Improvement in Cerebral Vasoreactivity after 6 Months of Voxelotor Measured By Near-Infrared Spectroscopy (NIRS) in Sickle Cell Disease Patients

Introduction:

Neurovascular damage is one the main causes of morbidity and mortality in adults with sickle cell disease (SCD). This vulnerability is partly explained by chronic anemia and hemolysis, leading to endothelial dysfunction that can be associated with an impairment of cerebral vaso-reactivity. Near Infrared Spectroscopy (NIRS) has emerged in recent years as a non-invasive method to measure relative amounts of oxyhemoglobin (OxyHb), deoxyhemoglobin (DeoxyHb), Tissue Saturation Index (TSI) and total hemoglobin (Total Hb) in brain tissue in real time. OxyHb variation is a reflection of cerebral perfusion, which we have shown to be improved during erythracytapheresis in SCD patients with steno-occlusive arterial disease. NIRS can also be used to measure cerebral vaso-reactivity by an apneic maneuver that increases arterial CO2, resulting in vasodilation that increases cerebral blood flow. The HEMOPROVE study (NCT05199766) is an open-label, single-arm, single-dose Phase II study in SCD patients treated with Voxelotor 1500 mg daily for 48 weeks. The primary endpoint of this study is to evaluate the effect of Voxelotor on reducing intravascular hemolysis parameters after 48 weeks of treatment. An interim analysis of the HEMOPROVE trial was performed to evaluate the effect of 6 months of Voxelotor in SCD patients and its determinants on cerebral vascular reactivity measured by NIRS. Final 48-week results may provide additional insight.

Method:

SS or S–beta0 Thal patients were included if they were more than one month from a vaso-occlusive crisis, 3 months from a transfusion. A stable dose for at least 3 months was required for patients treated with hydroxyurea (HU) or angiotensin-converting enzyme inhibitors. Patients with Moyamoya were excluded. NIRS was performed continuously in the two cerebral hemispheres during 5 minutes. The areas of interest were studied with the two sensors, or optodes, corresponding to the border zones between the territory of the anterior cerebral artery and the middle cerebral artery, which are the zones the most injured in individuals with SCD. Cerebral oxygen saturations (TSI) and OxyHb variations were measured over time. Data were analyzed at predefined time points according to pre- or post-apnea periods: steady state (mean), 30 seconds of apnea, 1 min and 3 min after apnea onset (peak max.). Cerebral vasoreactivity was assessed by measuring OxyHb in real time before and after apnea; vasoreactivity was defined as a positive increase in OxyHb before/after apnea. Data are presented as median [IQR]. Correlations were performed using a Spearman test, paired data comparisons were made with a Wilcoxon test (Graphpad9, PRISM).

Results:

NIRS were evaluable at 6 month of follow-up in 14 patients. Homozygous SS genotype was showed in 86%. The median age was 43 years [35 - 56], the sex ratio F/M was 0.5 and 57% of the patients were treated with HU. We observed a significant increase in Hb from 7.3 g/dL [6.6 - 7.9] at M0 to 8.7 g/dL [8.0 - 9.9] at M6 (p<0.05); lactate dehydrogenase (LDH) decreased significantly from 689 UI/L [549 - 965] to 476 UI/L [338 - 593] (p<0.05). TSI at baseline increased significantly in both hemispheres from 59.9% [56.9 - 61.5] at M0 to 63.1% [60.0 - 66.8] at M6 (p<0.05). We found a correlation between decrease in LDH and increase in TSI during apnea in both hemispheres (right, p=0.03; r= -0.59; left hemisphere, p=0.01; r= -0.67). Six patients (12 hemispheres) were evaluable for analysis of vasoreactivity, defined as a significant increase in OxyHb before and after apnea. Vasoreactivity was present in all hemispheres at M0 (p<0.05) and M6 (p<0.05). An increase in vasoreactivity was observed after 6 months of voxelotor treatment from 3.9 UA [2.9 - 7.7] at M0 to 9.4 UA [7.8 - 12.9] at M6 (p<0.05).

Conclusions:

An improvement in vasoreactivity was observed in both hemispheres after 6 months of treatment with Voxelotor. The improvement in hemolysis was associated with better cerebral blood oxygen saturation during apnea.