RESUMO
Objective: In the pivotal DEFINE and CONFIRM trials for dimethyl fumarate (DMF), patterns of brain volume changes were different, potentially due to low sample sizes and because MRIs were analyzed at two different reading centers. We evaluated effects of DMF on brain volume change in patients with multiple sclerosis (MS) through reanalysis of pooled images from DEFINE/CONFIRM trials in one reading center. Methods: MRIs from DEFINE/CONFIRM at weeks 0, 24, 48, and 96 from patients randomized to twice-daily DMF or placebo (PBO) were reanalyzed at the Cleveland Clinic to measure brain parenchymal fraction (BPF). To account for pseudoatrophy, brain volume estimates were re-baselined to calculate changes for weeks 48-96. Results: Across studies, 301 and 314 patients receiving DMF and PBO, respectively, had analyzable MRIs. In weeks 0-48, mean ± SE percentage change in BPF was -0.44 ± 0.04 vs. -0.34 ± 0.04% in DMF vs. PBO, respectively, whereas in weeks 48-96, mean ± SE percentage change in BPF was -0.27 ± 0.03 vs. -0.41 ± 0.04% in DMF vs. PBO, respectively. The mixed-effect model for repeated measures showed similar results: in weeks 48-96, estimated change (95% confidence interval) in BPF was -0.0021 (-0.0027, -0.0016) for DMF vs. -0.0033 (-0.0039, -0.0028) for PBO (35.9% reduction; p = 0.0025). Conclusions: The lower rate of whole brain volume loss with DMF in this pooled BPF analysis in the second year vs. PBO is consistent with its effects on relapses, disability, and MRI lesions. Brain volume changes in the first year may be explained by pseudoatrophy effects also described in other MS clinical trials.
RESUMO
In delayed-release dimethyl fumarate (DMF)-treated patients, absolute lymphocyte count (ALC) often declines in the first year and stabilizes thereafter; early declines have been associated with development of severe prolonged lymphopenia (SPL). Prolonged moderate or severe lymphopenia is a known risk factor for progressive multifocal leukoencephalopathy (PML); DMF-associated PML is very rare. It is unknown whether genetic predictors of SPL secondary to DMF treatment exist. We aimed to identify genetic predictors of reduced white blood cell (WBC) counts in DMF-treated multiple sclerosis (MS) patients. Genotyping (N = 1,258) and blood transcriptional profiling (N = 1,133) were performed on MS patients from DEFINE/CONFIRM. ALCs were categorized as: SPL, < 500 cells/µL for ≥6 months; moderate prolonged lymphopenia (MPL), < 800 cells/µL for ≥6 months, excluding SPL; mildly reduced lymphocytes, < 910 cells/µL at any point, excluding SPL and MPL; no lymphopenia, ≥910 cells/µL. Genome-wide association, HLA, and cross-sectional gene expression studies were performed. No common variants, HLA alleles, or expression profiles clinically useful for predicting SPL or MPL were identified. There was no overlap between genetic peaks and genetic loci known to be associated with WBC. Gene expression profiles were not associated with lymphopenia status. A classification model including gene expression features was not more predictive of lymphopenia status than standard covariates. There were no genetic predictors of SPL (or MPL) secondary to DMF treatment. Our results support ALC monitoring during DMF treatment as the most effective way to identify patients at risk of SPL.
