KMT2A rearrangement

P1/2, N=66, Active, not recruiting, Institut de Recherches Internationales Servier (I.R.I.S.) | Trial completion date: Jun 2027 --> Dec 2027 | Trial primary completion date: Jun 2026 --> Dec 2026

One proposed mechanism for the development of both hematologic malignancies in this patient is the acquisition of a KMT2A rearrangement, raising the possibility of clonal evolution resulting in therapy-related or secondary leukemia. Another explanation is the presence of a common clonal stem cell progenitor harboring a JAK3 mutation.

Indeed, the use of selective BCL-2 antagonists (e.g. venetoclax) and FLT3 inhibitors (e.g. midostaurin, gilteritinib) which target specific molecular characteristics of leukaemic cells, has enhanced outcomes and survival rates...Spurred on by the recent FDA approval of revumenib, menin inhibitors hold the potential to further shift the treatment paradigm for this patient population. Here, we aim to provide a comprehensive overview of the pathogenesis of KMT2A rearrangements, with a focus on KMT2A fusion genes and proteins within paediatric AML patients. Additionally, we summarise the challenges arising from resistance to menin inhibitors, and we touch on the potential of combination therapies to expand the efficacy of menin inhibition and mitigate some of the resistance mechanisms employed by leukaemic clones.

Our study revealed the heterogeneous outcomes of KMT2A-rearranged AML patients and clarified the impact of HSCT across different age groups.

P1, N=24, Not yet recruiting, Massachusetts General Hospital

This case adds to the limited literature reporting cup-like nuclear morphology in B-ALL, which is typically associated with varied cytogenetic abnormalities, including BCR::ABL1 fusion and hyperdiploidy [3, 4]. The findings emphasize the critical role of FCI and molecular studies in distinguishing AML from B-ALL or mixed phenotype acute leukemias.

No amplifications or deletions were seen. This genomic landscape study highlights significant genomic differences between KMT2Ar and KMT2Awt AML patients, which may enrich our understanding of the molecular profile and clusters of mutations in AML.

P3, N=160, Recruiting, Princess Maxima Center for Pediatric Oncology | Active, not recruiting --> Recruiting

This vulnerability is mechanistically linked to the leukemia's dependence on active transcription. Our findings delineate the unique molecular profile of NUTM1-r leukemias, revealing specific vulnerabilities that rationalize their favorable clinical outcomes and suggest opportunities for modified therapeutic strategies.

Treatment with the dual EZH1/2 inhibitor UNC1999 and 5-azacytidine reactivated these PRC2 target genes, specifically in AML-HSPCs, toward normal gene expression patterns. These findings suggest that targeting Polycomb repression offers a promising epigenetic strategy for improving outcomes in KMT2A-rearranged AML.

There is an urgent need for effective targeted drugs for KMT2Ar AML. Continuous research and clinical trials will be key to improving patient prognosis and advancing precise treatment for this challenging leukemia subtype.

Collectively, these ncRNAs integrate into the complex regulatory circuits of KMT2A-r ALL, revealing their potential as biomarkers for disease classification, risk stratification, and treatment response prediction. Understanding their interplay with KMT2A fusion proteins not only provides new insights into leukemogenesis but also highlights promising opportunities for therapeutic intervention and precision medicine in this high-risk leukemia subtype.