Introduction: First-line treatment of acute myeloid leukemia (AML) with venetoclax and azacytidine (VenAza) is both effective and safe, including in the elderly population. Nevertheless, it carries a risk of hematologic toxicity, with an incidence of 42% of both Grade 3 neutropenia and febrile neutropenia in the VIALE-A trial (DiNardo, NEJM, 2020). In clinical practice, hematologic toxicity can lead to overzealous dose-reductions, treatment delays or suspension, determining suboptimal outcomes; in contrast, timely support with G-CSF analogs and judicious delays associate with the best results.

Through this study, we aim to describe the real-word experience of a single-center with a treatment protocol focusing on optimizing exposure to Ven and minimizing dose-reductions or delays.

Methods: We analyzed all patients (pts) with a diagnosis of AML who started 1st line treatment with a VenAza doublet in our Center with the first day of the first cycle falling from 01-01-2023 to 01-31-2025. Patients treated with Ven-decitabine or with triplet combinations were excluded. Data cut-off was 03-01-2025.

Data was analyzed as person-cycles, looking at the incidence of neutropenia, the need for G-CSF support, Ven cycle reductions and cycle delays. Ven dose-reductions due to drug-drug interactions were performed according to published guidelines, and are not taken into account.

Results: We analyzed 48 pts (56.3% female); half retrospectively fulfilled VIALE-A inclusion criteria (age 75 years or older, or comorbidities contraindicating intensive induction chemotherapy), while half would have been ineligible for VIALE-A, and eligible for chemotherapy. The median age was 66.6 years at diagnosis (20.0-78.8 years), and 66.7 years at the start of VenAza. This cohort translated into a total of 236 person-cycles of VenAza, 20.3% of which (n=48) were first cycles (C1) of treatment.

A total of 60.0% of cases were neutropenic on C1D1 (2.2% mild neutropenias, 22.2% moderate, 15.6% severe and 20.0% very severe), with a median absolute neutrophil count (ANC) of 0.77 G/L (0.016-10.78).

The median number of days of Ven administration per cycle was 28 (3-28) with 54.7% of cycles comprising 28 days of Ven; causes for cycle reduction were hematological toxicity in 66.4% of cycles, a non-programmed stop in 20.0% due to complications (including hematologic and non-hematologic toxicity, as well as unrelated comorbidities), death on-cycle from unknown causes in 2.8%, progressive disease in 1.9% and problems with drug dispensing in 0.9%.

The median ANC at D1 of each cycle excluding C1 was 1.15 G/L (0.027-11.2); 61.0% of cycles started with neutropenia (24.2% mild, 25.8% moderate, 7.7% severe and 3.3% very severe). Among cycles started after a documented bone marrow complete remission (CR) was achieved, 60.9% were started with neutropenia (25.6% mild, 27.6% moderate, 7.1% severe, 0.6% very severe), with a median ANC of 1.15 G/L (0.06-11.21); cycles performed before CR had a higher incidence of severe (14.1%) and very severe (19.7%) neutropenia, p<0.001.

Excluding C1, 64.4% of cycles were delayed; the median cycle delay was 8 days (range: 1-209), and in 75% of cycles the delay was 15 days or less. The median cycle duration was 4.9 weeks, with 75% of cycles lasting 40 days or under. In 8.5% of cycles, the pts were admitted due to infectious complications, leading to a significant shortening of treatment with Ven (18.4±9.1 vs 23.9±5.7 days, p<0.001).

Considering cycles that were delayed, the median ANC on the intended first day was 0.19 G/L, corresponding to 50.8% of cases of very severe and 21.5% of cases of severe neutropenia. In 7.7% of cases, treatment was delayed in the absence of neutropenia, due to other clinical complications (in 4.6%) and logistic issues (national holidays, in 3.1%). Filgrastim was used solely on demand, exclusively in pts with a documented CR, and was used in support of one-fifth (19.4%) of cycles in CR that were delayed, and on-cycle in 7.4% of cycles in CR.

Median OS was 21.4 months from diagnosis in the full cohort and in VIALE-A ineligible pts, with a median OS not-reached in pts who would have been eligible for VIALE-A.

Conclusions:Our series, including both elderly or unfit pts, and younger chemotherapy-eligible pts, was able to reach a median OS of almost two years, with a median of 4.9-week cycles with 28 days of Ven, with on-demand G-CSF support, showing how an effort to maximize Ven exposure can lead to optimal outcomes.

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2025
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