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L-glutamine reduces painful crises associated with sickle cell disease
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Adults and children with sickle cell disease who received prescription-grade oral L-glutamine alone or with hydroxyurea experienced fewer painful sickle cell crises than patients who received placebo, according to phase 3 study results published in The New England Journal of Medicine.
“In the current trial, in which the majority of patients received concomitant hydroxyurea, the
number of pain crises per patient was significantly lower in the L-glutamine group than in the placebo group and differed between trial groups by a median of one event over 48 weeks,” Yutaka Niihara, MD, CEO of Emmaus Life Sciences, and colleagues wrote. “The time to the first pain crisis began to diverge within 2 weeks after the start of the treatment period, with sustained separation of curves over the duration of the trial.”
The FDA approved L-glutamine oral powder (Endari, Emmaus Life Sciences) for the reduction of severe sickle cell disease-related complications in patients aged 5 years or older in 2017.
A previous phase 2 trial comparing l-glutamine with placebo showed that patients who received L-glutamine experienced fewer acute pain crises and hospitalizations, without greater toxicity.
These data led researchers to conduct a phase 3 trial, preliminary results of which HemOnc Today previously reported.
Researchers randomly assigned 230 patients (aged 5 to 58 years; 53.9% women) with sickle cell anemia or beta-zero thalassemia 2:1 to receive pharmaceutical-grade L-glutamine (n = 152) or placebo (n = 78), twice daily at a 0.3-g/kg dose — with a maximum dose of 30 kg per day — followed by a 3-week tapering period and 2-week observation period.
All patients had at least two episodes of sickle cell crises in the previous year.
The number of pain crises through 48 weeks served as the study’s primary endpoint. Secondary
efficacy endpoints included the number of hospitalizations for sickle cell disease-related pain, the number of visits to an ED for sickle cell-related pain, and changes in hemoglobin and hematocrit
levels and reticulocyte count from baseline through 48 weeks.
Patients who received pharmaceutical-grade L-glutamine experienced a median three crises compared with four among the placebo group (P = .005), representing a 25% difference. Patients who received pharmaceutical-grade L-glutamine also experienced 33% fewer hospitalizations than patients who received placebo (2 vs. 3; P = .005).
Investigators did not observe a significant difference in the number of ED visits that did not result in hospitalization, or in the change in hemoglobin level, hematocrit level or reticulocyte count, between the groups.
Two-thirds of all patients received concomitant hydroxyurea. Researchers observed a consistent treatment effect across hydroxyurea use subgroups; the RR was 0.77 (95% CI, 0.58-1.03) among patients who used hydroxyurea and 0.78 (95% CI, 0.51-1.20) among those who did not.
“A subgroup analysis according to hydroxyurea use indicated that the benefits of pharmaceutical-grade L-glutamine therapy were consistent regardless of whether the patients were receiving hydroxyurea,” researchers wrote.
More patients in the placebo-treated group experienced adverse events (100% vs. 98%), as well as serious adverse events (87.1% vs. 78.2%) than the pharmaceutical-grade l-glutamine group.
Low-grade nausea, noncardiac chest pain, fatigue and musculoskeletal pain occurred more frequently among patients in the pharmaceutical-grade L-glutamine group.
Two patients assigned L-glutamine experienced sudden cardiac death during the trial, both of whom had a long history of organ failure and coexisting medical conditions, according to the researchers.
Because L-glutamine has different mechanisms of action and safety than hydroxyurea, combination use is likely advantageous, Caterina P. Minniti, MD, professor of clinical medicine and pediatrics at Einstein College of Medicine, and director of the Sickle Cell Center for Adults at Montefiore Medical Center, wrote in a related editorial.
“In the era of personalized medicine, there is a need to identify subgroups of patients within the population of patients with sickle cell disease who are most likely to benefit from such therapy,” Minniti wrote. “Currently, no simple and reproducible biomarker of oxidative stress exists that can guide clinicians in identifying patients who are most likely to have a response and in monitoring adherence and effectiveness.”
Also, data showing how often to monitor for toxicity are lacking, and caution is warranted in prescribing pharmaceutical-grade L-glutamine to patients with sickle cell disease with renal and hepatic dysfunction due to potential for higher mortality and toxic effects.
“Of note, in the [previous] two randomized trials of L-glutamine involving patients with sickle cell disease, three deaths occurred in the L-glutamine groups, as compared with none in the placebo groups; the deaths were not considered to be related to the study drug,” Minniti wrote. “In the absence of specific guidelines, I believe that L-glutamine may be prescribed to persons older than 5 years of age who have any sickle genotype and continue to have episodes of acute disease exacerbations despite appropriate use of hydroxyurea or to those who cannot or do not use hydroxyurea.” – by Melinda Stevens
Disclosures: Niihara reports employment with and personal fees from Emmaus Medical. Please see the study for all other authors’ relevant financial disclosures. Minniti reports grant support and personal fees from Global Blood Therapeutics, grant support from Bayer outside the submitted work and a pending patent for topical sodium nitrite formulation.
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