Heatmap of patients with active disease at study theray initiation, showing CBF subtype, ACA, treatment group and mutational groups

Cox multivariate for overall survival in the full cohort with backward model selection not including DNMT3A-ASXL1-TET2 (DAT) and TRANSCRIPTION FACTORS

Representativeness of study participants

Cox regression univariate analysis for overall survival

Cox multivariate model for relapse free survival for the full cohort

Survival stratified by CBF subtype and treatment arm

Menin inhibition leads to an antileukemic effect through hematopoietic differentiation. Treatment with the menin inhibitor revumenib results in clinical remissions in relapsed or refractory (R/R) acute myeloid leukemia (AML) with either rearrangement of lysine methyltransferase 2A (KMT2A) or mutation in nucleophosmin 1 (NPM1), leading to regulatory approval of this drug. However, determinants of response to revumenib have not been fully elucidated. We examined the immunophenotype of leukemia cells by flow cytometry, in sequential bone marrow specimens from 48 patients with R/R AML treated with revumenib. We observed dynamic changes in the immunophenotype after treatment in 16 of 31 (52%) patients, characterized by a switch from a myeloid/stem-like to a monocytic or myelomonocytic immunophenotype, or vice versa, or by substantial changes in the intensity of antigen expression or in patterns of leukemia-associated immunophenotypes. Morphologic remission with undetectable measurable residual disease (MRD) by flow cytometry following revumenib was associated with improved overall survival, with a median of 23.6 months compared with 20.8 months in patients with morphologic response and detectable MRD, and 3.2 months in non-responders. In summary, treatment monitoring of AML by flow cytometry, following menin inhibition, requires recognition of phenotypic changes associated with differentiation.

Cox MVA for OS in the full cohort with forward variable selection

Cox multivariate for relapse free survival in the full cohort with backward variable selection not including DNMT3A-ASXL1-TET2 (DAT) and TRANSCRIPTION FACTORS

Fludarabine, cytarabine, and G-CSF-based therapy (FLAG) yields approximately 60% 5-year overall survival (OS) in core-binding factor (CBF) acute myeloid leukemia (AML), with potential added benefit with gemtuzumab ozogamicin (GO). Although measurable residual disease (MRD) status via optimal quantitative polymerase chain reaction (qPCR) response (OPR; qPCR <0.1% at the end of induction and <0.01% during/after consolidation) of fusion transcripts predicts survival, the impact of baseline myeloid mutations on OPR and survival with FLAG remains uncertain. We interrogated these factors in 219 first-line patients with CBF-AML (median age 52 years; range, 19-80) treated on a phase II trial (NCT00801489); 51% received FLAG-GO and 49% FLAG idarubicin. Baseline mutations included 49% kinase pathways (non-MAP kinase), 44% MAP kinase, 11% DNMT3A-ASXL1-TET2, and 7% transcription factors. Five-year relapse-free survival and OS were 67% and 74% overall, respectively, 77% and 80% with FLAG-GO. On multivariate analysis, baseline mutations did not affect OPR or survival, whereas FLAG-GO favored both. In CBF-AML, FLAG-based therapy possibly attenuates the prognostic impact of concurrent baseline genomics. SIGNIFICANCE:In CBF-AML treated with conventional intensive chemotherapy, usually 7 + 3, baseline mutations in KIT, chromatin modulators, cohesin complex, etc., garner suboptimal MRD clearance and survival. In our analysis, FLAG-based therapy abrogated the impact of baseline mutations on OPR and survival in CBF-AML, while showing promising long-term survival using FLAG-GO.

Survival stratified by status of additional cytogenetic abnormality (ACA)

Survival stratified by the presence of RAS mutations at high burden (>1 mutation with VAF>5% for both or single mutation with VAF >20%)

Cox multivariate model for relapse free survival in the full cohort with forward variable selection

Coverage by gene and codon(s) tested with >250x coverage in the clinical grade targeted myeloid gene sequencing

Multivariate logistic regression analysis to study factors associated with an Optimal PCR Response (OPR)

Cox multivariate model with backward variable selection for overall survival in patients who achieved an End of induction (EOI) Optimal PCR Response (OPR)

Cox multivariate model for overall survival for the full cohort

Cumulative incidence of relapse and non-relapse mortality as competing events stratified by the treatment groups

Patient disposition (Outcomes as of data cutoff: Dec 31, 2024)

Survival stratified by the presence or absence of DNMT3A-ASXL1-TET2 (DAT) mutation