Identifying patients at risk of prolonged neutropenia and enhanced risk of complications during AZA-VEN induction for AML Free

Prolonged neutropenia and infectious complications represent an important concern during the first induction cycle of azacitidine-venetoclax (AZA-VEN) for newly diagnosed AML. Currently, there are no consistent approaches to identify which patients are at highest risk for infectious complications during induction. Our observation is that the duration of neutropenia after AZA-VEN is heterogeneous, with some patients experiencing only short-duration neutropenia, associated with a low risk of treatment-related morbidity. We therefore sought to identify patterns and risk factors associated with prolonged neutropenia and associated complications during first-line AZA-VEN therapy.

A retrospective analysis of adults with newly diagnosed AML receiving AZA-VEN from 3 Australian and French centers. AZA 75mg/m² sc for 7 days was combined with VEN 400mg/d, dose adjusted for azole prophylaxis, with VEN duration at physician discretion. Patients with baseline leukocytosis >50 G/L were excluded, as this group often received concomitant cytoreductive therapy as a confounding factor. Duration of neutropenia was the cumulative number of days with neutrophils (N) < 0.5 G/L between days 1 and 35 of C1 of AZA-VEN.

155 patients treated between 03/2016 and 01/2025 were included. Baseline characteristics included male sex (63%), median age 73.5y (range 28–90), ECOG 0–1 (72%), N 0.9 G/L (0-20.4), marrow blasts 29% (1-98%), adverse ELN2022 risk (79%), NPM1^mut (10%), IDH1/2^mut (34%), FLT3-ITD/N/KRAS^mut (22%) or TP53^mut (29%). AML status was de novo, secondary or therapy-related in 41%, 38% or 21% of patients, respectively. C1 was delivered as an inpatient in 75%, with a median time in hospital of 18 days (range 3–116). Median VEN duration was 21 days (range 7–28). Marrow blast clearance was achieved in 61%. G-CSF was commenced in 8% prior to marrow assessment, with 52% commencing G-CSF thereafter.

The median duration of grade 4 neutropenia in C1 was 23 days, censored by day 35 or C2 initiation, whichever occurred first. The proportion with C1 neutropenia duration 0–7, 8–14, 15–21, 22–28, 29-35 days was 24, 12, 11, 23, and 30% and this was associated with higher rates of febrile neutropenia: 14, 21, 29, 51 and 73%, respectively. K-means clustering analysis of the distribution of neutropenic duration revealed two sub-populations. One group (41%) had a short period of neutropenia (N-short; median 5.5 days, range 0-17), whereas a second group (59%) experienced longer neutropenia (N-long; median 28.5 days, range 18-35). For the N-short group, the median time to onset of grade 4 neutropenia was day 18 (range 5-34), whereas in the N-long group, 60% had grade 4 neutropenia on C1D1.

Among the N-long and N-short cohorts, rates of composite response (CR/CRi/MLFS) were comparable (59 vs 58%), but G-CSF use trended to be higher in the N-long group (58 vs 42%, p=0.055). In terms of complications, the N-long group had a significantly higher risk of febrile neutropenia (61 vs 16%; p<0.001) and neutropenic sepsis (31 vs 10%; p=0.036). Rates of ICU admission (8 vs 13%) and 30-day mortality (4 vs 3%) were comparable. Although a similar number initiated C1 as outpatients (29% vs 22%), rehospitalization trended to be more frequent in the N-long (70% vs 50%, p=0.2), with comparable duration in both groups (median 10 vs 9 days).

To identify factors predicting duration of neutropenia, univariate analysis included age, ECOG, marrow blasts, Hb<10 g/dL, Plts <50 G/L, N <0.5 G/L on day 1, ELN risk, karyotype, TP53, NPM1, IDH1/2 status and planned VEN duration. The only factor associated with N-long during C1 was N <0.5 G/L on day 1 of therapy. Importantly, VEN duration was not a determining factor for distinguishing patients likely to have long vs short neutropenic duration in C1. In multivariate analysis, baseline neutropenia was the sole independent predictor of N-long (odds ratio 17.5; p<0.001)

Patients receiving AZA-VEN have a variable risk of prolonged neutropenia not directly related to disease burden, genetic risk factors or duration of venetoclax therapy. Patients with/without grade 4 neutropenia on day 1 of AZA-VEN have an expected median duration of neutropenia lasting 30 vs 11 days. As baseline neutropenia was associated with a significantly higher risk of febrile neutropenia and septicemia, this parameter may aid risk stratification of patients who warrant closer monitoring until neutrophil recovery.