Introduction:

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by mutations in the β-globin gene, resulting in the production of sickle hemoglobin (HbS). The HbSS genotype is the most common and severe form. Despite therapeutic advances, SCD remains associated with substantial morbidity, largely due to recurrent vaso-occlusive crisis (VOCs) triggered by hemoglobin polymerization, red cell rigidity, hemolysis, and vascular obstruction. Crizanlizumab, a P-selectin inhibitor, was approved by the FDA in 2019 to reduce the frequency of VOCs. However, its real-world effectiveness has not been fully established. In this study, we assessed the impact of crizanlizumab on VOC incidence compared to hydroxyurea using a large, real-world dataset.

Methods:

We performed a retrospective cohort study using the TriNetX research network, a federated database of de-identified electronic health records from multiple healthcare organizations. Adults aged ≥18 years with HbSS genotype and at least one documented VOC in the year prior to treatment were included. Patients were categorized into two treatment cohorts: crizanlizumab and hydroxyurea. Propensity score matching (1:1) was perforormed to balance key confounders including age, sex, HbS level, HbF level, and disease activity. The primary outcome was the rate of VOCs at 3 months, 1 year, and 3 years following treatment initiation. Secondary outcomes included hospitalization rates. Relative risks (RRs), 95% confidence intervals (CIs), and p-values were reported.

Results:

A total of 202 patients were included after matching, with 101 patients in each cohort. The mean age was 35.3 years, and 70.3% were female in both groups. Patients treated with crizanlizumab had a mean HbS of 45.9% and HbF of 4.9%, compared to 64.9% and 8.6% respectively, in the hydroxyurea group. Crizanlizumab was associated with a significantly higher risk of VOCs at 3 months (RR 1.37, 95% CI 1.05–1.78, p=0.016), 1 year (RR 1.36, 95% CI 1.13–1.62, p=0.001), and 3 years (RR 1.12, 95% CI 1.00–1.26, p=0.048). Hospitalization rates did not differ significantly between groups: 3 months (RR 0.64, 95% CI 0.41–1.03, p=0.06), 1 year (RR 1.00, 95% CI 0.71–1.42, p=1.0), and 3 years (RR 0.92, 95% CI 0.68–1.24, p=0.57).

Conclusion:

In this real-world matched cohort analysis, patients with HbSS sickle cell disease treated with crizanlizumab experienced consistently higher rates of VOCs compared to those receiving hydroxyurea. While crizanlizumab was designed to reduce VOC frequency, these findings raise important questions about its effectiveness in clinical practice. These results highlight the continued utility of hydroxyurea and underscore the need for further research to clarify the role of crizanlizumab and to identify which patients are most likely to benefit from its use.

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2025
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