Parameters Associated with Improved Peripheral Oxygen Extraction in Sickle Cell Patients Treated with Voxelotor

Introduction: The combination of chronic hemolysis and severe cardiopulmonary damage has a profound impact on prognosis and functional capabilities in patients with sickle cell disease (SCD). Voxelotor, which reduces the HbS polymerization has shown efficacy in increasing plasmatic Hb concentration (Hb). The effects of this Hb rise might be counterbalanced by its higher affinity for O₂, potentially reducing its peripheral delivery. There are currently no data exploring the complex interplay between Voxelotor effects on peripheral O2 delivery, O2 binding to Hb, erythropoietin (EPO) levels, and functional resonance through exercise. 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 on peripheral O2 extraction during exercise 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 HU. Patients included benefited from a multi-organ evaluation at baseline (M0), after 6 (M6) and 12 months of treatment. For the present analysis, only patients who underwent a comprehensive cardiopulmonary stress evaluation at M0 and M6 were analyzed – involving a 6-minute walk test (6MWT) and a standardized incremental exercise protocol up to 4 mmol. L^-1 blood lactate level (BL4), with concomitant gas exchange and echocardiography measurements. Peripheral O₂ extraction at BL4 was directly measured using arterio-veinous difference D(A-V) O₂ (= VO₂ [mL/min] / cardiac output (L/min) at BL4). In addition to standard clinical and biological parameters, plasma level of EPO was measured and P50 was obtained from oxygen dissociation curve performed on a Hemox analyzer (TCS Scientific). Wilcoxon test was used to compare M0 and M6 parameters. Using BL4 - D(A-V) O₂ relative change from M0 to M6 as an endpoint and performing multivariate linear regression analysis applying ordinary least square estimator (OLS) on (M6-M0) delta (∆) parameters, we sought to find determinants of peripheral O₂ extraction evolution under Voxelotor.

Results: 14 SCD patients had an incremental exercise at M0 and M6. Mean age was 44±10 years, sex ratio F/M was 0.5 and 57% were treated under HU. Hemoglobin level markedly rose under treatment by a mean increase of 2.0±1.1 g.dL^-1 per patient (7.1±0.7 vs. 9.1±1.3, p<0.001). P50 decreased from 30.85 [28.92-32.75] to 22.97 Torr [21.06-24.9] (p<0.001). EPO was performed in 11 patients with a median of 107 [57-242] at M0 and 75 mU/L [47-170] at M6 (ns). Notably, EPO increased in 5/11 patients (46%), while it decreased or remained stable in 6/11 patients (54%). Patients with an increase in EPO showed a more pronounced decrease in P50 (20.88 [18.85-22.46] vs 24.58 torr [21.95-27.38], p = 0.02). Overall, lactate curves through exercise remained identical under treatment, as well as D(A-V) O₂ at BL4 (71±12 vs. 67±10 O₂ mL / L, p=0.3) while SpO2 considerably increased at 6 months. Multivariate OLS regression showed that the best-fitting model to explain an increase in D(A-V)O2 at BL4 between M0 and M6 of treatment with Voxelotor included a decrease in EPO, an improvement in dyspnea (Borg scale after 6MWT), and a decrease in P50 (adjusted R²=0.94).

Conclusion: Oxygen delivery to tissues under Voxelotor is an important issue that is difficult to assess. In fact, the treatment increases Hb but maintains it in the oxygenated R conformation, partially reducing oxygen release. Using reference methods, we were able to gain a better understanding of this complex equilibrium. Our interim analysis after 6 months of treatment shows that tissue oxygen extraction increases in patients with a decrease in EPO and dyspnea. Paradoxically, the lower the P50 in these patients, the more beneficial the effect, probably via the increase in Hb and the rheological improvements we also studied. Further investigations are needed to confirm and refine our results.