From the Journals

Phase 3 results shed light on L-glutamine use in SCD

Publish date: July 19, 2018
By
Andrew D. Bowser

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Breakthrough raises practical questions

Results of this phase 3 trial were “much awaited” and illustrate the efficacy of L-glutamine in reducing the number of acute vasoocclusive episodes in patients with sickle cell disease.

However, as with any new breakthrough in medicine, there are now compelling questions that need to be answered, Caterina P. Minniti, MD, said in an accompanying editorial.

How to handle cost is one such question. One year of treatment with pharmaceutical-grade L-glutamine carries an estimated cost of $40,515 versus $1,700 for a year of hydroxyurea, but whether the price tag will hinder prescribing of the newer agent has yet to be seen, according to Dr. Minniti.

“This agent certainly has been slow to enter the market because prescribing L-glutamine for patients requires many steps, which may dissuade busy practitioners from actively prescribing it,” she said.

Another question is whether it should be used alongside hydroxyurea, as was done in two-thirds of patients in the present trial. Concomitant use is possible and “most likely advantageous” given that L-glutamine has a different toxicity profile and putatively different mechanism of action from hydroxyurea, Dr. Minniti said.

Who should receive L-glutamine is another important question. Dr. Minniti said that, based on previous trial data, caution may be warranted in giving L-glutamine to patients with significant renal and hepatic dysfunction, but she added that its role could be broad.

“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,” she said in the editorial.

Caterina P. Minniti, MD, is with the division of hematology at Montefiore Medical Center at Einstein College of Medicine, New York. These comments are excerpted from her accompanying editorial ( N Engl J Med. 2018;379:292-4 ). Dr. Minniti reported disclosures related to Global Blood Therapeutics and Bayer, along with a patent pending for a topical sodium nitrite formulation.


 

FROM THE NEW ENGLAND JOURNAL OF MEDICINE

Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.

The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.

RBCs in a blood specimen of a 6-year-old boy with sickle cell disease CDC/Janice Haney Carr

Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.

“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.

The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta0-thalassemia and two or more pain crises in the previous year.

Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.

Participants were contacted by telephone weekly during the study to encourage adherence.

A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.

The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).

Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.

Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.

The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.

The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.

Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.

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