Journal
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
Volume 19, Issue 3, Pages 157-161Publisher
CIG MEDIA GROUP, LP
DOI: 10.1016/j.clml.2018.12.005
Keywords
Hypomethyalting agents failure; Immune; Innate immunity; MDSC; T reg cells
Categories
Funding
- Incyte
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This is a phase II study exploring the activity and pharmacodynamics of INCB024360, an oral inhibitor of the enzyme indoleamine 2,3-dioxygenase, in previously treated patients with myelodysplastic syndromes. Background: INCB024360 is an oral inhibitor of the enzyme indoleamine 2,3-dioxygenase (IDO), which catalyzes the degradation of tryptophan to kynurenine. Preclinical data suggest that IDO1 inhibition by INCB024360 will increase T cell proliferation, and decrease T regulatory cells and myeloid derived suppressor cells suppressive activity. We conducted a phase II study to explore activity and pharmacodynamics of INCB024360 in patients with myelodysplastic syndromes. Patients and Methods: All patients were treated with INCB024360 600 mg orally twice a day for at least 16 weeks. Fifteen patients were enrolled. The median age was 72 years. The International Prognostic Scoring System risk was low in 27% (n = 4), intermediate-1 in 47% (n = 7), and intermediate-2 in 27% (n = 4). All patients had prior azacitidine. Results: The best response was stable disease in 12 (80%) patients and progressive disease in 3 (20%) patients. The treatment was relatively well-tolerated. One patient developed hypothyroidism and adrenal insufficiency (grade 2), and 1 patient had low testosterone level. The mean IDO expression was 39% at baseline and 26% after treatment (n = 9; P = .4). The mean burst forming unit-erythroid changed from 72 to 191 colonies/10(6) (n = 5; P = .036), and the mean colony forming unit-granulocye, monocyte from 62 to 180 colonies/10(6) (n = 6; P = .5). The mean myeloid derived suppressor cell % (CD33Lin-HLA cells) was 29.5% at baseline compared with 27.6% after treatment (n = 9; P = .7). The mean T-regulatory effector memory cell % changed from 9.6% at screening to 7.4% at end of treatment (n = 14; P = .8). The mean kynurenine/tryptophan ratio decreased from 45 at baseline to 26 (42% reduction) at cycle 2, day 1 (P < .005). Conclusion: Future directions may include testing INCB024360 early in the course of the disease.
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