When L-glutamine was approved by the US Food and Drug Administration in 2017 as a therapy to reduce acute complications in patients with sickle cell disease (SCD), it was a welcome addition to the limited range of treatment options for this population.1 After a phase 3 trial of the drug showed a reduction in the number of pain crises in SCD, L-glutamine became the first therapy approved for SCD treatment since the 1998 approval of hydroxyurea.1,2 Thus far, however, uptake and adherence have been lower than likely anticipated.

Vivien Sheehan, MD, PhD

“L-glutamine has had a minimal effect on SCD,” according to Vivien Sheehan, MD, PhD, pediatric hematologist/oncologist at Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta in Georgia and associate professor of pediatrics at Emory University School of Medicine in Atlanta. “I have observed its use at 2 large SCD centers in Atlanta and Houston [in Texas] and, at most, 5% of patients have accepted a prescription and many discontinued the medication,” she said. Adherence remained poor even when L-glutamine was shipped to the patient’s home, as was the case in Houston.

The poor initiation of and adherence to the drug may be attributed to multiple factors. From the perspective of Jane Little, MD, professor of medicine in the division of hematology and oncology in the School of Medicine at the University of North Carolina (UNC) at Chapel Hill and director of the UNC Comprehensive Sickle Cell Program, L-glutamine has proven to be “very expensive and awkward for patients to take, and since it takes time to experience benefits, one has to be committed to the idea that it will work.”3

In a retrospective study published in December 2020 in the American Journal of Hematology, Ogu et al investigated the acceptance, barriers, and adherence associated with L-glutamine use among adult patients with SCD who had experienced at least 1 vaso-occlusive crisis per year. Over a 14-month period, 111 patients (57% female; mean age, 36 years) received prescriptions for L-glutamine oral powder. The sample was comprised primarily of patients with hemoglobin SS (HbSS) type (81%), followed by HbSC (12%), HbSβ+-thal (5%), and HbSβ0-thal (2%). Most patients were covered by Medicare/Medicaid (89%) and were on concomitant treatment with hydroxyurea (74%).1

At follow-up visits, clinicians asked patients about any barriers they may have encountered in obtaining the medication and adhering to the twice-daily dosing. The pharmacy team further assessed adherence based on whether patients were refilling L-glutamine on time and taking it consistently and as prescribed, and via calculation of the medication possession ratio (MPR; the sum of a day’s supply for all fills in a given time period divided by the number of days in that period). They also inquired about side effects and whether these resulted in discontinuation of L-glutamine.1

According to the results, 19% of patients were taking L-glutamine at the end of the study period, while 42% had discontinued the drug due to reasons including “poor adherence, as defined by patients who did not refill after the initial/subsequent prescriptions (mean refill 1.79 times) and/or missed follow up appointments, side effects, no perceived benefit, and pregnancy/breastfeeding,” Ogu et al wrote. This subset of patients discontinued use after a median of 47 days following prescription.1

Additionally, 4% of patients had filled the prescription but never initiated therapy due mainly to fear of side effects, and 35% of patients had never filled the prescription due to barriers such as high copayment, denial of insurance authorization, or inability of the pharmacy to reach patients after approval of authorization. Authorization was denied for 10% of patients with Medicare/Medicaid and 42% of those with private insurance.1

The most common side effects related to L-glutamine use were gastrointestinal symptoms including nausea, constipation, and abdominal pain. While 13% of patients discontinued use due to side effects, these were “successfully mitigated in a subset of patients, by asking them to decrease their dose and frequency of administration and work up to recommended dose in a few weeks,” as described in the study.1

Among the patients still taking L-glutamine at the end of the study period, the average MPR was 0.73 (MPR ≥0.80 reflects good adherence), which the authors noted was comparable to the 77.4% adherence rate of participants in the phase 3 trial that led to FDA approval of L-glutamine, as well as the MPR for other chronic diseases, specifically diabetes (0.75) and hypertension (0.78).1

“From our report, it is critical to evaluate and mitigate barriers to initiation and adherence to L-glutamine, to ensure its availability to and acceptance by the patient population it gained approval and was intended for,” the authors concluded.1

Dr. Sheehan stated that the major barrier to adherence is the unpalatable powder formulation, and difficulty in detecting efficacy represents another factor that may deter adherence.4

“No laboratory values change, and the clinical trial reported a decline of pain events from 4 to 3 per year, which requires a lot of persistence and careful observation on the part of the patient to see an effect,” she explained. “Physicians are still uncomfortable with the lack of a mechanism to explain the effect, and lack of a biomarker or laboratory test to follow for efficacy.” Further research is needed to address these gaps.5

Dr. Little added that she would want to prescribe L-glutamine more often if it could be determined that it changes the course of the disease in terms of pathophysiology or symptoms. Currently, she generally limits its use to patients who have failed other pain management strategies.

“I really want to focus efforts on getting patients on more robust disease-modifying therapy like hydroxyurea,” she said. At present, L-glutamine is “simply not the first or second drug I look to for disease or symptom modification.”

References

  1. Ogu UO, Thomas M, Chan F, et al. L-glutamine use in adults with sickle cell disease: Clinical trials where success meets reality. Am J Hematol. 2021;96(1):E38-E40. doi:10.1002/ajh.26021
  2. Niihara Y, Miller ST, Kanter J, et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A phase 3 trial of L-glutamine in sickle cell disease. N Engl J Med. 2018;379(3):226-235. doi:10.1056/NEJMoa1715971
  3. Carden MA, Little J. Emerging disease-modifying therapies for sickle cell disease. Haematologica. 2019;104(9):1710-1719. doi:10.3324/haematol.2018.207357
  4. Sadaf A, Quinn CT. L-glutamine for sickle cell disease: Knight or pawn?Exp Biol Med (Maywood). 2020;245(2):146-154. doi:10.1177/1535370219900637
  5. Kanne CK, Reddy V, Sheehan VA. Rheological effects of L-glutamine in patients with sickle cell diseaseBlood. 2019;134(Suppl_1):3567. doi:10.1182/blood-2019-128891