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Treatment with oral decitabine/cedazuridine (Inqovi) plus venetoclax (Venclexta) demonstrated high response activity and encouraging survival outcomes in patients with treatment-naive high-risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukemia (CMML), according to results from a single-center phase 1/2 trial (NCT04655755).¹

The findings, presented at the 2025 ASH Annual Meeting and Exposition, showed that patients treated with the regimen (n = 69) achieved an overall response rate (ORR) of 91% per International Working Group (IWG) 2006 criteria, including a 45% complete remission (CR) rate and a 46% marrow CR (mCR) rate. Responses occurred early, with a median time to first response of 1 cycle (range, 1-3) and a median of 1 cycle to best response (range, 1-5). Patients received a median of 3 cycles (range, 1-25). Response classification using updated IWG 2023 and ELN 2022 criteria showed consistent depth of remission, with CR rates of 54% and 64%, respectively.

The median overall survival (OS) for the full cohort reached 30 months, with 1- and 3-year OS rates of 68.8% and 40.7%, respectively. Median event-free survival (EFS) was 21.2 months, and the respective 1- and 3-year EFS rates were 60.7% and 32.6%. The median duration of response had not yet been reached (NR; 95% CI, 29-NR) at a median follow-up of 25 months (95% CI, 20-33).

“Decitabine/cedazuridine with venetoclax is a feasible and safe combination for [patients with] HR-MDS and CMML,” lead study author Alex Bataller, MD, PhD, explained in his presentation of the data. “This combination is associated with a high ORR, [and responses] occur early in the treatment. The median OS of patients treated with decitabine/cedazuridine and venetoclax is 30 months, with a high proportion of patients undergoing hematopoietic stem cell transplantation [HSCT].”

Bataller currently serves as an assistant professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

A total of 38 patients proceeded to HSCT, with best responses comprising CR (n = 18), mCR (n = 19), and no response (n = 1). The median number of cycles prior to HSCT was 2 (range, 1-11). The median OS among the HSCT subgroup was NR, with 1- and 3-year OS rates of 70.4% and 50.7%, respectively. Six patients experienced disease progression or transformation to acute myeloid leukemia after HSCT, and 8 patients died in CR following HSCT.

What was the design and patient enrolment criteria of the trial?

The phase 1/2 clinical trial evaluating oral decitabine/cedazuridine with venetoclax in treatment-naive HR-MDS or CMML with excess blasts was designed as a single-center, open-label, dose-escalation and -expansion study. Patient enrollment at MD Anderson occurred between January 2021 and August 2024.²

Eligible participants included individuals with previously untreated HR-MDS, defined by an International Prognostic Staging System (IPSS) intermediate-2 or high-risk category, or CMML with excess blasts. The study was structured in two phases.¹ Phase 1 followed a standard 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Two dose levels were evaluated:

• Dose level 0: decitabine/cedazuridine 35 mg/100 mg for 5 days plus venetoclax at 200 mg for 14 days (3 patients; no dose-limiting toxicities [DLTs] observed)
• Dose level +1: decitabine/cedazuridine 35 mg/100 mg for 5 days plus venetoclax at 400 mg for 14 days (6 patients; no DLTs observed)

Based on the absence of DLTs, dose level +1 was declared the RP2D.

Phase 2 focused on assessing the efficacy of the RP2D, enrolling 60 additional patients treated with decitabine/cedazuridine 35 mg/100 mg for 5 days in combination with venetoclax at 400 mg for 14 days per cycle.

In total, 74 patients were screened, and 69 were enrolled across both phases of the trial. The design supports a systematic evaluation of safety, tolerability, and preliminary efficacy of oral decitabine/cedazuridine combined with venetoclax.

Which baseline clinical and molecular features characterized the study population?

The median age at enrollment was 71 years (range, 21-94), and 71% of participants were male. Patients had a median bone marrow blast level of 12% (range, 6%-18%).

Most patients carried a WHO 2016 diagnosis of MDS (86%), 13% had CMML, and 1 patient (1%) had atypical CML. Cytogenetic risk based on revised IPSS (IPSS-R) criteria further underscored the high-risk nature of the cohort: 39% had good-risk cytogenetics, 25% had intermediate risk, 12% had poor risk, and 25% had very poor risk. Therapy-related neoplasms were present in 22% of patients.

Among those with MDS, IPSS-R risk classifications revealed that 59% were categorized as very high risk, 29% as high risk, and 12% as intermediate risk. Modified IPSS scoring aligned with this pattern, with 61% of patients classified as very high risk, 32% as high risk, and 7% as moderate-high risk.

What was the safety profile observed with the combination of decitabine/cedazuridine and venetoclax in patients with high-risk MDS and CMML?

Grade 3 adverse effects (AEs) occurred in 78% of patients; the rates of grade 4 and grade 5 AEs were 91% and 12%, respectively.

Cytopenias were the most frequent high-grade toxicities. Grade 3 anemia occurred in 42% of patients, and grade 4 thrombocytopenia and neutropenia occurred in 65% and 71%, respectively. Febrile neutropenia was observed in 19% of patients. Serious infectious complications included grade 3 to 5 sepsis (12% grade 3; 3% grade 4; 6% grade 5) and pneumonia (9% grade 3; 3% grade 5). Additional infectious effects,such as viremia and skin infections occurred in 9% of patients each.

“Infection prophylaxis and dose modifications are crucial to prevent excessive toxicity of this combination,” Bataller emphasized in his presentation. Seventy-five percent of patients underwent dose reductions during treatment.

References

1. Bataller A, Bouligny IM, Bazinet A, et al. Oral decitabine/cedazuridine in combination with venetoclax in treatment-naïve high-risk MDS or CMML: updates of a phase 1/2 clinical trial. Blood. 2025;146(suppl 1):237. doi:10.1182/blood-2025-237
2. Venetoclax in combination with ASTX727 for the treatment of treatment-naive high-risk myelodysplastic syndrome or chronic myelomonocytic leukemia. ClinicalTrials.gov. Updated October 3, 2025. Accessed December 7, 2025. https://www.clinicaltrials.gov/study/NCT04655755