Multicenter phase 1b-2 trial of glutaminase inhibition in combination with azacytidine in advanced myelodysplastic syndromes

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. A multicenter phase 1b-2 trial in the United States evaluated the combination of the selective glutaminase inhibitor telaglenastat (CB-839) and azacytidine in patients with advanced myelodysplastic syndromes (MDS). The dose-escalation study included six patients and the dose-expansion study included 24 patients. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53%. The median overall survival was 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses. The authors conclude that these data demonstrate the safety and efficacy of telaglenastat and azacytidine in patients with MDS.