Venetoclax/HMA Combo Demonstrates Real-World Efficacy in Unfit AML

Venetoclax (Venclexta) plus a hypomethylating agent (HMA) confirmed its efficacy in patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy, according to results from the prospective, real-world GIMEMA AML2320 study (NCT04589728) published in the British Journal of Haematology.¹

What was the efficacy of venetoclax/HMA in a real-world setting?

After a median follow-up of 23 months (range, 0.1-41.9), the median overall survival (OS), the primary end point, was 13.0 months (95% CI, 11.4-15.7). The 1-year and 2-year OS rates were 52.4% (95% CI, 45.4%-60.5%) and 29.6% (95% CI, 22.8%-38.5%, respectively. Early mortality rates were low, at 2.6% at 30 days and 6.7% at 60 days. Median OS varied by 2017 European LeukemiaNet (ELN2017) risk category at 24.5 months, 15.4 months, and 8.9 months for favorable-, intermediate-, and adverse-risk disease, respectively.

Among secondary end points, the composite complete remission (cCR) rate was 73% by the completion of cycle 4, with 54% of patients responding before cycle 2. Achievement of cCR within cycle 4 was associated with significantly longer OS (19.1 vs 9.1 months; P = .001). Patients who received venetoclax at 400 mg without concomitant azole antifungals had improved OS compared with those on reduced doses with azoles (18.2 vs 11.4 months; P = .015).

What was the safety of venetoclax/HMA?

A total of 130 grade 3 or higher adverse events (AEs) were reported. Infectious complications accounted for 34.9% of grade 3 AEs, including febrile neutropenia (14.3%), pneumonia (11.1%) and sepsis or septic shock (7.9%). Four grade 5 AEs occurred, of which 3 were infectious in nature; tumor lysis syndrome occurred in 1 case.

“Our findings confirm the observations of the pivotal VIALE-A trial [NCT02993523] and offer additional practical considerations to assist decision-making in clinical practice,” corresponding author Adriano Venditti, MD, professor of hematology at the University of Rome Tor Vergata, wrote in the publication with study coinvestigators.^1,2 “The GIMEMA AML2320 trial confirmed the efficacy of [venetoclax]/HMAs in a prospective, real-world unfit population.”

How was GIMEMA AML2320 designed?

GIMEMA AML2320 is a prospective, multicenter, observational study conducted by the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA). The study included 193 patients with newly diagnosed AML who were unfit for intensive chemotherapy and who received venetoclax plus azacitidine (Vidaza) or decitabine (Dacogen) between November 2020 and December 2021. The median age was 74 years (range, 49-85), and 45% of patients were 75 years or older.

The primary end point of the study was OS. Secondary end points included cCR, disease-free survival, and safety.

Patients 18 years and older with a confirmed diagnosis of previously untreated primary or secondary AML per WHO criteria, eligibility to receive HMAs plus venetoclax, and ineligibility to receive intensive chemotherapy were able to enroll on the study. Those with acute promyelocytic leukemia, prior frontline treatment for AML, or prior treatment with HMAs were excluded from the study.

To benchmark the results against the pivotal trial, the investigators performed an anchored matching-adjusted indirect comparison (MAIC) with the phase 3 VIALE-A trial, which established venetoclax plus azacitidine as a standard of care in this setting. After matching (effective sample size, 72.8), the median OS was comparable between the real-world cohort and the VIALE-A population (14.8 vs 14.9 months; P = .6).

As an observational study, GIMEMA AML2320 lacked the randomization and controlled conditions of a clinical trial; the authors positioned it as prospective real-world evidence complementing, rather than replacing, randomized data.

References

1. Palmieri R, Piciocchi A, Soddu S, et al. Real-world outcomes of venetoclax plus hypomethylating agents in unfit acute myeloid leukaemia: results of the GIMEMA AML2320 trial. Br J Haematol. Published online July 23, 2026. doi:10.1111/bjh.70752
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.