Hematopoietic Stem Cell Transplant and Brain Volume Changes in Adults With Sickle Cell Disease

Clinical Snapshot

Key Findings

• P Value: Group difference p < 0.001

• Effect Size: Successful HSCT: -0.055%/year vs Graft failure: -0.42%/year (7-fold difference)

• Primary Outcome: Brain parenchymal fraction (BPF) decline rate

• Nnt Or Sensitivity: Hemoglobin change association: 0.035%/year BPF preservation per unit Hb increase (95% CI 0.017, 0.053)

• Confidence Interval: Successful HSCT: 95% CI -0.12, 0.006; Graft failure: 95% CI -0.57, -0.26

Clinical Application

Limited to specialized transplant centers with expertise in SCD and access to advanced MRI neuroimaging Relevant to Australian comprehensive cancer centers and blood and marrow transplant units. HSCT for SCD may be considered under special access schemes through TGA. Neuroimaging surveillance protocols could inform Australian SCD management guidelines Adults with severe sickle cell disease being considered for hematopoietic stem cell transplant

Abstract

BACKGROUND AND OBJECTIVES: Adults with sickle cell disease (SCD) are at risk of decline in brain health and cognition, even without clinical stroke. SCD-related changes on MRI include brain atrophy and T2 fluid attenuated inversion recovery (FLAIR) white matter hyperintensity (WMH) growth. Hematopoietic stem cell transplant (HSCT) can be curative, but conditioning regimens risk new complications, particularly for adults with accumulated organ damage. We tested whether successful HSCT for adults with SCD was associated with reduced brain atrophy or WMH growth. METHODS: In this cohort study, adults with severe SCD underwent HSCT as part of 5 research protocols at the National Institutes of Health Clinical Center, including autologous gene therapy, HLA-matched donor HSCs, and haploidentical HSCs. Serial brain MRI scans acquired before and after transplant for up to 12 years included 3D T1-weighted and axial FLAIR sequences. Longitudinal brain volumes, segmented using FreeSurfer and corrected for total intracranial volume (TICV), were used to measure brain parenchymal fraction (BPF). A deep learning algorithm segmented WMH volumes from FLAIR sequences. Volumes were log2-transformed as a percentage of TICV. We tested whether HSCT success (persistent engraftment vs graft failure) or change in hemoglobin (Hb) (post-pre-HSCT) was associated with the rate of brain atrophy or WMH growth using mixed-effects linear regression. Random effects included scanner, participant intercept, and slope, while fixed effects included age and sex. RESULTS: Seventy-seven participants (mean age 32 ± 9 years, 43% female) who underwent HSCT were followed for a median 5.3 years (interquartile range [IQR] = 4.6). For 65 participants with successful HSCT, BPF declined nonsignificantly (-0.055%/year; 95% CI -0.12, 0.006; p = 0.08). Twelve participants with graft failure had a 7-fold greater BPF decline (-0.42%/year; 95% CI -0.57, -0.26; p < 0.001; group difference p < 0.001). A smaller change in Hb after HSCT was associated with steeper BPF decline (0.035%/year per unit Hb; 95% CI 0.017, 0.053; interaction p < 0.001). WMH growth was similar in both groups (0.038% vs 0.030% per year; interaction p = 0.50) and was associated with older age and baseline WMHs, but not treatment success. DISCUSSION: Successful HSCT was associated with preserved brain volume, but not WMH growth, another brain health biomarker. Whether these HSCT-related brain structural changes translate to cognitive preservation remains to be determined. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT02140554 registered 2014-05-14, first enrollment February 2015; ClinicalTrials.gov NCT00061568; registered 2004-07-16, first enrollment July 2004; ClinicalTrials.gov NCT02105766; registered 2014-04-01, first enrollment April 2014; ClinicalTrials.gov NCT03077542; registered 2017-03-10, first enrollment April 2017; ClinicalTrials.gov NCT00977691; registered 2009-12-14, first enrollment December 2009. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in adults with sickle cell disease, successful hematopoietic stem cell transplant is associated with slower declines in BPFs over a median period of 5 years, compared with patients with transplant failure.

References

1. 1.Kern, K. C., Inam, Z., Hsieh, M. M., Tisdale, J., Fitzhugh, C. D., Limerick, E. M., Gebremeskel, A. S. K., White, T., Jordan, L. C., & Lynch, J. K. (2026). Hematopoietic stem cell transplant and brain volume changes in adults with sickle cell disease. Neurology. https://doi.org/10.1212/WNL.0000000000218050