P115: REAL-WORLD DATA ON THE EFFICACY OF PHARMACEUTICAL-GRADE L-GLUTAMINE IN PREVENTING SICKLE CELL DISEASE-RELATED ACUTE COMPLICATIONS AND HEMOLYSIS IN PEDIATRIC AND ADULT PATIENTS.
Authors: N Elenga, G Loko, M Etienne-Julan, R AlOkka, A Adel, M Yassin
Journal: HemaSphere (2022)

Background: Oxidative stress is a key contributors to the pathophysiology of sickle cell disease (SCD) and related complications including acute pain (vaso-occlusive crisis VOC) and acute chest syndrome (ACS) [1, 2]. L-glutamine (L-Gln), a precursor of nicotinamide adenine dinucleotide (NAD), has been shown to play a key role in the regulation of oxidative stress[3]. In a pivotal Phase 3 trial, L-Gln demonstrated significant reduction in VOCs, hospitalizations, and ACS events compared to placebo in patients with SCD, with or without hydroxyurea (HU) use, over a 48-week period [4]. In September 2021, a re-analysis of the trial data revealed that L-Gln decreased the number of VOCs by 45% [5]. Aims: To confirm the efficacy of pharmaceutical-grade L-glutamine in pediatric and adult patients with SCD at follow-up time points of 24, 48 and 72 weeks. Methods: In a retrospective study conducted from October 2019 to April 2020, 19 patients (4 patients from Qatar and 15 patients from French Guyana) were treated orally with L-Gln (0.3mg/kg) twice daily. Laboratory parameters (hemoglobin levels (Hg), hematocrit proportion (Ht), WBC counts, reticulocyte counts, and LDH levels) were measured at baseline and follow-up time points. Clinical parameters (number of VOCs, hospitalizations, days hospitalized, ACS events, and blood transfusions) were documented for the year prior to treatment initiation as baseline values. These parameters were also collected at 24, 48, and 72 weeks from treatment initiation. Adverse events (AEs) were also collected during the treatment period. The data values at 24, 48, and 72 weeks have been annualized. Statistical analysis was performed using MedCalc Version 20.015. Results: 19 patients (HbSS, age range, 8–54 years; 53% patients <18 years) were retrospectively analyzed. 63% of the patients were receiving HU at baseline and 47% received concomitant HU during the study. Compared to baseline, patients had significantly fewer VOCs at 24, 48, and 72 weeks following L-Gln therapy (median change from 3.0 to 0; P<0.00001). Compared to baseline, there were fewer hospitalizations (median change from 3.0 to 0; P<0.00001) and patients spent fewer days in hospital (median change from 15.0 to 0; P<0.00001). Moreover, at 24, 48, and 72 weeks, the number of blood transfusions was considerably lower than at baseline (median, from 3.0 to 0; P<0.00001). In the year prior to treatment initiation, 2 patients reported a single ACS event, but, no such events were observed during therapy. Following treatment with L-Gln, the mean Hg level increased significantly from baseline to 72 weeks (8.2 to 8.8 g/dL; P<0.001) with peak mean increase from baseline of 11.2% at 48 weeks. A similar increasing trend was observed for Ht from baseline to 72 weeks (24% to 27%; P<0.001) with highest mean improvement from baseline of 15.5% at 48 weeks. Conversely, mean reticulocyte counts and LDH levels were significantly reduced at follow-up time points compared to baseline (P=0.003 and P<0.001, respectively). Only few AEs occurred and were mild. No compliance issue was reported. Conclusions: This study demonstrated that L-Gln therapy in SCD patients from Qatar and French Guyana resulted in significant and sustained improvements in clinical outcomes (number of VOCs, number and duration of hospitalizations, and number of blood transfusions) and an increase in Hg and a reduction of hemolysis. 2 patients with a history of ACS did not experience any of those events during L-Gln therapy. References 1. Klings ES, Farber HW (2001) Role of free radicals in the pathogenesis of acute chest syndrome in sickle cell disease. Respir Res 2(5):280–5. https://doi.org/10.1186/rr70. 2. Morris CR, Suh JH, Hagar W, Larkin S, Bland DA, Steinberg MH, et al. (2008) Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 111(1):402–10. https://doi.org/10.1182/blood-2007-04-081703. 3. Niihara Y, Zerez CR, Akiyama DS, Tanaka KR (1998) Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am J Hematol 58(2):117–21. https://doi.org/10.1002/(sici)1096–8652(199806)58:2<117::aid-ajh5>3.0.co;2-v. 4. Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, et al. (2018) A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med 379(3):226–35. https://doi.org/10.1056/NEJMoa1715971. 5. Zaidi AU, Estepp J, Shah N, Alkindi S, Ezzat H, Lam H, et al. (2021) A reanalysis of pain crises data from the pivotal l-glutamine in sickle cell disease trial. Contemp Clin Trials 110:106546. https://doi.org/10.1016/j.cct.2021.106546.