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Brain Atrophy after High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Multiple Sclerosis (HALT-MS)
Abstract
Background:
High-Dose Immunosuppressive Therapy (HDIT) and Autologous Hematopoietic Cell Transplantation (HCT) for Multiple Sclerosis (HALT-MS) was a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression while on MS disease-modifying therapy. High rates of short-term brain volume loss have been observed following similar treatments.
Objectives:
To model the time-courses of whole-brain (WB), grey-matter (GM), and white-matter (WM) volume loss in HALT-MS subjects to better understand the effect of this treatment on brain atrophy in MS.
Methods:
We measured percentage WB, GM, and WM volume changes (Pairwise Jacobian Integration) over up to 5 years in twenty-four RRMS patients who underwent BEAM (BiCNU, Etoposide, Ara-C, Melphalan) chemotherapy-based HDIT and HCT. A non-linear mixed-effects model was applied to the volume trajectory data, with the total dose of BEAM chemotherapy and the baseline volume of T1-weighted WM lesion (T1LV) as predictors of treatment-related volume loss. We estimated the rates of both short-term treatment-related and long-term volume loss. Subgroup analysis included comparing the short-term and long-term rates of volume loss between the patients with and without gadolinium-enhancing lesions at baseline.
Results:
Rapid short-term volume loss occurred in all compartments: 0.98% (SE: 0.60), 1.2% (0.77), and 1.6% (0.84) in WB, GM, and WM, respectively. Total BEAM dose was a significant predictor of the rate of volume loss in all compartments. T1LV was a significant predictor for WB and WM volume loss. The average long-term rates of volume loss after the initial treatment-related effects slowed to -0.22%/y (SE: 0.075), -0.12%/y (0.081), and -0.15%/y (0.11) in the WB, GM, and WM, respectively.
Patients with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM volume loss (-1.83% vs. -0.40%, p=0.003) and WB volume loss (-1.90% vs. -0.76%, p=0.002) at 1-year follow-up, and significantly higher long-term rate of GM volume loss (-0.26%/y vs. -0.0051%/y, p=0.025). The difference in long-term WB loss did not reach significance (-0.32%/y vs. -0.13%/y, p=0.081).
Conclusion:
Brain volume loss may accelerate for months after HDIT/HCT due to the effects of chemotherapy-related toxicity and progression of WM lesion-related degeneration. However, over the long-term, adequate immunosuppression and HCT can reduce rates of brain volume loss to the range observed in normal aging.
Authors
Presenting Author
Hyunwoo Lee
Montreal Neurological Institute and Hospital, McGill University
Additional Authors
Kunio Nakamura
Cleveland Clinic
Sridar Narayanan
Montreal Neurological Institute and Hospital, McGill University
Robert A Brown
Montreal Neurological Institute and Hospital, McGill University
Richard A Nash
Colorado Blood Cancer Institute
Douglas L. Arnold
Montreal Neurological Institute and Hospital, McGill University
Brain Atrophy after High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Multiple Sclerosis (HALT-MS)
Abstract
Background:
High-Dose Immunosuppressive Therapy (HDIT) and Autologous Hematopoietic Cell Transplantation (HCT) for Multiple Sclerosis (HALT-MS) was a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression while on MS disease-modifying therapy. High rates of short-term brain volume loss have been observed following similar treatments.
Objectives:
To model the time-courses of whole-brain (WB), grey-matter (GM), and white-matter (WM) volume loss in HALT-MS subjects to better understand the effect of this treatment on brain atrophy in MS.
Methods:
We measured percentage WB, GM, and WM volume changes (Pairwise Jacobian Integration) over up to 5 years in twenty-four RRMS patients who underwent BEAM (BiCNU, Etoposide, Ara-C, Melphalan) chemotherapy-based HDIT and HCT. A non-linear mixed-effects model was applied to the volume trajectory data, with the total dose of BEAM chemotherapy and the baseline volume of T1-weighted WM lesion (T1LV) as predictors of treatment-related volume loss. We estimated the rates of both short-term treatment-related and long-term volume loss. Subgroup analysis included comparing the short-term and long-term rates of volume loss between the patients with and without gadolinium-enhancing lesions at baseline.
Results:
Rapid short-term volume loss occurred in all compartments: 0.98% (SE: 0.60), 1.2% (0.77), and 1.6% (0.84) in WB, GM, and WM, respectively. Total BEAM dose was a significant predictor of the rate of volume loss in all compartments. T1LV was a significant predictor for WB and WM volume loss. The average long-term rates of volume loss after the initial treatment-related effects slowed to -0.22%/y (SE: 0.075), -0.12%/y (0.081), and -0.15%/y (0.11) in the WB, GM, and WM, respectively.
Patients with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM volume loss (-1.83% vs. -0.40%, p=0.003) and WB volume loss (-1.90% vs. -0.76%, p=0.002) at 1-year follow-up, and significantly higher long-term rate of GM volume loss (-0.26%/y vs. -0.0051%/y, p=0.025). The difference in long-term WB loss did not reach significance (-0.32%/y vs. -0.13%/y, p=0.081).
Conclusion:
Brain volume loss may accelerate for months after HDIT/HCT due to the effects of chemotherapy-related toxicity and progression of WM lesion-related degeneration. However, over the long-term, adequate immunosuppression and HCT can reduce rates of brain volume loss to the range observed in normal aging.
Authors
Presenting Author
Hyunwoo Lee
Montreal Neurological Institute and Hospital, McGill University
Additional Authors
Kunio Nakamura
Cleveland Clinic
Sridar Narayanan
Montreal Neurological Institute and Hospital, McGill University
Robert A Brown
Montreal Neurological Institute and Hospital, McGill University
Richard A Nash
Colorado Blood Cancer Institute
Douglas L. Arnold
Montreal Neurological Institute and Hospital, McGill University