KMT2A rearrangement

P1, N=60, Recruiting, Liping Dou

Patients with lineage switch have dismal outcomes and optimal therapies remain unknown, thus there is a large unmet need to better understand the biology, define the diagnosis, and determine the therapeutic approaches to lineage switch. Here, we address these needs providing a review of the current biology of lineage switch, the relationship to different genetic subtypes and present definitions and recommendations for immunophenotypic and molecular monitoring.

Importantly, distinct genetic lesions appear to correlate with specific immunophenotypic patterns, suggesting biologically meaningful disease subsets and providing insights into mechanisms of lineage plasticity and leukemogenesis. This review summarizes the current understanding of the immunophenotypic and genetic landscape of MPAL, emphasizing the integration of morphologic, immunophenotypic, cytogenetic, and molecular findings into diagnosis and subclassification.

HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

Novel menin inhibitors, including revumenib, bleximenib, ziftomenib, and enzomenib, are currently under clinical evaluation, and selected updated clinical results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting. This brief review summarizes the key findings and discusses the emerging clinical questions regarding combination strategies, treatment sequencing, and molecularly defined use of menin inhibitors.

Gene set enrichment analysis (GSEA) indicated enrichment of MAPK signaling, AP-1-mediated stress response, and epithelial-mesenchymal transition (EMT)/migration-associated pathways in CD68-high models. Together, these findings suggest that CD68 contributes to a pro-tumorigenic and stress-adaptive phenotype in pedAML and may represent a biologically relevant therapeutic target.

This combination was associated with high response rates and durable remissions, with an acceptable safety, in heavily pretreated patients with AML harboring alterations susceptible to menin inhibition.

P=N/A, N=20, Recruiting, University of Freiburg

This case highlights the diagnostic complexity and aggressive clinical course of neonatal MPAL, particularly in the absence of KMT2A rearrangements, and emphasizes the biological heterogeneity of this entity. Strict application of WHO/ICC lineage-defining criteria is essential to ensure accurate classification. Exchange transfusion may serve as a feasible bridging cytoreductive strategy in neonates with life-threatening hyperleukocytosis when leukapheresis is not available, although its effects are temporary and do not replace definitive therapy. Early recognition, prompt supportive management, and improved molecular characterization are critical to optimizing outcomes in this rare and high-risk population.

Patients treated with venetoclax plus intensive chemotherapy (Ven+IC) showed the best composite complete remission (CRc) rate and OS compared to intensive chemotherapy, venetoclax plus reduced-intensive chemotherapy, and reduced-intensive chemotherapy (CRc rate: 89.5% vs. 62.4% vs. 57.3% vs. 61.4%; median OS: not reached vs. 39.9 months vs. 34.8 months vs. 12.7 months). Multivariate analysis identified multiparameter flow cytometry minimal residual disease negativity post-induction therapy, allogeneic hematopoietic stem cell transplantation, and Ven+IC as independent favorable prognostic factors for event-free survival (EFS), and KMT2A::MLLT4 fusion, EVI1 overexpression were independent unfavorable prognostic factors for EFS. In summary, our study showed characteristics and prognostic implications in newly diagnosed KMT2Ar AML in China.

Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

allo-HSCT in CR(1) significantly improves prognosis in these patients. The KMT2A-PTD group showed poor response to conventional intensive chemotherapy but achieved significantly improved prognosis with venetoclax-based therapy.