PMID- 35690010 OWN - NLM STAT- MEDLINE DCOM- 20220721 LR - 20220721 IS - 2211-0356 (Electronic) IS - 2211-0348 (Linking) VI - 64 DP - 2022 Aug TI - Immunological consequences of cladribine treatment in multiple sclerosis: A real-world study. PG - 103931 LID - S2211-0348(22)00442-4 [pii] LID - 10.1016/j.msard.2022.103931 [doi] AB - BACKGROUND: Cladribine is a synthetic deoxyadenosine analogue approved for the treatment of highly active relapsing multiple sclerosis (RMS). Cladribine is considered to be a semi-selective immune-reconstitution therapy (IRT) that induces long-term remission following short course of treatment. Here, we evaluated the effect of cladribine on immune cell reduction and reconstitution during the first two years of treatment. METHODS: We analyzed our longitudinal, prospective, real-world cohort of 80 cladribine-treated RMS patients from two tertiary centers in Germany. Laboratory testing was conducted monthly and included evaluation of cellular as well as soluble parameters. Laboratory outcomes were correlated with infectious adverse events (AEs) and clinical or paraclinical disease activity. RESULTS: Selective alterations in immune cell populations occurred following cladribine treatment, with the most marked effects observed in year two of treatment. Specifically, a rapid reduction in CD56(+) natural killer cells (nadir: month 1 (year 1) and 14 (year 2); -37 and -41% from baseline) was followed by a greater reduction in CD19(+) B cells (nadir: month 2 and 14; -81 and -82%); a moderate effect on CD4(+) (nadir: month 3 and 15; -48 and -61%) and CD8(+) T cells (nadir: month 5 and 18; -40 and -48%). Despite the marked effect on B cells, immunoglobulin levels were unaffected. There was no or minimal effect on thrombocytes and innate immune cells. Clinical and paraclinical disease activity was unrelated to the observed immune alterations. Lymphopenia was the most commonly observed AE (86.3% of patients; grade III-IV lymphopenia: 38.8%). The cumulative incidence of infections was 55% with cladribine treatment, which were mostly mild or moderate. In total, 19 herpes infections developed in 8 (10%) cladribine-treated patients; all cases were dermatomal and 94.7% of the herpetic infections occurred during a period of lymphopenia. CONCLUSIONS: The immunophenotyping data obtained in our real-world setting are comparable to those demonstrated in pivotal clinical trials and provide further evidence that cladribine may represent a form of IRT. However, regarding the side-effect profile of cladribine, severe lymphopenia (exceeding grade II CTCAE) was more frequent, which may have prompted the development of herpes infections. Of note, lymphocyte dynamics did not correlate with clinical and paraclinical measures of disease activity in the two-year follow-up period. CI - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Rolfes, Leoni AU - Rolfes L AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. Electronic address: leoni.rolfes@med.uni-duesseldorf.de. FAU - Pfeuffer, Steffen AU - Pfeuffer S AD - LWL Clinics Muenster, Muenster Germany. FAU - Huntemann, Niklas AU - Huntemann N AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. FAU - Schmidt, Mariella AU - Schmidt M AD - Department of Neurology with Institute of Translational Neurology, University of Muenster. FAU - Su, Chuanxin AU - Su C AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. FAU - Skuljec, Jelena AU - Skuljec J AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. FAU - Aslan, Derya AU - Aslan D AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. FAU - Hackert, Jana AU - Hackert J AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. FAU - Kleinschnitz, Konstanze AU - Kleinschnitz K AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. FAU - Hagenacker, Tim AU - Hagenacker T AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. FAU - Pawlitzki, Marc AU - Pawlitzki M AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. FAU - Ruck, Tobias AU - Ruck T AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. FAU - Kleinschnitz, Christoph AU - Kleinschnitz C AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. FAU - Meuth, Sven G AU - Meuth SG AD - Department of Neurology, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany. FAU - Pul, Refik AU - Pul R AD - Department of Neurology, University Medicine Essen, Essen; Germany/Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany. LA - eng PT - Journal Article DEP - 20220529 PL - Netherlands TA - Mult Scler Relat Disord JT - Multiple sclerosis and related disorders JID - 101580247 RN - 0 (Immunosuppressive Agents) RN - 47M74X9YT5 (Cladribine) SB - IM MH - CD8-Positive T-Lymphocytes MH - Cladribine/adverse effects MH - Humans MH - Immunosuppressive Agents/adverse effects MH - *Lymphopenia/chemically induced MH - *Multiple Sclerosis/chemically induced/drug therapy MH - *Multiple Sclerosis, Relapsing-Remitting/chemically induced/drug therapy MH - Prospective Studies MH - Recurrence OTO - NOTNLM OT - Adverse events OT - Cladribine OT - Immunology OT - Inflammation OT - Multiple sclerosis OT - Reconstitution EDAT- 2022/06/12 06:00 MHDA- 2022/07/22 06:00 CRDT- 2022/06/11 18:27 PHST- 2022/04/25 00:00 [received] PHST- 2022/05/27 00:00 [accepted] PHST- 2022/06/12 06:00 [pubmed] PHST- 2022/07/22 06:00 [medline] PHST- 2022/06/11 18:27 [entrez] AID - S2211-0348(22)00442-4 [pii] AID - 10.1016/j.msard.2022.103931 [doi] PST - ppublish SO - Mult Scler Relat Disord. 2022 Aug;64:103931. doi: 10.1016/j.msard.2022.103931. Epub 2022 May 29.