sickle cell disease

L-Glutamine for Sickle Cell Disease: A Landmark FDA Approval

Shaina M. Willen, MD

Willen SM. L-glutamine for sickle cell disease: a landmark FDA approval [Published online August 3, 2018]. Consultant360.


Sickle cell disease (SCD) is an inherited blood disorder affecting approximately 100,000 individuals in the United States and millions worldwide and is characterized by significant morbidity and early mortality. In 1998, hydroxyurea was approved by the US Food and Drug Administration (FDA) and has been the only FDA-approved medication for SCD for the past 20 years.

In multiple prospective research studies of adults and children with SCD, hydroxyurea has consistently demonstrated improvement by reducing acute clinical complications such as painful vaso-occlusive events and acute chest syndrome, decreasing hospitalizations, and improving survival. However, the use of hydroxyurea has been somewhat limited by variable efficacy, dose-dependent cytopenias, and concerns regarding fertility and pregnancy.

On July 7, 2017, the FDA approved Endari (L-glutamine oral powder) for individuals aged 5 years and older to reduce severe complications of SCD. While this was an exciting development for the SCD community, the results of the phase-3 randomized controlled trial of L-glutamine in SCD were not published until earlier this month in the New England Journal of Medicine. This lapse between the FDA approval and the results presented in a peer-reviewed manuscript have caused some providers to delay recommending L-glutamine for their patients until now.

Participants in the study were aged 5 to 58 years and had experienced 2 or more episodes of acute vaso-occlusive pain within the 12 months prior to study enrollment. A total of 230 individuals were randomly assigned to receive treatment with high-dose (0.3g/kg of body weight twice daily) L-glutamine (n = 152) or placebo (n = 78) for 48 weeks.

Results of the study demonstrated that those participants in the treatment group receiving L-glutamine experienced significantly fewer episodes of vaso-occlusive pain (median 3 vs 4), fewer hospitalizations (median 2 vs 3), fewer days spent in the hospital (median 6.5 vs 11), and fewer episodes of acute chest syndrome (8.6% vs 23.1%) compared with those receiving placebo. During the study, approximately two-thirds of participants in both groups were receiving concomitant hydroxyurea therapy.

Common side effects of L-glutamine reported in the study were mild and included low-grade nausea, noncardiac chest pain, fatigue, and musculoskeletal pain. A total of 5 participants receiving L-glutamine withdrew from the study early due to side effects. 

The results reported in this study demonstrate an exciting development in treatment for adults and children with SCD, for whom there are limited therapeutic options. The favorable side-effect profile of L-glutamine may offer an alternative to those who cannot tolerate or decline hydroxyurea or who may not have access to hydroxyurea therapy. However, these data are only the first step. Individuals included in the study were those with hemoglobin (Hgb) SS or S-beta thalassemia zero; therefore, efficacy is uncertain among those with other sickle cell phenotypes—such as HgbSC or S-beta thalassemia plus.

The current study does not answer the question of whether L-glutamine is synergistic with hydroxyurea or can be prescribed instead of the current standard therapy. Additionally, given the multi-organ dysfunction that occurs in SCD, additional studies are needed to understand if improvements are seen in long term vascular injury in this patient population, including silent cerebral infarcts, pulmonary hypertension, and chronic kidney disease.

L-glutamine should be offered to adults and children with SCD, but the research community needs to continue to work hard to identify additional therapies to improve the lives of the many adults and children with this debilitating and life-limiting disease.

Shaina M. Willen, MD, is a pediatric hematologist in the Department of Pediatrics, Division of Hematology/Oncology, at the Vanderbilt Meharry Center for Excellence in Sickle Cell Disease at Vanderbilt University Medical Center in Nashville, Tennessee.