Abstract Details

Title Revealing the Immune Cell Subtype Reconstitution Profile in Cladribine Treated Patients at the 96 Week Timepoint (CLARITY) Using Deconvolution Algorithms

Topic Multiple Sclerosis

Presentation(s) P11 - Poster Session 11 (8:00 AM-9:00 AM)

Poster/Presentation
Number 9-016

Objective Characterize immune cell transcriptomic signatures in peripheral blood from patients with relapsing-remitting multiple sclerosis during immune repopulation at 96 weeks in the CLARITY study using advanced computational algorithms and to correlate these signatures with corresponding flow cytometry data of main lymphocyte subtypes.

Background Cladribine tablets (CT) cumulative licensed dose of 3.5mg/kg (CT3.5), administered as two short oral courses over 2 years, transiently reduces total lymphocyte counts, with median values returning to normal range within 11 months and median B-cells by 6 months. Clinical efficacy of CT is sustained beyond lymphocyte recovery. Flow cytometric observations suggest long-lasting reductions in memory B-cells.

Design/Methods Gene expression data (U133 Plus 2.0 array) in whole blood samples at 96 weeks were available from patients randomized to placebo (n=57), CT3.5 (n=62) or CT 5.25mg/kg (CT5.25, n=70). These were analyzed with the CIBERSORT deconvolution algorithm (to estimate absolute fractions of 22 immune cell subtypes) and the xCell signature-based method (cell type enrichment analysis for 43 immune cell subtypes). Wilcoxon Rank Sum tests compared between treatment arms. Spearman's rank correlation coefficient was used to measure the relationship between signatures and cell counts. P-values <0.05 were considered nominally significant.

Results At 96 weeks, the relative abundance of naïve B-cells in CT3.5+5.25mg/kg treated patients was significantly higher vs placebo. Plasma cells and class-switched memory B-cells were significantly reduced with CT vs placebo. The M2 macrophage signature was significantly enhanced with CT vs placebo. Cell abundance of both naïve and memory CD4⁺ and CD8⁺ was significantly reduced with CT vs placebo. Deconvolution signature scores were positively and significantly correlated with corresponding flow cytometry data (r: 0.68–0.72 CD19+ B-cells, 0.71 CD4+ T-cells, 0.67–0.69 CD8+ T-cells).

Conclusions At 96 weeks following CT treatment in Year 2, changes in leukocytes suggestive of a shift towards an anti-inflammatory phenotype were detected.

Authors/Disclosures
PRESENTER	No disclosure on file
Gavin Giovannoni, MD (QMUL)	Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck KGaA. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche-Genentech. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Astoria Biologica. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zenas. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medscape.
Thomas Leist, MD, PhD, F�鶹��ýӳ�� (Thomas Jefferson University)	Dr. Leist has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Leist has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Leist has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Leist has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Genentech. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Horizon. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Seono. Dr. Leist has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Wittness with DHHS HRSA.
Per Soelberg Sorensen	No disclosure on file
Ursula Boschert Shafaatian (C/o Serono)	Ursula Boschert has nothing to disclose.
Julie E. Demartino	No disclosure on file
	No disclosure on file

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