PracticeUpdate Conference Series ASH 2018

L-Glutamine Benefits Consistent Regardless of History of Sickle Cell Disease Crises But findings are limited by their dependence on post hoc

analyses in small subgroups. T herapy with Endari, a prescrip- tion-grade pharmaceutical form of L-glutamine, was consistently effective in reducing the frequency of pain episodes in both pediatric and adult sickle cell disease patients, irre- spective of their history of sickle cell crises. In 2017, the United States Food and Drug Administration (FDA) approved L-glutamine powder for oral administra- tion to reduce the acute complications of sickle cell disease in patients aged 5 years and older. The FDA approval was based on the results of a randomized, double-blind, placebo-controlled trial of L-glutamine in 230 patients aged 5 to 58 over 48 weeks. With that approval, L-glutamine became only the second therapy – along with hydroxyurea – for the prevention of acute vaso-occlusive pain events. Patients in the trial were randomly assigned in a 2:1 ratio to receive either L-glutamine (152 patients) or placebo (78 patients). L-glutamine, whether administered alone or with hydroxyurea, reduced the frequency of sickle cell pain episodes by 25% (a median of three sickle cell crises for the L-glutamine study arm compared with four in the placebo arm) and hospitalizations by 33% (a median of two hospitalizations in the L-glutamine group and three in the placebo group). These results were achieved with no serious adverse events in the treatment as compared with the placebo arm. Here, researchers led by Yutaka Nihara, MD, of Emmaus Medical, Inc. in Torrance, California, manufacturers of Endari, and the University of California in Los Angeles, further evaluated the trial data in order to examine any differences in the effect of L-glutamine on sickle cell patients depending on the frequency of their sickle cell crises prior to study screening. For this analysis Dr. Nihara and his colleagues divided patients into three

categories: those who had two sickle cell crises in the year previous to screening (low, n=79), those who expe- rienced three to five (moderate, n=112), and those who experienced six or more (high, n=38), using data collected from their medical records when they entered the trial. Of the patients in the low subgroup, those in the treatment arm had a mean of 2.57 crises, compared with 2.95 in the placebo arm. Of those patients in the moderate subgroup, those in the treat- ment arm had 3.19 crises, compared with 4.28 in the placebo arm. Finally, among those in the high subgroup, those in the treatment arm had 4.77 crises, while patients in the placebo arm had 5.85. The ratio of the rate of crises in the L-glutamine arm to the rate of crises on placebo was similar in all categories (low 0.87, moderate 0.74, and high 0.82, with a rate ratio < 1.0 favoring the L-glutamine treatment effect). “The apparent lower rate ratio in those that had 3 to 5 crises in the year prior to screening may be due to having the largest sample size of the three cate- gories,” Dr. Nihara and his colleagues observed, and concluded that the analysis “indicates that the benefit of L-glutamine treatment observed in the phase III trial is consistent regardless of the history (1 year) of crises prior to the initiation of L-glutamine therapy.” In commenting on this study, John J. Strouse, MD, PhD, of Duke Health in Durham, North Carolina, told Elsevier’s PracticeUpdate that while it shows similar relative risk reduction in the sub- groups, “all subgroup analyses should be interpreted carefully based on small numbers and post hoc analyses.” As for how he uses this new therapy in practice Dr. Strouse said, “I use L-glutamine in patients that cannot tolerate hydroxyurea, or I will add it to hydroxyurea if their response is inadequate to hydroxyurea alone.”

Fever and symptoms of cytokine release syndrome were seen in 3 patients within 2 days of starting pembrolizumab. Other adverse effects associated with PD-1 inhibition included a case each of acute pancreatitis, hypothyroidism, arthralgia, and urticaria, as well as 4 patients with grade 3 to 4 cytopenias, all of which were either tolerable or reversible upon dis- continuation of the treatment. No grade 5 toxicities occurred. Dr. Maude and her colleagues called the response to treatment with PD-1 inhibitors “promising” in the cases of patients with early B cell recovery and bulky extramed- ullary disease. However, they also pointed out that PD-1 inhibition had a partial, but no durable effect, in all 4 B-ALL patients with poor initial marrow response to CAR T-cell ther- apy alone. This suggests, they reported, “a different mechanism such as [activation induced CAR T death] may be responsi- ble for poor initial responses.” “We showed that PD-1 checkpoint inhib- itors can be safely combined with CD19 CAR T-cell therapy and that this mecha- nism may be useful to improve CAR T cell persistence,” Dr. Maude concluded. “This strategy may particularly benefit patients with poor persistence marked by early B cell recovery, as well as those with bulky extramedullary disease.”

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ASH 2018 • PRACTICEUPDATE CONFERENCE SERIES