Benefit-Risk of Voxelotor, Crizanlizumab, and L-Glutamine in Sickle Cell Disease: A Systematic Review.

BACKGROUND: Newer pharmacologic therapies for sickle cell disease target different clinical domains, complicating class-level comparison. Postapproval developments, including voxelotor withdrawal and regulatory reassessment of crizanlizumab, warrant a therapy-specific reassessment of benefit and risk. METHODS: We searched PubMed/MEDLINE, Scopus, Web of Science Core Collection, and CINAHL through April 4, 2026, for clinical evidence on L-glutamine, crizanlizumab, and voxelotor. Two reviewers independently screened records, assessed full texts, extracted data, and appraised methodological concerns. Core randomized evidence was distinguished from early randomized, linked follow-up, supportive secondary, and contextual evidence. Pooling was considered only for independent studies with clinically comparable outcomes and compatible follow-up. RESULTS: Of 742 records identified, 398 remained after deduplication, 52 full-text reports were assessed, and eight studies contributed to the structured synthesis. L-glutamine reduced vaso-occlusive crisis burden in the pivotal trial (rate ratio, 0.75; 95% confidence interval, 0.62-0.90). Crizanlizumab prolonged time to first vaso-occlusive crisis in SUSTAIN (hazard ratio, 0.50; 95% confidence interval, 0.33-0.75), but evidence remained dependent on one core randomized trial. Voxelotor primarily improved hemoglobin response (risk ratio, 7.84; 95% confidence interval, 3.52-17.4). No primary pooled meta-analysis was performed because comparable independent evidence was sparse, follow-up differed, linked reports overlapped, and several safety outcomes were noninformative. CONCLUSIONS: The evidence supports therapy-specific benefit signals rather than a pooled class-level conclusion. Benefit-risk interpretation should distinguish vaso-occlusive morbidity from hemoglobin-centered outcomes and account for replication, durability, and safety completeness.