Vu H. Duong

Azacitidine (Aza) plus venetoclax (Ven) is standard treatment for older/unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). The approved 28-day (D) Ven schedule is associated with prolonged cytopenias, causing frequent dose reductions and cycle delays. Retrospective studies show similar efficacy and reduced toxicity with abbreviated Ven dosing, but prospective data is lacking. We conducted OPTI-AML(NCT03013998), a prospective randomized phase 2 trial comparing 28D Ven (AV28) versus 14D (AV14) with Aza (75mg/m²x7D) for C1-2 in genomically agnostic ND-AML patients ≥60 years. The primary endpoint was complete remission (CR) rate achieved at any time with two cycles of therapy. Between 2023-2025, 169 patients received AV28 (n=83) or AV14 (n=86). CR across two cycles was 49.4% (AV28) versus 43% (AV14); difference of 6.4% [90%CI:-6.1% to 19.0%], not meeting non-inferiority criteria. Patients with NPM1/ IDH2 mutations had higher CR rates with AV28 (60.9% vs. 33.3%), while CR rates were equivalent (45%) for other subgroups. Composite CR rates were 80.7% (AV28) versus 68.6% (AV14) and MRD negativity was similar (77.6% vs. 76.5%). Although AV28 had more frequent treatment interruptions, count recovery after C2, grade ≥3 adverse events and early mortality were similar. In conclusion, the study did not demonstrate non-inferiority of AV14 compared with AV28 during C1-2 in an unselected ND-AML cohort. However, as the confidence interval for the difference covered 0, CR rate for AV28 was not significantly different than AV14. Certain subgroups may benefit from prolonged Ven exposure, but these findings require validation in larger studies, especially as triplet regimens evolve.

Frameshift mutations in exon 12 of nucleophosmin 1 ( NPM1 ^mut ) are among the most common mutations in acute myeloid leukemia (AML) and have historically been considered favorable‐risk in the absence of FLT3 ‐ITD. In the European LeukemiaNet (ELN) 2024 risk‐classification for patients treated with hypomethylating agents plus venetoclax (HMA + VEN), NPM1 ^mut is not considered favorable when co‐occurring with signaling gene (SG) mutations (i.e., FLT3 ‐ITD, NRAS , KRAS ). However, due to limited numbers in the original analysis, the prognostic impact of SG mutations in NPM1 ‐mutant AML remains unclear. We evaluated the prognostic significance of NPM1 ^mut with and without SG mutations in two independent cohorts of patients ≥ 60 years with ELN 2024 favorable‐ or intermediate‐risk AML treated with HMA + VEN. Cohort 1 included 322 patients treated in the academic setting. NPM1 ^mut ( n = 61) was associated with a nonsignificantly longer overall survival (OS) compared to NPM1 wild‐type ( NPM1 ^wt ) (median, 53.05 vs. 17.03 months, p = 0.10). In multivariable analysis (MVA), SG mutations were not independently prognostic within the NPM1 ^mut subgroup. Cohort 2 included 816 patients from a real‐world community‐treated cohort. NPM1 ^mut ( n = 124) had a longer OS compared with NPM1 ^wt (median, 15.3 vs. 14.4 months, p = 0.03). In MVA, NRAS, KRAS , and FLT3 ‐ITD were independent unfavorable prognostic factors; NPM1 ^mut with, compared to without, SG co‐mutation had a shorter OS (median, 9.4 vs. 31.6 months, p = 0.001). These findings suggest SG mutations negate the favorable impact of NPM1 ^mut in older patients treated with HMA + VEN. Prospective clinical trials are needed to investigate the use of combination therapies to improve outcomes in this high‐risk subgroup.

Grade 3 or Higher Toxicities or Toxicities Observed in 10% or More Patients – Excluding Those Defined as Unrelated or Unlikely Related to Protocol Treatment.

A. Gating strategy applied on PBMCs samples evaluated by flow cytometry. CD8+ T cell memory was defined based on the expression of CD45RA and CCR7 (CD197). Cell surface phenotype (PD-1, CD39, and CD69) and intracellular activation (Ki-67) markers were quantified on CD8+ effector T cell (TEFF) based on indicated gates. B, CD8+ naïve and memory T cells in long-and short-survivors quantified before and after the treatment. C, Representative flow cytometry plots showing CD8+ T cells activation in PBMC samples from a short survivor. PD-1+ Ki-67+ expression on CD8+ T cells compared before and after the treatment.

Representativeness of Study Participants

List of Patients Who Experienced Immune-related Adverse Events AEs.

Specific genes sequenced in bone marrow mononuclear cells.

A& B. Frequency (A) and intensity (B) of PD-1+ CD8+ T cells by gender) before (PRE), after second treatment cycle (C2D1 or C2D8; EARLY), and after third or fourth treatment cycle (C4D1, C4D8 or C5D1; LATE). CD8+ T cell expressing CD39 (C) and CD69 (D). F: females, M: males

Median overall survival was longer among patients whose T cells harbored ASXL1 mutations (green) than for those without the mutation (red) or with only myeloid mutations (blue), but ASXL1 mutation status was not associated with survival in a univariate analysis by the logrank test (p=0.11). In a multivariate analysis using a Cox proportional model and adjusted by age at study entry, gender, diagnosis, and the number of prior treatment regimens, ASXL1 was significantly associated with survival (p=0.001 based on likelihood ratio test).