The combination of venetoclax plus decitabine is shown to be as effective and have a better safety profile when compared with the current chemotherapy-based standard of care (SOC) of cytarabine plus an anthracycline in younger, fit patients with acute myeloid leukemia (AML), according to a phase IIb study published in Blood.1
In the intent-to-treat group, the composite complete remission (CRc) rate after induction therapy — the study’s primary endpoint — was 89% (84 of 94 patients) in the venetoclax plus decitabine arm compared with 79% (74 of 94 patients) in the idarubicin and cytarabine control arm (non-inferiority p=0.0021). Additionally, patients treated in the venetoclax-containing arm had a lower rate of grade 3 or higher infections, 32%, compared with 67% in the chemotherapy arm. Patients in the venetoclax plus decitabine arm also experienced a shorter severe thrombocytopenia duration at a median of 13 days compared with a median of 19 days among patients in the chemotherapy arm (p<0.001).
“This study provides the first results of a large, randomized study of [intensive chemotherapy compared with venetoclax plus decitabine] for younger, fit patients with AML,” said Courtney D. DiNardo, MD, MSCE, a hematologist and clinical researcher at MD Anderson Cancer Center in Houston, who was not involved in the study. “For me, the key is that patients with European LeukemiaNet (ELN) 2022 adverse-risk disease, which by definition, do not respond as well to standard intensive chemotherapy, had similar to improved response rates and fewer adverse events (AEs) with the venetoclax plus decitabine therapy.”
Currently, the SOC for younger, fit patients with AML is a combination of cytarabine and an anthracycline such as idarubicin. The ELN risk classification system for patients with AML was updated in 2022, detailing which treatment-naïve patients are more or less likely to respond to and be cured with standard intensive chemotherapy alone.2
“In patients with adverse-risk disease, the likelihood of long-term durable remissions with standard intensive chemotherapy is low, which is why a lower-intensity effective combination like venetoclax plus decitabine may be an appropriate front-line therapy for these higher risk subgroups,” Dr. DiNardo said. Generally, studies have shown that the intensive so-called 7+3 regimen results in a 46% complete response (CR) rate among adverse-risk patients and about 80% to 90% in favorable- and intermediate-risk groups.3,4
In the current study, researchers, led by Jing Lu, MD, of the First Affiliated Hospital of Soochow University and the National Clinical Research Center for Hematologic Diseases in Suzhou, China, compared the standard intensive chemotherapy regimen to venetoclax plus decitabine among treatment-naïve, younger patients with AML because prospective data on the efficacy and safety of venetoclax plus decitabine in these patients are lacking.
A total of 188 patients with AML aged 18 to 59 years who were eligible for intensive chemotherapy were randomized 1:1 to receive venetoclax plus decitabine or idarubicin and cytarabine at one of three cancer centers in China. Patients who achieved a partial remission underwent re-induction with the initial regimen and repeated bone marrow assessment. Consolidation therapy, including one to four cycles of high-dose cytarabine (HiDAC)-based chemotherapy (2 g/m² every 12 hours on days 1-3), was given to patients in CR or CR with incomplete hematologic recovery (CRi). An allogeneic hematopoietic cell transplantation (alloHCT) was recommended for the adverse- or intermediate-risk groups and favorable-risk patients with a high relapse risk as dynamically assessed by physicians.
The median patient age was 45 years in the venetoclax arm and 40 years in the chemotherapy arm. Of the 188 patients, 182 (97%) completed induction therapy on protocol. Of the 84 patients in the venetoclax arm who achieved CRc after initial induction therapy and re-induction, 78% achieved CRc after initial induction. Of the 74 patients who achieved CRc after initial induction therapy and re-induction in the chemotherapy arm, 75% achieved CRc after initial induction.
The difference in CRc between venetoclax plus decitabine and chemotherapy was 10.6% (95% CI 0.2-21.3). Using a non-inferiority margin of 5%, the p value from the Farrington-Manning test for non-inferiority was 0.0021, showing non-inferiority of venetoclax plus decitabine at the 2.5% significance level.
Measurable residual disease negativity after induction was observed in 80% (67 of 84) of venetoclax plus decitabine–treated patients compared with 76% (56 of 74) in the intensive chemotherapy arm.
In a subgroup analysis, the authors found that venetoclax plus decitabine had better outcomes for patients older than 40 years and in those patients with epigenetic modifier mutations (IDH1/IDH2, DNMT3A, ASXL1, TET2).
“Venetoclax plus decitabine was generally well tolerated, with key AEs of cytopenias and cytopenia-related infections, but with an incidence far less than among patients receiving standard intensive chemotherapy,” Dr. DiNardo said.
“The patients randomized to venetoclax plus decitabine either went on to consolidative alloHCT or to cytarabine-based consolidation regimens. This is important, as the venetoclax plus decitabine combination alone is not curative, and thus consolidation is necessary,” noted Dr. DiNardo.
For Dr. DiNardo, standard intensive chemotherapy should remain the standard for younger, fit patients with ELN favorable–risk AML because they respond well to the regimen. For patients with adverse-risk biology, such as those with splicing factor mutations, complex cytogenetics, or both, venetoclax plus decitabine followed by an HCT could be considered as a noninferior regimen with reduced AEs and toxicities, according to Dr. DiNardo.
Currently, a U.S.-based trial of more than 150 younger, fit patients with AML is comparing these two regimens to confirm the results of the current trial that was conducted in Chinese patients only. The trial is being conducted by Amir Fathi, MD, at Massachusetts General Hospital in Boston.5
Any conflicts of interest declared by the authors can be found in the original article.
References
- Lu J, Xue S, Wang Y, et al. Venetoclax and decitabine versus intensive chemotherapy as induction in young patients with newly diagnosed AML [published online ahead of print, 2025 Feb. 26]. Blood. doi: 10.1182/blood.2024027217.
- Döhner H, Wei AH, Appelbaum F, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. 2022;140(12):1345-1377.
- Ohtake S, Miyawaki S, Fujita H, et al. Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 2011;117(8):2358-2365.
- Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010;28(5):808-814.
- ClinicalTrials.gov. NCT04801797. Venetoclax + azacitidine vs. induction chemotherapy in AML. March 18, 2024. Accessed March 12, 2025. https://clinicaltrials.gov/study/NCT04801797.
