The GLOBE Trial: Efficacy and Safety of L-Glutamine Plus Hydroxyurea Versus Hydroxyurea Alone in Sickle Cell Anemia – A Double-Blind, Randomized Study

Background: Hydroxyurea (HU) reduces complications of sickle cell anemia (SCA), but the response is variable. L-glutamine, an antioxidant that improves redox balance, addresses a distinct pathophysiological pathway and may provide additional clinical benefit when added to HU. We evaluated HU plus L-glutamine versus HU alone in pediatric/adolescent SCA.
Methods: In a 6-month, double-blind, placebo-controlled trial, 53 patients with HbSS or HbS/β0-thalassemia were randomized to HU + L-glutamine (n=27) or HU + placebo (n=26) while continuing HU (~20 mg/kg/day). The primary endpoint was vaso-occlusive crisis (VOC) frequency; secondary endpoints included acute chest syndrome (ACS), hospitalizations, and hematologic parameters. Analyses were intention-to-treat with baseline-adjusted models for key outcomes.
Results: Over 6 months, the HU + L-glutamine group experienced significantly fewer VOCs (1.00 ± 0.73 vs. 1.65 ± 0.80; p = 0.003) and ACS episodes (0.19 vs. 0.77; p = 0.006). Hospitalizations declined by 40% (p = 0.04). Hemoglobin rose more in the combination arm (+0.78 vs. +0.32 g/dL; p = 0.028), with larger reductions in reticulocytes (p = 0.04) and greater HbF increase (+6.2% vs. +1.6%; p < 0.001). Adherence exceeded 80% in both arms, and no serious adverse events occurred.
Conclusions: Adding L-glutamine to HU significantly reduced VOCs, ACS, and hospitalizations, while improving hemoglobin and hemolysis markers, without added toxicity. The combination’s efficacy likely reflects synergistic effects on oxidative stress and sickle cell pathophysiology. This well-tolerated combination may improve SCA control, but larger confirmatory trials are needed.