The GLOBE Trial: Efficacy and Safety of L-Glutamine Plus Hydroxyurea Versus Hydroxyurea Alone in Sickle Cell Anemia -...

Hydroxyurea (HU) reduces complications of sickle cell anemia (SCA), but the response is variable. L-glutamine, an antioxidant that improves redox balance, is implicated in 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.

In a 6-month, double-blind, placebo-controlled trial, 53 patients with HbSS or HbS/β⁰-thalassemia were randomized to the HU + L-glutamine (n=27) or the HU + placebo (n=26) group while continuing HU at ~20 mg/kg/day. The primary endpoint was vaso-occlusive crisis (VOC) frequency; secondary endpoints included acute chest syndrome (ACS), hospitalizations, and hematological parameters. Analyses were performed for intention-totreat with baseline-adjusted models for key outcomes.

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 (Hb) 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 fetal Hb increases (+6.2% vs. +1.6%; p<0.001). Adherence exceeded 80% in both arms and no serious adverse events occurred.

Adding L-glutamine to HU significantly reduced VOCs, ACS, and hospitalizations while improving Hb 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.