L‐glutamine use in adults with sickle cell disease: Clinical trials where success meets reality
Authors: Ugochi O. Ogu, Merin Thomas, Florence Chan, Leena Vattappally, Gracy Sebastian, Andrew Crouch, Shuo You, Caterina P. Minniti
Journal: American Journal of Hematology (2020)

In 2017, the US Food and Drug Administration (FDA) approved Endari (L-glutamine oral powder) for patients age 5 years and older with sickle cell disease (SCD) to reduce sickle cell-related acute pain events and hospitalizations.1 This was applauded as the first medication approval for SCD in almost 20 years, following hydroxyurea (HU) in 1998. A phase three trial that led to its approval showed that L-glutamine decreased the number of pain crises in SCD patients. We report our experience with barriers to accessibility to a new medication such as L-glutamine, and patients' adherence in adults with SCD in an urban adult sickle cell center. To our knowledge, this report is a first of its kind. After prospectively establishing internal guidelines for the use of Endar (L-glutamine oral powder), adult patients with SCD seen in clinic at a large urban adult SCD center were prescribed L-glutamine via a local specialty pharmacy, over a 14-month period. Adult patients with any sickle cell disease genotype, with one or more VOC per year, regardless of HU use were offered the medication. Patients with severe renal and/or hepatic disease were not approached. This was a retrospective study based on informal assessment during routine follow up visits by medical chart review. Upon return to clinic, patients were asked about barriers to obtaining the medication and adherence to the twice a day dosing. Institutional Review Board (IRB) approval was obtained for medical chart review. The pharmacy team conducted interviews with patients during routine monthly follow-ups to assess patients' adherence and medication tolerability. Medication adherence was determined by patients refilling on time, responding if they were taking it consistently and were taking the medication as prescribed. Patients were asked to describe side effects experienced, and whether they led to medication discontinuation. Adherence was also evaluated by calculating the medication possession ratio (MPR) utilizing pharmacy records. The MPR was calculated by dividing the sum of a day's supply for all fills in a period by the number of days in the time period. Good adherence is defined as an MPR ≥0.80, with an MPR of 1 corresponding to 100% adherence. The MPR was compared to a sample set of two chronic diseases with multiple medications (diabetes and hypertension), within the same time frame of the study. A total of 111 patients with SCD (57% females) were prescribed L-glutamine over the study period, with a mean age of 36 years (range: 21-70 years). The cohort consisted of 90 patients (81%) with Hb SS, 13 (12%) with Hb SC, six (5%) with Hb Sβ+, and two (2%) with Hb Sβ0. A total of 99 patients (89%) were under Medicare/Medicaid insurance while 12 (11%) were private insurance holders. And, 74% of patients were on concomitant HU and 1% on chronic transfusions (>6 months). At the end of the 14-month period, 21 patients (19%) were actively taking L-glutamine, 47 (42%) had discontinued it, 39 (35%) never filled the prescription, and four (4%) had received the drug but never initiated therapy. Of the 39 who never filled the initial prescription, barriers included denial of prior authorizations, high co-payment, and inability of pharmacy to contact patient after approval was obtained (Table 1). Of the four who received medication but never initiated therapy, fear of side effects was the main barrier. Reasons for discontinuing L-glutamine included 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 (Table 1). Side effects were mostly gastrointestinal (GI): nausea, abdominal pain and constipation. Average MPR for the 21 patients that were still taking L-glutamine was 0.73, similar to the adherence reported in the landmark phase three trial (77.4%).1 The mean fill rate was 1.79 fills for a total of 68 patients who filled the prescription. For patients who filled more than once, the mean fill rate was 2.51 fills for a total of 48 patients. About half of the patients (32/68, 47%) filled two or fewer times. Pharmacy records of a sample set of two chronic diseases with multiple medications (diabetes and hypertension), within the same time frame of the study, was used to estimate average MPR for different drug classes of the chronic diseases, and were found to be 0.75 and 0.78 respectively. This is the first study that addresses both acceptance of a new medication by the sickle cell population and the barriers to obtaining it. We identified significant barriers to the initiation of L-glutamine in our urban adult SCD patient population and a high rate of self-discontinuation. Patients who discontinued L-glutamine, did so after a median of 47 days after the initial prescription. The most common reasons for not initiating therapy, present in ~70% of the cases, were insurance-related issues, such as prior authorization denial or high deductible/co-pays. About 10% of patients on Medicare/Medicaid had denied prior authorizations, compared to 42% of private insurance holders. In ~30% of the cases patients were not reachable or had other issues for not filling it, despite obtaining prior authorization, which may indicate a lack of interest on their part. A small number of patients (six) reported discontinuing due to side effects. Side effects which were mostly GI-related 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. After 14 months, only 21/111, ~20% of the original cohort of patients prescribed L-glutamine, reported taking it. The MPR of the patients that were taking the medication was 0.73, similar to the adherence in the L-glutamine study (77.4%)1 and to MPR for other chronic diseases, such as diabetes and hypertension, 0.75 and 0.78 respectively. We did not assess whether adherence to other sickle cell medications was affected by introduction of L-glutamine. As experienced with HU, over a decade elapsed from initial FDA approval to its being accepted and widely used; unfortunately, adherence remains sub-optimal to this day.2 In our population, we could not calculate HU adherence via MPR due to non-centralized dispensing (subjects used various pharmacies). This would have provided a direct comparison of drug adherence within the same subject pool. However, in a systemic review, the adherence rate for HU and other prescribed sickle cell disease regimens such as penicillin prophylaxis and iron chelation ranged from 16%-89%.2 Two new medications for sickle cell disease have attained FDA approval since L-glutamine, based on positive results of double-blinded, randomized placebo-controlled clinical trials.3, 4 With new drugs approved and several more in the pipeline, it is evident that the management of sickle cell disease has entered the era of combination therapy.5 The importance of acceptance, availability and adherence to any new medication cannot be over-emphasized. 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. Larger prospective studies are warranted to assess the reproducibility of our data in other patients' populations across the country and to investigate whether the introduction of a new drug affects adherence to HU. C.M. reports consulting with Novartis, Global Blood therapeutics, Emmaus Life science, C.S.L. Boering, Roche. U.O. reports consulting with Vertex Pharmaceuticals. Concept and design: C.P.M., U.O.O. Acquisition, analysis, or interpretation of data: C.P.M., U.O.O., M.T., F.C., L.V., G.S., A.C., S.Y. Drafting of the manuscript: U.O.O. Critical revision of the manuscript for important intellectual content: C.P.M., U.O.O., F.C.