Modified Venetoclax Dose Outperforms Standard Care in Unfit AML Patients

A reduced dose or shorter duration of venetoclax when used in patients with acute myeloid leukemia (AML) who are not fit for intensive treatment can not only maintain efficacy but also significantly improve clinical outcomes through enhanced treatment persistence, according to new research published in Leukemia & Lymphoma.¹

The combination of venetoclax with hypomethylating agents (HMA) has fundamentally shifted the treatment paradigm for unfit, older adults with AML. Although the landmark VIALE-A trial established the 400-mg, 28-day cycle as the standard of care, ² real-world studies have reported shorter median survival with hematological toxicities resulting in treatment reduction and interruption.^3,4 New research now shows that reduced doses or shorter durations of venetoclax can not only maintain efficacy but also significantly improve clinical outcomes through enhanced treatment persistence.¹

“The high rate of treatment discontinuation due to [venetoclax]-related hematological toxicities underscores the challenges inherent in this therapeutic approach,” the authors wrote. “A significant percentage of patients require [venetoclax] dose reductions or discontinuation due to cytopenia, particularly neutropenia leading to infectious complications.”

The prospective study evaluated the impact of a shorter duration and a reduced dose of venetoclax on 4431 adult patients who were newly diagnosed with AML compared with the standard dose. Patients had received at least 1 cycle of induction therapy with venetoclax and 5-azacitidine. The findings challenge the maximal tolerated dose philosophy,⁵ suggesting that for many patients, the toxicity of the 28-day standard compromises long-term survival when patients need to discontinue treatment early.

A Survival Advantage in De-Escalated Therapy

Three distinct venetoclax dosing strategies were evaluated:

• Group A (n = 12) received the standard 400-mg dose for 28 days
• Group B (n = 15) received 400 mg for a shortened 14-day duration
• Group C (n = 18) received a reduced dose of 100 mg for 21 days

The median follow-up from treatment initiation to last date was 16.7 months (range, 0-52). Both of the modified regimens outperformed the standard of care. The complete remission (CR) rates for the modified groups (B and C) were both 67% compared with 58% in the standard care group (A). In addition, the composite remission rates (CRc), defined as marrow CR with or without hematological recovery, were also higher: 73% for Group B, 72% for Group C, and 58% for Group A.

The median time from treatment to CRc was 32 days for Group A, 26 days for Group B, and 28 days for Group C. Median overall survival was “significantly shorter” for the patients on the standard regimen compared with the adjusted regimens (HR, 0.46; 95% CI 0.21-0.98; P = .033). The overall mortality rates were 67% in Group A, 47% in Group B, and 50% in Group C.

Febrile neutropenia occurred at a much higher rate in Group A in 92% of patients compared with 73% in Group B and 78% in Group C. Groups B and C also had a shorter duration of febrile neutropenia, and the incidence of severe neutropenia was lower compared with Group A.

“Therefore, shorter duration and reduced dose [venetoclax] regimens appear to support quicker hematological recovery,” the researchers noted.

The key limitation of the study was the small sample size and short follow-up, and the authors suggested further studies can “clarify the effects and safety of the administration schedule.”

References

1. Okta S, Ueda-Akagi Y, Mitsuyoshi T, Ono K. Reduced dose and shorter duration venetoclax regimens are effective for newly diagnosed acute myeloid leukemia patients not considered fit for intensive treatment. Leuk Lymphoma. Published online December 25, 2025. doi:10.1080/10428194.2025.2604566

2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971

3. Ucciero A, Pagnoni F, Scotti L, et al. Venetoclax with hypomethylating agents in newly diagnosed acute myeloid leukemia: a systematic review and meta-analysis of survival data from real-world studies. Cancers (Basel). 2023;15(18):4618. doi:10.3390/cancers15184618

4. Gross Z, Tauveron-Jalenques U, Aspas Requena G, et al. Real world use of azacitidine and venetoclax in acute myeloid leukemia in frontline and relapse/refractory settings: multicenter study from French AURAML Group. Blood. 2023;142(Supplement 1):590. doi:10.1182/blood-2023-187331

5. Stampfer HG, Gabb GM, Dimmitt SB. Why maximum tolerated dose? Br J Clin Pharmacol. 2019;85(10):2213-2217. doi:10.1111/bcp.14032