Comparative efficacy of novel therapies for sickle cell disease: A network meta-analysis of hydroxyurea, voxelotor, crizanlizumab, and l-glutamine

Abstract Background: Multiple pharmacologic agents are now approved for the management of sickle cell disease (SCD), including hydroxyurea, voxelotor, crizanlizumab, and L-glutamine. However, no head-to-head randomized controlled trials (RCTs) exist to compare their relative efficacy and safety. We conducted a network meta-analysis (NMA) of available RCTs to indirectly compare these therapies with respect to clinical and hematologic outcomes. Methods: A systematic literature search was performed across PubMed, Embase, and Cochrane CENTRAL through June 2025. RCTs evaluating hydroxyurea, voxelotor, crizanlizumab, or L-glutamine in patients with SCD were included. Primary outcomes were annualized rate of vaso-occlusive crises (VOCs) and change in hemoglobin concentration. Secondary outcomes included hospitalization rate, transfusion requirement, and serious adverse events. A random-effects frequentist NMA model was used. SUCRA-based treatment rankings were explored when data permitted. Given variations in trial designs and endpoints, results were interpreted cautiously. Results: Eleven RCTs enrolling 3,412 patients were included. Hydroxyurea demonstrated a consistent reduction in VOC frequency in both pediatric and adult populations. Crizanlizumab, based on the SUSTAIN trial, showed a significant reduction in annual VOCs, particularly in patients with a high baseline VOC rate. Voxelotor, as shown in the HOPE trial, increased hemoglobin by approximately 1.1 g/dL compared to placebo, with limited impact on VOC frequency. L-glutamine showed modest but significant reductions in both VOCs and hospitalizations in the phase 3 trial by Niihara et al., with a favorable safety profile. While a preliminary SUCRA analysis suggested hydroxyurea and crizanlizumab ranked higher for VOC reduction, and voxelotor for hemoglobin improvement, no statistically conclusive hierarchy could be established due to heterogeneity and indirectness of comparisons. Conclusions: In the absence of head-to-head trials, this network meta-analysis offers an indirect comparison of modern SCD therapies. Hydroxyurea and crizanlizumab appear most effective for reducing VOC frequency, while voxelotor provides the greatest improvement in hemoglobin concentration. L-glutamine demonstrates balanced efficacy with a low adverse event rate. These findings support individualized treatment selection based on patient phenotype, clinical goals, and tolerability. Formal head-to-head trials and real-world comparative studies are needed to further refine treatment sequencing and combination strategies in SCD.