Introduction: Outcomes of patients (pts) with newly diagnosed (ND) acute myeloid leukemia (AML) and adverse-risk cytomolecular features, including TP53 mutations (mut), and those with previously treated antecedent myeloid neoplasm (referred to as treated secondary [ts]-AML) remain poor, highlighting the need for newer novel frontline combinatorial therapies. The triplet regimen of azacitidine (AZA) + venetoclax (VEN) + gilteritinib (GILT) has been shown to be safe and effective in older/unfit pts with ND FLT3-mut AML (Shortetal., JCO 2024). Recent preclinical data suggest synergistic antileukemic efficacy with the VEN + GILT combination in adverse-risk FLT3-wild type (wt) AML, including in patient-derived xenograft models of TP53-mut AML; mechanistically explained by GILT-mediated downregulation of the antiapoptotic protein MCL-1 (Janssenet al., Blood 2022). We therefore conducted a phase II study to evaluate the AZA + VEN + GILT triplet in ND adverse-risk FLT3-wt AML.

Methods: Single-center phase II clinical trial for pts ≥18 years of age with ND FLT3-wt AML that is either 1) adverse-risk per ELN 2022 or 2) ts-AML, regardless of ELN 2022 risk. The primary endpoint is the rate of composite complete remission (CRc), defined as sum of complete remission (CR) and CR with incomplete hematologic recovery (CRi). Secondary endpoints are rates of measurable residual disease (MRD) negativity by flow cytometry, proportion of pts getting allogeneic stem cell transplantation (ASCT), relapse-free survival (RFS), overall survival (OS), and safety. Astellas Pharma Inc. provided study funding and drug support.

Results: 15 pts have been treated between 8/2024 - 6/2025 with median age 71 years (range 52 – 86). Seven pts (47%) had ts-AML, including treated myelodysplastic syndrome (MDS) in five pts (4 with HMA only, 1 with HMA + VEN), and two pts with treated myeloproliferative neoplasm (hydroxyurea in both, ruxolitinib in 1 pt). All 15 pts (100%) had adverse-risk disease by ELN 2022. TP53 mut was present in nine pts (60%) with median VAF of 52% (range, 21% - 73%); allTP53 mut pts had complex cytogenetics and three (33%) had >1 TP53 mut.

The overall CRc rate was 53% (CR in 6 pts, CRi in 2 pts); one additional pt attained MLFS. One pt (7%) had an early death due to pneumonia prior to response assessment. The CRc rates in TP53 mut and non-TP53 mut pts were 44% (4/9) and 67% (4/6), respectively, while the CRc rates in ts-AML and non-ts-AML were 29% (2/7) and 75% (6/8), respectively. Among 7 responders with evaluable MRD testing, 5 (71%) attained MRD negativity by flow cytometry (including 3 pts with TP53-mut AML). At the time of trial enrollment, 11 pts (73%) were deemed to be suitable candidates for ASCT. Overall, 4 pts (27% of the overall cohort and 36% of ASCT-eligible pts) underwent ASCT in first remission (2 pts with TP53-mut AML), with a median time from response to ASCT of 3.4 months.

With a median follow-up of 7.6 months (95% CI: 6.4- 9.4 months), 6 pts (40%) have died (4 in the context of relapsed/refractory AML, 1 in MLFS, and 1 early death). None of the 8 pts who attained CRc have relapsed, with a median follow-up of 8.0 months for these pts. At last follow-up, 9 pts (60%) remain alive, and 8 pts (53%) are in ongoing remission (4 with ASCT and 4 without ASCT). The median OS and RFS have not been reached.

The median number of cycles received was 2 (range 1 - 5). Most common grade 3-5 non-hematologic adverse events (AE), regardless of treatment attribution, included infections (40%), febrile neutropenia (33%) and hypertension (20%). Among the 9 pts who received at least one consolidation cycle, 4 (44%) had a dose reduction of one or more study drugs (AZA in 3 pts, VEN in 3 pts, GILT in 2 pts), all due to myelosuppression. There were 3 on-study deaths, 1 early death due to pneumonia (cycle 1, day 20), 1 due to sepsis while in MLFS (cycle 1, day 79), and 1 due to disease progression in the setting of refractory leukemia (cycle 1, day 25).

Conclusions: The triplet combination of AZA + VEN + GILT shows encouraging efficacy in our cohort of very high-risk FLT3-wt AML, including in TP53-mut and/or ts-AML. Responses are maintained as of last follow-up in all responding patients. Treatment-emergent AEs were similar to those previously reported with this regimen. The study is ongoing with planned correlatives on longitudinal samples for assessment of mechanisms of response/relapse; updated results will be presented at the meeting.

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2025
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