Mortality and alcohol consumption
Authors: R. Doll, R. Peto
Journal: BMJ (1995)

<h3>Objective:</h3> To compare rates of lymphopenia in patients with high disease activity (HDA) and patients without HDA in CLARITY/CLARITY EXT. <h3>Background:</h3> In CLARITY, patients with HDA relapsing multiple sclerosis had clinical and magnetic resonance imaging responses to cladribine tablets 10mg (3.5mg/kg cumulative dose over 2 years [CT3.5]) that were generally better than non-HDA patients. <h3>Design/Methods:</h3> Patients were retrospectively analyzed using distinct HDA criteria: 1. High relapse activity (HRA): ≥2 relapses in the year before study entry whether on disease modifying drugs (DMD) or not; 2. HRA+ disease activity on treatment (DAT): ≥1 relapse AND ≥1 T1 gadolinium-enhancing or ≥9 T2 lesions in the year before study entry while on other DMDs. The CT3.5 group were patients exposed to CT3.5 in Years 1 and 2, while the CT7.0 group received further courses of CT in Years 3 and 4. Adverse Event of Special Interest (AESI) lymphopenia was analyzed across CLARITY and CLARITY EXT and was determined by absolute lymphocyte count (ALC). <h3>Results:</h3> In CT3.5 at Year 2 (CT3.5-Y2), AESIs/100 patient-years were similar in HRA (n=196) and HRA+DAT (n=219) subgroups (11.50; 13.09) and similar between corresponding non-HDA groups (14.08 [n=489]; 13.46 [n=466]). In CT7.0 at Year 4 (CT7.0-Y4) rates approximately doubled from CT3.5-Y2. Median ALC nadir (x10/L) for CT3.5-Y2 HRA and HRA+DAT were 0.71 and 0.70; median nadirs were 0.65 in corresponding non-HDA subgroups. CT7.0-Y4 had lower nadirs than CT3.5-Y2. CT3.5-Y2 incidence of Grade 3 lymphopenia, was similar between HDA and non-HDA subgroups whereas, CT7.0-Y4 was lower. Overall, Grade 3 lymphopenia incidence was lower in CT3.5-Y2 than CT7.0-Y4. Grade 4 lymphopenia incidence was low in all subgroups. <h3>Conclusions:</h3> There were no relevant differences between HDA and non-HDA groups in: AESI lymphopenia incidence, ALC nadir, and time to ALC nadir. Disease activity at baseline appeared unrelated to lymphopenia incidence during CLARITY/CLARITY EXT. <b>Disclosure:</b> Dr. Cook has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck, Bayer HealthCare, Sanofi-Aventis, Neurology Reviews, Biogen Idec, Teva Pharmaceuticals, Bayer HealthCare, Merck, Actinobac Biomed, Teva Pharmaceuticals, Biogen Idec and Actinobac Biomed, Inc. Dr. Cook has received research support from Bayer HealthCare. Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Biogen, Novartis, Teva Neuroscience and Roche Diagnostics Corporation. He has also received consultancy fees for advisory board meetings for Merck-Serono, Genzyme-Sanofi, Synthon BV, and Physicians’ Summit and several medical education meetings. Dr. Giovannoni has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders (Elsevier). Dr. Giovannoni has received research support from Takeda Pharmaceutical Company. Dr. Vermersch has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Almirall, Bayer, Biogen, Celgene, GlaxoSmithKline, Merck Serono, Novartis, Sanofi, Servier, and Teva. Dr. Vermersch has received research support from Almirall, Bayer, Biogen, Celgene, GlaxoSmithKline, Merck Serono, Novartis, Sanofi, Servier, and Teva. Dr. Soelberg Sorensen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, EMD Serono, Teva, Sanofi-Aventis, Sanofi Genzyme, Biogen, Merck &amp; Co., Novartis Pharmaceuticals, Teva, MedDay Pharmaceuticals, GSK, and Novartis Pharmaceuticals. Dr. Soelberg Sorensen has received research support from Biogen, Merck, Teva, Novartis Pharmaceuticals, Roche, and Sanofi Genzyme. Dr. Keller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck KGaA. Dr. Jack has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck KGaA, Darmstadt, Germany.