Venetoclax, ASTX727 Combination Shows Promise Against MDS, CMML

A combination of venetoclax and ASTX727 appears safe and demonstrates preliminary efficacy in patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) with excess blasts, according to the interim results of a phase I/II study.

Sangeetha Venugopal MD, MS, and colleagues from the University of Texas MD Anderson Cancer Center, discussed the findings during the 2022 Society of Hematologic Oncology (SOHO) Annual Meeting.

ASTX727 is an oral fixed-dose combination of hypomethylating agent (HMA) decitabine (35 mg) and cytidine deaminase inhibitor cedazuridine (100 mg).

The interim results included 19 patients, with a median age of 72 years (range, 54-94 years). The patients had a median bone marrow blast count of 12% (range, 6-18%) and harbored a median of four mutations (range, 1-9 mutations).

The overall response rate (ORR) was 95% (n=18), with three patients achieving complete remission (CR; 16%) and 15 achieving marrow CR (79%). All patients achieved a response within one cycle, among which seven patients, including one with a TP53 mutation, proceeded to hematopoietic stem cell transplant.

At a median follow-up of 5.9 months, the median overall survival (OS; range, 1.0-12.1 months) was not reached, and the one-year OS survival probability was 61%. The median event free survival (EFS) was not reached, and the one-year median EFS probability was 56%. The median duration of response was not reached (range, 0.9-11.1 months).

The single-arm, phase I/II study continues to enroll patients with treatment-naïve, higher-risk MDS (intermediate-2 or high-risk categories per the Revised International Prognosis Scoring System) or CMML with excess blasts of 5% or greater. Patients are administered ASTX727 orally daily on days one through five and venetoclax orally daily on days one through 14 of a 28-day cycle. Response assessment by bone marrow examination is done on day 28.

The primary objective of phase I of the study is to determine the safety and tolerability of the venetoclax plus ASTX727 combination, while the objective of phase II is to determine the ORR.

“The total-oral regimen of [venetoclax] plus ASTX727 combination appears to be a promising strategy for high-risk MDS or CMML patients and may alleviate the burden of chronic, long-term parenteral HMA treatment,” the researchers stated.

Reference

Venugopal S, Kantarjian H, Maiti, et al. phase I/II study of venetoclax in combination with ASTX727 (decitabine/cedazuridine) in treatment-naïve high-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML). Abstract #MDS-520. Presented at the 2022 Society of Hematologic Oncology (SOHO) Annual Meeting, September 28-October 1, 2022.