Integrated Lymphopenia Analysis in Younger and Older Patients With Multiple Sclerosis Treated With Cladribine Tablets

Abstract

Cladribine tablets (CladT) preferentially reduce B and T lymphocyte levels. As aging is associated with a decline in immune function, the effect of CladT on lymphocyte levels may differ by age. This post hoc analysis combined data from the Phase 3 CLARITY, CLARITY Extension, and ORACLE-MS studies to examine the effect of age (≤50 or >50 years) on lymphopenia following CladT 3.5 mg/kg (CladT3.5; cumulative dose over 2 years) treatment over 96 weeks. Both CladT3.5 and placebo were given over Weeks 1 and 5 (Year 1 treatment) and Weeks 48 and 52 (Year 2 treatment) from the start of the studies. Absolute lymphocyte count (ALC) and levels of lymphocyte subsets were examined in 1564 patients (Age ≤50 [placebo: N=566; CladT3.5: N=813]; Age >50 [placebo: N=75; CladT3.5: N=110]). In both age groups, following CladT3.5 treatment, nadir for ALC occurred at Week 9 (8 weeks following start of Year 1 treatment) and Week 55 (7 weeks following start of Year 2 treatment) of the 96-week period; for CD19+ B lymphocytes, nadir occurred at Week 9 (Year 1) and Week 52 (Year 2). For CD4+ T lymphocytes, nadir occurred at Week 16 (Year 1) in both age groups, and at Weeks 60 and 72 (Year 2) in the Age ≤50 and >50 groups, respectively. Nadir for CD8+ T lymphocytes occurred at Week 16 (Year 1) and Week 72 (Year 2) in the Age ≤50 group and levels remained in the normal range; nadir occurred at Week 9 (Year 1) and Week 96 (Year 2) in the Age >50 group. Lymphocyte recovery began soon after nadir following CladT3.5 treatment and median levels reached normal range by end of the treatment year in both age groups. By Week 96, ~25% of patients treated with CladT3.5 reported ≥1 episode of Grade ≥3 lymphopenia (Gr≥3L). The rate of certain infections was numerically higher in older versus younger patients who experienced Gr≥3L. In conclusion, CladT3.5 had a similar effect on ALC and lymphocyte subsets in both younger and older patient groups.

Trial registration: ClinicalTrials.gov NCT00213135 NCT00641537 NCT00725985.

Keywords: age; cladribine tablets; lymphocyte subsets; lymphopenia; multiple sclerosis.

Conflict of interest statement

The authors declare that this study received funding from EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA (CrossRef Funder ID: 10.13039/100004755). The funder had the following involvement with the study: designing the study, collecting and analyzing the data. The authors had full control of the manuscript and provided their final approval of all content. GG has received speaker honoraria and consulting fees from Abbvie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, Celgene-BMS, FivePrime, GlaxoSmithKline, GW Pharma, Janssen, Merck & Co., Merck Healthcare KGaA, Darmstadt, Germany, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and research support unrelated to this study from Biogen Idec, Merck & Co., Novartis, and Ironwood. PKC declares being an advisor or consultant for Accordant, Biogen, Bristol Myers Squibb, Celgene, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Janssen, Mylan, Novartis, and Viela Bio, and receiving grants for clinical research from Actelion, Alkermes, Celgene, Corrona LLC, Genentech/Roche, MedDay, NINDS, and Novartis. PV has received honoraria or consulting fees from Biogen, Sanofi-Genzyme, Novartis, Merck Healthcare KGaA, Darmstadt, Germany, Celgene, Roche, AB Science, and Imcyse; and research support from Biogen, Sanofi-Genzyme, and Merck Healthcare KGaA, Darmstadt, Germany. BW has received consulting fees from Biogen, Celgene, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Novartis, and Sanofi-Genzyme. JA is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. AN is an employee of Merck Healthcare KGaA, Darmstadt, Germany. AG was employed by Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA at the time of the study. He is now a consultant for Merck Healthcare KGaA, Darmstadt, Germany. CL is an employee of EMD Inc. Mississauga, Ontario, Canada, an affiliate of Merck KGaA. TPL received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Inc., Rockland, MA, USA, an affiliate of Merck KGaA, Darmstadt, Germany, Novartis, ONO, Pfizer and Teva Neuroscience.

Copyright © 2021 Giovannoni, Coyle, Vermersch, Walker, Aldridge, Nolting, Galazka, Lemieux and Leist.

Figures

Graphical Abstract

Figure 1

Absolute lymphocyte count and lymphocyte subset levels over time (Week 0–96) from first dose of cladribine tablets 3.5 mg/kg or placebo by age, ≤50 years and >50 years. (A) absolute lymphocyte count, (B) CD19+ B, (C) CD4+ T, and (D) CD8+ T lymphocyte subsets. Notes: Treatment weeks are indicated by black arrows. Only visits with a sample size ≥10 are shown (On the lymphocyte subset graphs no data plotted for Age ≤50: Placebo [Weeks 36 and 55]; Age >50: Placebo [Weeks 36, 55, 60 and 84]; Age >50: CladT3.5 [Week 55]). Reference line (red) in (A) corresponds to ALC lower limit of normal of 1.02 x 109/L. Reference line (red) in (B–D) corresponds to lower limit of normal of 100, 350 and of 200 cells/µL, for CD19+ B, CD4+ T and CD8+ T lymphocytes, respectively. ALC, absolute lymphocyte count; CladT3.5, cladribine tablets 3.5 mg/kg; IQR, interquartile range.

Figure 2

Time to first episode of Grade ≥3 lymphopenia with cladribine tablets 3.5 mg/kg by age group.