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2500 Voxelotor Impact after 6 Months on Blood Rheology in Patients with Sickle Cell Disease

Program: Oral and Poster Abstracts
Session: 114. Sickle Cell Disease, Sickle Cell Trait, and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality)
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Gonzalo De Luna, MD1*, Laura Bencheikh, PhD2*, Philippe Connes, MD, PhD3*, Thomas D'Humieres, MD4,5*, Philippe Le Corvoiser, MD6*, Sihem Alouni, MD1*, Jamila Alhamrouni, MD1*, Raphaelle Arrouasse, MD6*, Dalila Bitari6*, Anoosha Habibi, MD1, Fatima Bensiradj, MD1*, Etienne Audureau, MD, PhD7*, Vincent Malcor Deydier De Pierrefeu, PhD7*, PA Natella, MD7*, Meghan Perkins, PhD2*, Laura Matabishi-Bibi, PhD2*, Caroline Barau, PhD8*, Marie Cambot, PhD2* and Pablo Bartolucci, MD, PhD1,9*

1Sickle Cell Referral Center, UMGGR, Department of Internal Medicine, Henri-Mondor University Hospital- UPEC, AP-HP, Créteil, France
2INNOVHEM, Créteil, France
3Laboratory CRIS EA647, Team "Vascular Biology and Red Blood Cell", University of Lyon, Lyon, France; Institut Universitaire de France, Paris, France, Villeurbanne, FRA
4CHU Henri Mondor. UPEC. AP-HP, CréTeil, France
5Paris Cardiovascular Research Center - PARCC, Inserm team 8, Paris, France
6INSERM, Centre d’Investigation Clinique 1430, Henri-Mondor University Hospital- UPEC, AP-HP, Créteil, France
7Unité de Recherche Clinique, Henri-Mondor University Hospital- UPEC, AP-HP, Creteil, France
8Plateforme de Ressources Biologiques, Henri Mondor Hospital, AP-HP, Creteil, France
9Université Paris-Est Créteil, INSERM U955, IMRB, Laboratory of excellence LABEX GRex, Créteil, France

Introduction

Blood viscosity has been suggested as a risk factor for vaso-occlusive crisis (VOC), which is mainly dependent on hematocrit and red blood cell (RBC) rheological properties. The HEMOPROVE study (NCT05199766) is an open-label, single-arm, single-dose Phase II study in Sickle Cell Disease (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 on Blood rheology in SCD patients and its determinants. Final 48-week results may provide additional insight.

Methods

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. Blood viscosity was measured at 225 s-1 with a cone/plate viscosimeter (Brookfield). Hematocrit-to-viscosity ratio (HVR), which is associated with a better microvascular oxygenation (Waltz et al. 2015), was calculated by dividing hematocrit by blood viscosity. RBC aggregation, RBC aggregates strenght and RBC deformability (EImax) were measured on a LORRCA ektacytometer/aggregometer (RR mechatronics), with oxygen gradient (to obtain the point of sickling, PoS). Data are presented in median [IQR]. Correlations were performed using a Spearman test, paired data comparisons with a Wilcoxon test (Graphpad10, PRISM).

Results

Median age was 41.5 years [35.3-50.3], sex ratio F/M was 0.5 and 12/20 patients were treated with HU. Hemoglobin (Hb) increased from 7.35 g/dL at M0 [6.6-8.3] to 8.85 g/dL [8.33-9.75] at M6 (p<0.0001) and hematocrit (Ht) from 21% [19.25-23] to 26% [24.25-28.75] (p<0.0001). Voxelotor treatment significantly increased blood viscosity (4.48 cP [4.08-5.33] vs. 5.42 cP [4.85-6.28] at M6, p = 0.0001). Three patients (all HU-treated) experienced a VOC but they did not have higher blood viscosity at baseline or after treatment, except for one with an increase to 7.79 cP. The HVR increased from 4.53 [3.96-4.93] at M0 to 4.88 [4.59-5.22] at M6 (p = 0.048), which suggests that the increase in blood viscosity was not proportional to the increase in hematocrit. The increase in RBC deformability (EImax of 0.45 [0.322-0.507] vs. 0.542 [0.497-0.577] at M0 and M6, respectively, p<0.0001) and the decrease of the PoS (pOs of 45.5 Torr [37.56-52.75] vs. 33.9 Torr [28.86-45.4] at M0 and M6, respectively, p = 0.007) shows improvement in RBC rheology and may explain the fact that blood viscosity did not rise as the Ht. RBC aggregation index (AI) was restored to the normal range by Voxelotor treatment (Tripette et al. 2009) increasing from 53.5% [46.69-61.18] at M0 to 61.37% [53.01-66.25] at M6 (p = 0.005) and the shear rate necessary to disaggregate RBC was also reduced at M6 (750s-1 [700-800] vs 693.8 s-1 [356.3-800], p = 0.0143). Interestingly, Hb was positively correlated with EImax (r = 0.4377, p = 0.005) and negatively correlated with the pOs (r = -0.43, p = 0.006), showing anemia improvement is due to the increase of RBC deformability and the decrease of RBC sickling.

Conclusions

Voxelotor increases blood viscosity in SCD patients, due to the increase in Hb and Ht. However, the magnitude of blood viscosity increase is partly lowered by the improvement of RBC deformability and the decreased propensity of RBC to sickle, resulting in greater HVR at 6 months of treatment. For one patient, an important blood viscosity increase could have been involved in the occurrence of a VOC complicated by an acute chest syndrome. A tight regulation of blood viscosity is necessary to maintain proper oxygen delivery and the changes induced by Voxelotor treatment probably require an adaptation to new rheological constrains, which could be favored by gradual introduction of the treatment. A larger study to evaluate the risk of VOC under Voxelotor treatment and identify predictive biomarkers still needs to be implemented.

Disclosures: De Luna: Vertex: Consultancy; Pfizer: Other: Sponsor HEMOPROVE trial NCT05199766. Habibi: Novartis: Consultancy; Theravia: Honoraria. Bartolucci: Bluebird: Consultancy; Novartis: Consultancy, Other: member advisory board and member steering commitee; Pfizer: Consultancy; Emmaus: Consultancy; Roche: Consultancy; Innovhem: Other: Founder; Addmedica: Consultancy, Other: member advisory board; JazzPharma: Consultancy.

*signifies non-member of ASH