https://orcid.org/0009-0003-0514-349X
Key Points
VEN-DEC showed not inferior response to IA-12 in young/fit patients with untreated AML.
VEN-DEC had fewer serious adverse events and shorter severe thrombocytopenia duration than IA-12.
Venetoclax (VEN) combined with hypomethylating agents is approved for frontline therapy in older/unfit patients with acute myeloid leukemia (AML). However, prospective data on this low-intensity therapy in treatment-naive younger patients with AML are lacking. This study investigated the efficacy and safety of VEN plus decitabine (VEN-DEC) as induction in untreated young fit patients with AML in a randomized trial. Patients aged 18 to 59 years eligible for intensive chemotherapy were randomized 1:1 to receive VEN-DEC or IA-12 (idarubicin and cytarabine). All patients achieved composite complete remission (CRc) underwent high-dose cytarabine consolidation. The primary end point was CRc rate after induction. Of 255 screened, 188 were enrolled and randomly assigned, with 94 in each group. In the intention-to-treat population, CRc was 89% (84/94) in the VEN-DEC group vs 79% (74/94) in the IA-12 group (noninferiority P = .0021), with measurable residual disease negativity rates of 80% (67/84) vs 76% (56/74), respectively. VEN-DEC showed superior CRc in patients aged ≥40 years (91% vs 75%) and those with adverse risk (91% vs 42%) or epigenetic mutations (91% vs 67%), but lower CRc in RUNX1::RUNX1T1 fusion cases (44% vs 88%) than IA-12. Patients in the VEN-DEC group experienced fewer grade ≥3 infections (32% vs 67%) and shorter severe thrombocytopenia duration (median, 13 vs 19 days; P < .001). At a median follow-up of 12.1 months, overall and progression-free survival were similar between groups. In conclusion, VEN-DEC demonstrated noninferior response rates with superior safety over IA-12 in young patients with AML. The trial was registered at www.clinicaltrials.gov as #NCT05177731.
Comments
Comment on Lu et al.: VEN-DEC from Young to Elderly—Redefining Induction Goals in AML
Affiliation: Unit of Blood Diseases and Bone Marrow Transplantation, Department of Clinical and Experimental Science, University of Brescia, ASST Spedali Civili di Brescia, Brescia, Italy
Lu et al. conducted a randomized trial in young (18–59 years), fit patients, comparing VEN-DEC to standard 3+71. VEN-DEC showed non-inferior composite complete remission (CRc- 89% vs 79%), fewer infections (32% vs 67%), and shorter thrombocytopenia. It also achieved a 91% CRc in ELN adverse-risk patients, far above the historical ~40% with intensive chemo2,3, and 91% in those >40 years. However, OS was not significantly different (median OS not reached), and the rate of patients bridged to allo-HSCT was similar (44%).
These results only partially align with Russo et al.4, who, in a multicenter phase 2 trial on older but transplant-eligible AML patients—traditionally excluded from curative paths—reported 69% CR and allo-HSCT in 83% of responders: an unprecedented result.
Lu’s study lacks data on VEN-DEC dose adjustments, outpatient use, number of cycles to CR, time to transplant, and fitness preservation—features favoring VEN-DEC in Russo’s trial and possibly leading to higher transplant rates.
The key difference lies in trial design: Lu tests efficacy vs standard, Russo builds a path to transplant. Yet both question whether intensive chemo is still required for cure.
If VEN-DEC allows safe, effective, inclusive induction across ages and risks, should we still accept 3+7 as dogma—or reimagine it as history?
References
1. Lu, J. et al. Venetoclax and Decitabine vs Intensive Chemotherapy as Induction for Young Patients with Newly Diagnosed AML. Blood blood.2024027217 (2025) doi:10.1182/blood.2024027217.
2. Döhner, H. et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 140, 1345–1377 (2022).
3. Kantarjian, H. et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J 11, 41 (2021).
4. Russo, D. et al. Venetoclax plus decitabine as a bridge to allogeneic haematopoietic stem-cell transplantation in older patients with acute myeloid leukaemia (VEN-DEC GITMO): final report. of a multicentre, single-arm, phase 2 trial. The Lancet Haematology 11, e830–e838 (2024)