P1438: l-glutamine: a novel and effective therapeutic tool for voc reduction in scd

Topic: 26. Sickle cell disease Background: L-glutamine plays an important role in the defense against oxidative stress, which is a contributor to the pathophysiology of sickle cell disease (SCD). Our metabolomic study also showed that L-glutamine may be an important player in vaso-occlusive crises (VOC) incidence. Therapy with L-glutamine (ENDARI) has demonstrated a significant decrease of VOC and acute chest syndrome in a prospective controlled study. L-glutamine used orally at 0.5 g per kilogram of body weight, is a drug currently used for sickle cell disease approved by the FDA and is available in France with the early access program. Aims: The aim of this study was to evaluate i) the clinical efficacy of L-glutamine in the reduction of VOC incidence, and ii) the evolution of biological parameters over a 6 month period to determine the mechanism of action of L-glutamine and its impact on SCD. Methods: Patients in the early access program for L-glutamine have been followed during one year in our referral center. Clinical follow-up was performed monthly. After given a written consent, patients could also be included in a biological follow up (Erythropedie collection). We analyzed the erythrocyte characteristics in patients treated with L-glutamine. Patient blood samples were obtained at D0 (before the start of treatment), D15, M2 and M6. The biological markers monitored were: association and dissociation oxygen affinity curves (HEMOX), viscosity, Osmoscan and oxyscan (LORRCA), density curve, RBC adhesion to TSP and VCAM, and RBC senescence parameters (ROS, Ca2+ and PS expression). Results were expressed in median with interquartile ranges. Wilcoxon test was performed to compare the evolution during time. Results: A total of 63 patients (age 20-52 years; sex ratio F/M 0.38) were included. Reasons for L-glutamine introduction were VOC recurrence in 58 patients, and interruption of HU for a paternity project with a history of ACS or VOC recurrence in 5. Of the 58 patients included for VOC recurrence, 64% (n=37) were also receiving HU treatment at baseline. Forty-five patients were followed almost one year, of which 13 patients had a complete 6 months biological follow-up. The remaining 18 patients either stopped the treatment of were lost to follow-up. In an intention to treat analysis, the median rate of hospitalized VOC decreased from 2 [1-5] to 1 [0-3] (P = 0.002) over a 12 month period. For patients included for a VOC or an ACS in the previous year, without another therapeutic modification, median rate of hospitalized VOC decreased from 1 [1-3.25] to 0 [0-2] (p=0.07). Biological follow-up over a 6 month period showed a significant improvement of the oxygen affinity association and dissociation curves as shown by a significant decrease of the P50 (p=0.04) and the hysteresis. Parameters of RBC senescence improved as demonstrated by a decrease in annexin V (p = 0.01), and intra-cellular Ca2+ levels (P = 00002). Viscosity, deformability and adhesion parameters did not reach a significant difference. Reported side effects were nausea (1.5%), weight gain (1.5%), stomachaches (4.7%), dry skin (1.5%), and burning sensation (1.5%). Summary/Conclusion: Preliminary analysis suggests a decrease in hospitalized VOC under L Glutamine in a real life experience practice. Mechanisms of action of L Glutamine are probably more complex than the effect on the NADH/NAD+ imbalance. Further studies are needed to better understand its role in SCD. Keywords: Acute chest syndrome, Vasoocclusive crisis, Sickle cell disease, Red blood cell