Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab

Abstract

ObjectiveTo examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.MethodsPatients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.ResultsLymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes.ConclusionsRepopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.

Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis

“…Evaluating mean numbers of lymphocytes subsets over time, we could not find a systematic difference in the immune-profiling between ATZ CR vs. PR patients. Our results are in line with other reports focusing on pooled analyses of immunological data of patients with or without disease activity (13,15). Due to the fact that the timing of reappearance of disease activity was individually different from patient to patient, we implemented an event-driven approach to analysis in our cohort.…”

“…These depletion-repopulation kinetics are purportedly responsible for the positive, long-term effects of ATZ on disease activity, and for its established side-effect profile, including secondary autoimmunity (10,13,14). Previous evaluations have not been able to make a link between the recovery of selected T and B cells and MS disease activity after ATZ treatment (13,15).…”

“…After ATZ infusion, follow up evaluation up to 7 years are presented. (B) ATZ treated patients that were retreated with ATZ additionally to two standard ATZ treatments are depicted (partial-responder, patient[10][11][12][13][14][15][16]. Clinical disease course including pre-treatment, relapse activity and MRI progress within yearly MRI scans before and after ATZ infusion and intervals of ATZ retreatment are shown threw yearly time intervals.…”

Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: Pooled analysis of the CARE-MS, extension, and TOPAZ studies

“…Treatment with alemtuzumab increases suppressive function of regulatory T (Treg) cells and shifts the cytokine balance toward a less inflammatory environment lasting years. 11,12 Analyses of total lymphocytes or subsets of CD4+ and CD8+ T cells (naïve, memory, Treg) and B cells (immature, mature, memory) detected no differences between CARE-MS patients with and without disease activity after alemtuzumab; 29,30 however, one study found that increased interleukin-17-producing CD4+ cells may be associated with relapses in alemtuzumab-treated patients. 11 Further examination of more refined subsets of lymphocytes may allow prediction of disease activity and subsequent need for additional courses.…”

Mitigating alemtuzumab-associated autoimmunity in MS

“… 3 , 4 Antibody-mediated secondary autoimmune disease in patients with MS treated with alemtuzumab approaches an incidence of 40%–50% in prolonged follow-up, with a peak incidence by the third year following treatment initiation and waning incidence thereafter. 5 – 16 …”