The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease

Abstract

Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments. This trial was registered at www.ClinicalTrials.gov as #NCT05018728.

Graphical abstract

Figure 1.

Relationship between DCS and ASL–MRI measures of blood flow. CBF (mL/min per 100 g) measured with ASL-MRI vs CBF_i (1 × 10⁻⁷ cm²/s) measured with DCS (n = 8 patients). Strong correlation between the 2 measures was observed (R² = 0.651; P = .015). The solid line denotes the best linear fit to the data, and the dotted lines indicate the 95% CI to this fit. The slope of the line of best fit was 1.00 (95% CI, 0.97-1.03), and the intercept was 60.6 (95% CI, 55.7-65.4). CI, confidence interval.

Figure 2.

Effects of voxelotor on cerebral hemodynamic markers. (A-C) Box plots of OEF, CBF_i (1 × 10⁻⁷ cm²/s), and CBV (mL per 100 g) from pretreatment (black) to 4, 8, and 12 weeks after treatment (red). ∗P < .05; ∗∗P < .01; and ∗∗∗P < .001 compared with pretreatment levels using 2-sided paired Wilcoxon signed-rank test. (D-F) Box plots of relative percent changes from pretreatment levels of oxygen extraction fraction (rOEF), cerebral blood flow (rCBF_i), and cerebral blood volume (rCBV) from pretreatment. The horizontal gray dotted line at 0 denotes no change from pretreatment levels. For each box plot, the central line denotes the median, and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. The whiskers extend to the most extreme data points not considered outliers. Individual connected gray dots represent each pretreatment and posttreatment matched pair for the 8 patients.