MLL mutation

Ziftomenib received its first approval on 13 Nov 2025 in the USA for the treatment of adults with relapsed or refractory AML with a susceptible NPM1 mutation who have no satisfactory alternative treatment options. This article summarises the milestones in the development of ziftomenib leading to this first approval for relapsed or refractory AML associated with an NPM1 mutation.

Our study demonstrates that patients with eAML subtype have a worse prognosis, unique molecular features and higher tumor burden. Allo-HSCT might be an effective way to improve prognosis. This study provides evidence critical for risk stratification and treatment optimization in eAML.

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.

In addition, patients with KMT2A mutation had shorter OS compared to those with wild type (HR, 4.605; P = 0.045), whereas other EMMs had no impact on prognosis in any type of ALL. Mutations in DNMT3A, IDH, PHF6 and KMT2A showed a significant prognostic effect in ALL or in its specific subtypes, which might contribute to risk stratification and treatment guidance in the management of ALL patients.

Surprisingly, we find that this combination is effective in selected AML models without mutations in MLL or NPM1, thus nominating dual inhibition of LSD1 and Menin as an attractive therapeutic approach for a mutationally diverse set of non-APL AMLs. Inhibition of LSD1 and Menin synergizes to induce differentiation of MLL-r and MLL-WT AMLs.Inhibition of Menin downregulates drivers of proliferation and stemness.Inhibition of LSD1 induces differentiation-associated inflammatory and interferon responses.LSD1 and Menin occupy different areas of the genome.

The platform holds promise for translation into pre-malignant screening applications in asymptomatic neonates and adults as well as measurable residual disease monitoring in malignancies. Furthermore, it provides a novel single-cell morphological data modality that complements existing molecular layers, including genomics, epigenomics, transcriptomics, and proteomics.

Non-sinonasal ITACs are rare, aggressive malignancies requiring accurate diagnosis and further molecular investigation to improve management and outcomes.

Concurrent mutations of MLL3 and POLE in UCEC signify a better immune response, which is validated in mouse models with Mll3-ablated colon cancer. Our study provides a pan-cancer spectrum of the MLL3 mutational event and will contribute to the understanding of the genetic evolution and disease management of cancers.

Brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone did not significantly improve OS or PFS overall; however, exploratory analysis indicated improved PFS in the KMT2A-r subset. KMT2A-r delineates an adverse-risk biology in nodal PTCL, aligns with non-TFH genomic hubs and markers of tumor burden, and may serve as a stratifier and hypothesis-generating target for BV-based strategies.

Multivariate analysis identified older age, a high white blood cell count, KMT2A::MLLT4, and KRAS mutations as independent adverse prognostic factors for both EFS and OS. These age-specific mutation profiles suggest distinct disease mechanisms across age groups and may help refine risk stratification and treatment strategies for pediatric KMT2A-r AML.

Allogeneic hematopoietic cell transplantation significantly improved survival, with 3-year OS rates of 75.2% in transplant recipients versus 22.5% in non-transplanted patients (P < 0.001), particularly in high-risk groups and when performed in first complete remission. These findings support the use of molecularly guided, risk-adapted therapy in KMT2A-altered AML.