Background: Anemia and pain are key features of sickle cell disease (SCD), leading to high morbidity and shorter life expectancy. Pain is associated with poor mental health and functional impairment, while anemia causes fatigue, low exercise tolerance, and disrupted sleep. The impact of anemia on the health-related quality of life (QOL) in patients with SCD is not well understood, and it is unclear if raising hemoglobin (Hb) levels improves QOL in SCD. In a Phase 1b/2 study of erythropoietin (EPO) treatment in patients with SCD on stable-dose hydroxyurea (ACHiEvE-SCD; NCT05451940), we observed a 3 g/dL Hb increase after 12 weeks of EPO treatment (Adeyemo et al. Blood. 2024). Here, we examine how this Hb increase affected various QOL domains.

Methods: In a prospective, open-label study conducted at Lagos University Teaching Hospital and the University of Pittsburgh, patients with SCD and baseline Hb ≤ 9 g/dL received escalating doses of EPO for 12 weeks, aiming for a Hb range of 10-11 g/dL. After 12 weeks of EPO, patients resumed routine care and were followed up for another 12 weeks. QOL was measured at baseline, 12 weeks (end of EPO treatment), and 24 weeks (end of study) using a portable electronic device and captured in an online database (REDCap). We used the 36-Item Short Form Health Survey (SF-36), previously studied in a Nigerian SCD population (Adeyemo et al. Pediatr Blood Cancer. 2015), and a composite QOL survey including the ASCQ-Me (Adult Sickle Cell Quality of Life Measurement System) Pain Episode Frequency and Severity, Pain Impact, and Emotional Impact Short Forms (SF). ASCQ-Me was validated in large U.S. adult SCD samples, with T-scores normalized to this population. Except for the ASCQ-Me Pain Episode Frequency and Severity SF, higher scores in SF-36 and ASCQ-Me indicate better perceived health. Scores from individual domains were compared between time points using paired t-tests.

Results: A total of 17 patients were enrolled in ACHiEvE-SCD, with 16 completing the 12-week treatment period. One patient was withdrawn from the study and excluded from analysis. Of the 16, only 3 patients continued regular EPO treatment during the observation period due to high out-of-pocket costs, but all completed the QOL assessments at the 3 timepoints. The mean age was 30 years (range 18–50); 9 (53%) were female; all had HbSS genotype and identified as African, Black, or African American. The mean Hb increased from 7.5 to 10.6 g/dL after 12 weeks of EPO treatment (p<0.001), followed by a drop in mean Hb to 8.5 g/dL at 24 weeks (p=0.002).

The SF-36 evaluated 8 domains and found that, compared to baseline, there were improvements in several QOL domains at 12 weeks, including Bodily Pain (76.8 at baseline vs. 91.9 at 12 weeks; p=0.029), Physical Functioning (69.3 vs. 78.1; p=0.045), Role Limitations due to Physical Health (50 vs. 75; p=0.034), Energy/Fatigue (57.8 vs. 72.2; p=0.008), Mental Health (69.8 vs. 78.5; p=0.025), and General Health Perceptions (65.6 vs. 78.4; p=0.005). EPO treatment did not affect the domains of Social Functioning or Role Limitations due to Emotional Problems. At 24 weeks, there was a decrease in absolute scores in all domains compared to 12 weeks, though General Health was the only domain that showed a significant decrease (78.4 vs. 69.7, p=0.004).

Consistent with the SF-36 results, ASCQ-Me Pain Impact T-scores increased from 53.1 to 59 (p=0.063) and Pain Frequency scores decreased from 37.8 to 35.1 (p=0.060) at 12 weeks, suggesting a trend toward pain reduction. Additionally, ASCQ-Me Emotional Impact T-scores increased from 53 to 59.3 at 12 weeks (p=0.002). ASCQ-Me Pain Impact and Emotional Impact T-scores remained higher at 24 weeks compared to baseline (p=0.003 and p<0.001, respectively).

Conclusion: In this pilot study, we treated chronic anemia in SCD with EPO to achieve a Hb level of 10-11 g/dL. This approach led to meaningful improvements in pain, fatigue, physical health, mental health, and emotional well-being, as measured by both the SF-36 and ASCQ-Me. Our data also show that EPO treatment did not increase pain in SCD; on the contrary it may have reduced it, thereby improving QOL. These intriguing results suggest that treating adults with SCD with EPO to reach higher Hb targets may provide broad benefits in QOL. Larger follow-up studies are necessary to confirm our findings in both adult and pediatric SCD populations, and to further explore the therapeutic potential of EPO in SCD.

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2025
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