Both cladribine and alemtuzumab may effect MS via B-cell depletion

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.

Figure 1. Cladribine targets mainly lymphocytes

Mean number of red blood cells and leucocytes following treatment with either placebo (n = 42–101. Typically, the lower limit of sample size was n = 63, except week on 55) or a total doses of either 3.5 mg/kg (n = 47–103. Typically, the lower limit of sample size was n = 67, except on week 55) or 5.25 mg/kg (n = 38–104. Typically, the lower limit of sample size was n = 62, except on week 55). Placebo (circle) or cladribine (CLAD) that was administered in monthly courses (inverse triangle) at 0, 5 and 48 and 52 weeks (diamond; 3.5 mg per dose) and additionally at 9 and 13 weeks (hexagon; 5.25 mg per dose). The results show the mean ± SEM of (A) red blood cells (B) platelets (C) white blood cells, (D) lymphocytes, (E) monocytes, (F) polymorphonuclear neutrophils, (G) eosinophils, or (H) basophils.

Figure 2. Cladribine preferentially depletes B lymphocytes compared with a modest depletion of T cells

The results represent the mean percentage ± SEM of blood lymphocytes compared with baseline following treatment with either placebo (circle; n = 56–79) or total doses of either 3.5 mg/kg (diamond; n = 62–82) or 5.25/kg (hexagon; n = 66–81) cladribine (CLAD) administered in monthly courses (inverse triangle) at 0, 5 and 48 and 52 weeks (3.5 mg per dose) and additionally at 9 and 13 weeks (5.25 mg per dose). Results show the numbers of (A) CD3⁺ T cells, (B) CD19⁺ B cells, (C) CD4⁺ T cells (D) CD8⁺ T cells, and (E) CD4⁺-naive and (F) CD4⁺ memory T cells.

Figure 3. The incidence of relapse does not relate to peripheral blood CD3, CD4, CD8, CD19, T- and B-cell levels

Cladribine (CLAD) was administered as weekly courses at 0, 5 and 48 and 52 weeks. The results represent the mean ± SEM absolute number (per cubic millimeter) of peripheral blood: (A) CD3, (B) CD19, (C) CD4, and (D) CD8 lymphocytes following treatment (inverse triangles) with oral CLAD in the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) trial administered with 3.5 mg/kg CLAD and those divided into groups who remained healthy (circle; n = 121–136 per group) or those who had at least 1 relapse (diamond; n = 29–34). pwRMS = people with relapsing MS.

Figure 4. Depletion of lymphocyte subsets following alemtuzumab and cladribine treatment

Cladribine (CLAD) was administered as weekly courses of CLAD at 0, 5 and 48 and 52 weeks (time of initiation of cycle; inverse triangle) or weekly courses of alemtuzumab (ALEM) at 0 and 52 weeks. The results represent the mean absolute number of peripheral blood lymphocytes (per cubic millimeter) during the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) trial in people with relapsing MS (pwRMS) treated with either placebo (circle; n = 68–80), CLAD 3.5 mg/kg (diamond; n = 77–86), CLAD 5.25 mg/kg (hexagon; n = 79–84), and pwRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) trial treated with 12 mg/d ALEM (square; n = 171–184).