Abstract Details

Title Absolute Lymphocyte Counts Are Not a Biomarker of Clinical Response in Patients Treated With Delayed-Release Dimethyl Fumarate

Topic Multiple Sclerosis

Presentation(s) P6 - Poster Session 6 (12:00 PM-1:00 PM)

Poster/Presentation
Number 9-003

Background

DMF treatment is associated with changes in circulating immune cells towards a naïve/anti-inflammatory phenotype in patients with relapsing-remitting multiple sclerosis (RRMS), regardless of magnitude of ALC changes. sNfL is an exploratory measure of disease activity and treatment response in MS.

Objective Explore associations between delayed-release dimethyl fumarate (DMF)-induced changes in peripheral lymphocytes, efficacy and serum neurofilament light (sNfL) levels. Describe ALC reconstitution post-DMF discontinuation.

Design/Methods

In PROCLAIM (EUDRA CT 20015-001973-42), a 96-week (W) phase 3b study of DMF 240 mg BID in patients aged 18-65 years (N=218), ALC, immune cell subsets, and proliferation markers were assessed by complete blood count and flow cytometry. Recent thymic emigrants (RTE) T-cells were assessed in a subset (n=10). Annualized relapse rate (ARR) was estimated from a negative binomial regression model, adjusted for baseline covariates. sNfL levels were measured using Single Molecule Array (NF-light^® Advantage).

Results Adjusted ARR was not associated with ALC across quartiles (Q) of change from baseline (CFB) ALC at W96 (ARR [95% CI] Q1: 0.11 [0.05, 0.23], Q2: 0.13 [0.07, 0.26], Q3: 0.06 [0.02, 0.14], and Q4: 0.17 [0.09, 0.31]). Change in EDSS and proportion of relapse-free patients were not associated with ALC quartiles. sNfL decreased by W96 (median %CFB: -21%, P<0.0001). sNfL %CFB did not differ across ALC, CD4⁺, or CD8⁺ T-cell categories. Greater numbers of proliferative (Ki67⁺ T cells) were observed in patients with greater ALC decline. CD4⁺/CD31⁺RTEs expanded. In patients with ALC <0.91×10⁹/L who discontinued DMF, ALC values increased to (median, range) 0.83x10⁹/L (0.63–1.91) by W16 (n=8) after discontinuation.

Conclusions

The magnitude of DMF-mediated changes in ALC was not associated with greater efficacy or sNfL change, suggesting ALC change is not a biomarker of DMF response. Increased T cell proliferation and RTE expansion, coupled with ALC increases, suggest the reversibility in ALC post-DMF discontinuation.

Support: Biogen

Authors/Disclosures
Erin Longbrake, MD, PhD, FAAN (Yale University) PRESENTER	Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving as a Consultant for TG Therapeutics. Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NGM Bio. Dr. Longbrake has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Longbrake has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme. Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Longbrake has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for ACTRIMS. Dr. Longbrake has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology. The institution of Dr. Longbrake has received research support from Genentech. The institution of Dr. Longbrake has received research support from Race to Erase MS. The institution of Dr. Longbrake has received research support from NINDS K23. The institution of Dr. Longbrake has received research support from Robert Patterson Leet Trust. The institution of Dr. Longbrake has received research support from Biogen. The institution of Dr. Longbrake has received research support from National MS Society. Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving as a Study Section Member with Department of Defense (CDMRP). Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving as a Programmatic Review with Department of Defense (CDMRP). Dr. Longbrake has received personal compensation in the range of $500-$4,999 for serving as a Study Section Member with National Institute of Health .
Yang Mao-Draayer, MD (University of Michigan, Department of Neurology)	Dr. Mao-Draayer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen Idec. Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme-Sanofi. Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen . Dr. Mao-Draayer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizone . Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genzyme-Sanofi. Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizone. Dr. Mao-Draayer has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen Idec. Dr. Mao-Draayer has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Janssen. The institution of Dr. Mao-Draayer has received research support from NIH . The institution of Dr. Mao-Draayer has received research support from Genzyme-Sanofi. The institution of Dr. Mao-Draayer has received research support from Novartis. The institution of Dr. Mao-Draayer has received research support from Genentech.
Paul Matthews, MD (Imperial College, London)	No disclosure on file
John F. Foley, MD, FAAN (Rocky Mountain MS Clinic)	The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Octave. Dr. Foley has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics . The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon Therapeutics. The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. Dr. Foley has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Foley has stock in InterPRO Bioscience. The institution of Dr. Foley has received research support from Biogen. The institution of Dr. Foley has received research support from Novartis. The institution of Dr. Foley has received research support from Octave. The institution of Dr. Foley has received research support from Genentech. The institution of Dr. Foley has received research support from Imstem. The institution of Dr. Foley has received research support from Aegir.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Becky J. Parks, MD (Blueprint Medicines)	Dr. Parks has received personal compensation for serving as an employee of Alexion Pharmaceuticals. Dr. Parks has stock in Biogen. Dr. Parks has stock in Illumina. An immediate family member of Dr. Parks has stock in Regeneron. Dr. Parks has stock in Blueprint Medicines. Dr. Parks has stock in Sanofi. An immediate family member of Dr. Parks has stock in Vertex. Dr. Parks has stock in AstraZeneca. The institution of an immediate family member of Dr. Parks has received research support from NIH/NCI. The institution of an immediate family member of Dr. Parks has received research support from Leukemia & Lymphoma Society. The institution of an immediate family member of Dr. Parks has received research support from AstraZeneca Scholar Award.
Ankur Sharma (Main Boys Hostel, Kem Hospital)	No disclosure on file
Dongxia Xing	No disclosure on file
	No disclosure on file
Eris Bame	No disclosure on file