Clinical and Laboratory Outcomes During Versus After EPO Treatment in Patients With Sickle Cell Disease: Insights From ACHiEvE-SCD

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Abstract Background Sickle cell disease (SCD) causes sickling of red blood cells, leading to painful vaso-occlusive episodes (VOEs) and severe anemia. Hydroxyurea (HU) is commonly used to manage VOEs in SCD but may not improve chronic anemia. Alternative treatments for anemia like erythropoietin (EPO) have been underutilized in SCD to date due to lack of data about their safety and efficacy. Our preliminary data demonstrated that 12 weeks of EPO treatment was safe and led to robust increases in hemoglobin (Hb) level in patients with SCD (Adeyemo et al. Blood. 2024). Here we present a comparison of the clinical and laboratory effects of 12 weeks of EPO treatment in combination with HU, followed by 12 weeks of clinical care and observation in patients with SCD. Our findings offer valuable insights into the potential benefits and limitations of using EPO in SCD management in high- and low-resource settings. Methods We conducted a Phase 1b/2 single-arm open-label pilot study at Lagos University Teaching Hospital (LUTH) in Nigeria and the University of Pittsburgh (Pitt) in the USA. We enrolled adult patients (≥18 years) with SCD (HbSS or HbS/β0-thalassemia), screening Hb ≤ 9.0 g/dL, on stable dose HU, and no recent blood transfusions, voxelotor, or Erythropoietin stimulating agents (ESA) treatment. EPO was provided free during the 12-week treatment period, after which participants could continue therapy as part of clinical care. Follow-up during the observation period included a 24-week clinic visit, as well as monthly phone calls to track blood transfusions, VOEs, and thromboses compared to historical baseline. Results Fourteen of 17 enrolled participants (all HbSS disease, 52.9% females, mean age 29.8 years) completed the 24-week follow-up as of December 31, 2024; their data are presented here. After 12 weeks of EPO treatment, mean Hb increased by 3.1 g/dL (from 7.5 to 10.5 g/dL; p < 0.001; Fig. 1A). At 24 weeks, mean Hb decreased by 2.0 g/dL (to 8.6 g/dL; p = 0.002). Lactate dehydrogenase (LDH) decreased at 12 weeks (from 397 to 256 U/L; p = 0.002; Fig. 1B) and increased at 24 weeks (to 350 U/L; p = 0.003). Indirect bilirubin decreased from 2.2 to 1.6 mg/dL at 12 weeks and remained decreased at 24 weeks (1.4 mg/dL). Hemoglobin F and mean corpuscular volume increased at 12 weeks (by 2.0% and 4.1 fL, respectively) and remained elevated at 24 weeks. Ferritin levels decreased from 748 to 506 ng/mL at 12 weeks and returned to 700 ng/mL at 24 weeks. No transfusions were required during the 24-week study period, compared to 11 transfusions (0.79 per patient-year) at baseline. VOEs decreased from 19 (1.36 per patient-year) at baseline to 0 during treatment and 3 (0.93 per patient-year) during the 12-week observation period. No thrombotic events occurred on this study. Only 3/14 (21.4%) participants continued EPO treatment after the initial 12-week period. One Pitt participant maintained her study dose of EPO (30,000 IU three times weekly) with insurance coverage and had continued Hb improvement (7.0, 9.6, and 10.0 g/dL at baseline, 12, and 24 weeks, respectively). Two LUTH participants continued intermittent, lower-dose EPO (10,000 IU three times weekly) based on what they could afford out-of-pocket, resulting in Hb decreases of 3.2 g/dL and 0.4 g/dL from 12 to 24 weeks. Seven additional LUTH participants wanted to continue EPO but could not afford the out-of-pocket costs, and no LUTH participants had insurance coverage. All participants were able to continue HU treatment through week 24. Conclusions Our findings demonstrate that EPO improves anemia in patients with SCD, with benefits reversing upon discontinuation. Similar patterns of change were observed with LDH, ferritin, and VOE rates, though larger studies are needed to assess whether EPO treatment impacts VOE rate. Additionally, cost and lack of insurance coverage present major barriers to EPO use, especially in low-resource settings. Future studies should focus on evaluating the long-term impact of EPO on transfusion burden, quality of life, and functional capacity, which would support broader insurance coverage and government support to make EPO accessible to patients with SCD. Figure 1Changes in Hb and LDH from baseline to 12-week treatment timepoint and 24-week follow up timepoint.

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