleted after the second course of alemtuzumab (N=369), reaching their lowest levels at 1 month after Course 2 (mean CD4+: 0.05; mean CD8+: 0.06; mean CD19+: 0.03 x 109/L). CD19+ counts repopulated quickly and reached the lower limit of normal (LLN; 0.1 x 109/L) by 3 months. T cells repopulated more slowly; CD8+ counts reached LLN (0.2 x 109/L) by about 6 months, and CD4+ counts reached LLN (0.5 x 109/L) at Month 24. Once reaching plateau (CD19+, 15 months; CD8+, 30 months; CD4+, 24 months), cell counts were stable through 48 months and remained above LLN. Depletion and repopulation of T and B cells were similar after 1 or 2 alemtuzumab retreatments (Course 3: n=79; Course 4: n=10).
Conclusions: The distinct pattern of lymphocyte repopulation began within weeks after alemtuzumab treatment, with T- and B-cell counts remaining stable through 48 months after reaching plateau. This pattern remained unchanged with retreatment. These effects may explain the durable efficacy of alemtuzumab in the absence of continuous treatment.
Disclosure:
Study support: Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.
ANB: Consulting fees/participated in clinical trials (Bayer, Biogen, Merck Serono, Novartis, Sanofi Aventis, Sanofi Genzyme, and Teva).
EH: Honoraria and grant support (Actelion, Biogen, Merck Serono, Novartis, Receptos, Roche, Sanofi Genzyme, and Teva) and support from Ministry of Education of Czech Republic, project PRVOUK-P26/LF1/4.
JK: Consulting and/or speaker fees (Bayer, Bio CSL, Biogen Idec, Merck Serono, Novartis, and Sanofi Genzyme) and principal investigator with funds to institution.
VL: Honoraria for consulting and speaking at symposia (Bayer, Biogen, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva, with approval by the HR-Department, Cologne General Hospital, University of Cologne).
KWS: Consulting and/or speaking fees (Biogen, Merck, Novartis, Roche, Sanofi Genzyme, and Synthon).
BS: Nothing to disclose.
PV: Consulting and/or speaking fees, and research support (Almirall, Bayer, Biogen, GlaxoSmithKline, Merck Serono, Novartis, Sanofi Genzyme, and Teva).
DHM and EC: Employees of Sanofi Genzyme.
SW: Consulting and/or speaking fees or principal investigator (Alkermes, Bayer, Biogen, EMD Serono, Sanofi Genzyme, and Teva).