Phase 1b/2 Study Supports Use of Telaglenastat and Azacytidine in Advanced MDS

A recent study published in Nature Cancer presents results from a clinical trial combining glutaminase inhibition with azacytidine (AZA) to treat advanced myelodysplastic syndromes (MDS). The trial, a phase 1b/2 study, examined the safety, tolerability, and efficacy of telaglenastat (CB-839) in conjunction with AZA. Their findings bolster support for the ongoing use of glutaminase (GLS) inhibition with CB-839 combinations in patients with myeloid malignancies.¹

Myeloid malignancy concept, blood cells floating | image credit: Eleni - stock.adobe.com

Cancer cells, particularly those in hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia(AML), rely heavily on glutamine for energy production through oxidative phosphorylation.² CB-839, a glutaminase inhibitor, targets the enzyme responsible for glutamine metabolism in cancer cells. By inhibiting glutaminase, CB-839 cuts off this essential energy source. Preclinical data demonstrated that combining CB-839 with AZA could enhance anti-cancer activity by impairing glutamine metabolism and disrupting DNA methylation.

The trial enrolled 30 participants with advanced MDS, 28 of whom received treatment with CB-839 and AZA. The median age of participants was 70 years (range 41-83 years). Thirty-six percent of participants had received prior MDS-directed therapy, including hypomethylating agents (HMAs), while 32% were diagnosed with therapy-related MDS, and 25% had chronic myelomonocytic leukemia (CMML).¹

The results from the study showed an overall response rate (ORR) of 54%. Among the 28 treated participants, 18% achieved complete remission (CR), and 36% achieved marrow complete remission (mCR). An additional 11% experienced hematologic improvement (HI). Twenty-five percent of participants successfully transitioned to allogeneic stem cell transplantation (SCT). The time to response occurred after a median of 2.3 treatment cycles (range 1-4 cycles).

Treatment-naïve patients achieved an ORR of 61%, with 28% achieving CR and 28% reaching mCR. Participants previously treated with other therapies, including HMAs, also responded to the combination therapy, with an ORR of 70%, although most achieved mCR rather than full CR. Of the 10 participants with complex cytogenetics, 7 responded, including 2 who reached CR and 2 who achieved mCR.

The median overall survival (mOS) for all participants was 11.6 months, with a 1-year overall survival rate of 46.4%. Treatment-naive participants were found to have a mOS of 21.6 months, while mOS was 6.8 months for previously treated participants. Cases of full CR were only observed in treatment-naïve participants.

The study also found that participants with higher expression of GLS had a significantly worse survival rate. Patients with high GLS had a mOS of 2.75 years compared to 5.76 years in low expressors (P = .004). This was found to be true regardless of age (P = .00923; HR = 1.964; 95% CI, 1.1816-3.266). "Our findings support the previously unrecognized role of glutamine in stem cells of persons with high-risk MDS, associated with overexpression of the specific glutamine transporter SLC38A1, facilitating glutamine uptake and its use," the authors explain.

The combination therapy of CB-839 and AZA was generally well-tolerated. The most common non-hematologic adverse events were nausea (52%), constipation (39%), and generalized weakness (17%). Grade 3 or higher adverse events included neutropenia (30%) and thrombocytopenia (26%). No cases of tumor lysis syndrome or differentiation syndrome were reported. The 30-day and 60-day mortality rates were reported as 0% and 3.6%, respectively.

For patients with higher-risk MDS, the standard of care typically involves HMAs like AZA or decitabine, which work to improve blood cell counts, reduce transfusion needs, and extend survival.³ The study's findings are positive for clinicians treating patients with higher-risk MDS, particularly those who have exhausted traditional treatment options. "These results support the ongoing exploration of GLS inhibition with CB-839 combinations in persons with myeloid malignancies," the authors conclude.

References:

1. Konopleva M, DiNardo C, Bhagat T, et al. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: clinical efficacy and correlative analyses. Nat Cancer. 2024; doi:10.1038/s43018-024-00811-3
2. Jin, J., Byun, J., Choi, Y., & Park, K. (2023). Targeting glutamine metabolism as a therapeutic strategy for cancer. Exp Mol Med. 2023;55(4):706-715. doi:10.1038/s12276-023-00971-9
3. Koenig KL, Borate U. New investigational combinations for higher-risk MDS. Hematology Am Soc Hematol Educ Program. 2022;2022(1):368-374. doi:10.1182/hematology.2022000351