Brain volume change after high-dose immunosuppression and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis

Hyunwoo Lee; Kunio Nakamura; Sridar Narayanan; Robert A Brown; Richard A Nash; Linda M Griffith; Kaitlyn C Steinmiller; Steven M Devine; George J Hutton; Uday Popat; Michael K Racke; George E Georges; James D Bowen; Douglas L Arnold

doi:10.1016/j.msard.2021.103149

Brain volume change after high-dose immunosuppression and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis

Mult Scler Relat Disord. 2021 Sep:54:103149. doi: 10.1016/j.msard.2021.103149. Epub 2021 Jul 12.

Authors

Affiliations

¹ McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada. Electronic address: Hyunwoo.Lee@mail.mcgill.ca.
² McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
³ McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; NeuroRx Research Inc., Montreal, QC, Canada.
⁴ McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada; ShadowLab Research Inc., Toronto, ON, Canada.
⁵ Colorado Blood Cancer Institute, Denver, CO, USA.
⁶ Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁷ Rho Inc., Chapel Hill, NC, USA.
⁸ Be The Match BioTherapies, National Marrow Donor Program (NMDP)/Be The Match, Center for International Blood and Marrow Transplant Research (CIBMTR), Minneapolis, MN, USA.
⁹ Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
¹⁰ Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
¹² Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
¹³ Swedish Medical Center, Seattle, WA, USA.

PMID: 34284316
DOI: 10.1016/j.msard.2021.103149

Abstract

Background: Brain volume loss (BVL) is commonly observed after high-dose immunosuppression and autologous hematopoietic cell transplantation (HDIT/HCT) for treatment of multiple sclerosis (MS). To better understand the mechanisms of underlying BVL associated with this treatment, we characterized the time courses of whole-brain (WB), grey-matter (GM) and white-matter (WM) volume loss in relapsing-remitting MS (RRMS) patients who received BEAM-based HDIT/HCT.

Methods: We used Jacobian integration to measure MRI-based WB, GM and WM volume changes up to 5 years after transplant in twenty-four RRMS participants who underwent BEAM-based HDIT/HCT. Using a two-piecewise mixed-effects model, we estimated the short-term (baseline to 1 year) and long-term (beyond 1 year) rates of BVL after HDIT/HCT. We also compared the rates based on the presence of gadolinium-enhancing lesions at baseline, and the maintenance of event-free survival during follow-up.

Results: On average, accelerated short-term BVL of -1.37% (SE: 0.21), -0.86% (SE: 0.28) and -2.18% (SE: 0.26) occurred in WB, GM and WM, respectively. Baseline T1-weighted MRI WM lesion volume was a significant predictor in the WB (short-term) and the WM (short-term and long-term). The average rates of BVL after the initial acceleration were -0.22%/y (SE: 0.10), -0.13%/y (SE: 0.11) and -0.36%/y (SE: 0.11) in the WB, GM and WM, respectively. Participants with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM (-1.56% vs. -0.27%, p = 0.01) and WB volume loss (-1.94% vs. -0.81%, p = 0.006) at 1 year follow-up as compared to those without gadolinium-enhancing lesions. WM volume loss was not significantly different (-2.59% vs. -1.66%, p = 0.16). Participants who maintained event-free survival had similar rates of BVL compared to those who did not.

Conclusions: BVL may accelerate for months after HDIT/HCT. However, over the long-term, adequate HDIT/HCT may reduce BVL rates to those similar to normal aging at the WB level.

Keywords: Atrophy; Chemotherapy; Hematopoietic stem cell transplantation; Magnetic resonance imaging; Multiple sclerosis; Relapsing-remitting.

MeSH terms

Atrophy / pathology
Brain / diagnostic imaging
Brain / pathology
Hematopoietic Stem Cell Transplantation*
Humans
Immunosuppression Therapy
Magnetic Resonance Imaging
Multiple Sclerosis* / pathology
Multiple Sclerosis, Relapsing-Remitting* / diagnostic imaging
Multiple Sclerosis, Relapsing-Remitting* / pathology
Multiple Sclerosis, Relapsing-Remitting* / therapy