Glutaminase Inhibition Plus Azacitidine Promising for Advanced MDS

Combining the selective glutaminase inhibitor telaglenastat with azacitidine is safe and effective for advanced myelodysplastic syndrome (MDS) management. This is according to findings from a single-arm, open-label, phase Ib/II study published in Nature Cancer.

Lead author Courtney D DiNardo, MD, MSCE, of the University of Texas MD Anderson Cancer Center in Houston, wrote that the two agents formed “a combined metabolic and epigenetic approach” for advanced MDS. She noted “[m]alignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation.”

The investigation involved a dose-escalation study with a cohort of six patients and a dose-expansion study with a cohort of 24 patients. Single-cell RNA sequencing was used to evaluate evidence of myeloid differentiation in patients who responded to the combination.

The combination therapy was well tolerated by the study participants, who had an objective response rate of 70% and a median overall survival of 11.6 months. Complete remission within bone marrow occurred in 53% of participants.

“Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort,” Dr. DiNardo concluded.

Reference

DiNardo CD, Verma D, Baran N, et al. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses. Nat Cancer. 2024. doi:10.1038/s43018-024-00811-3