MLL rearrangement

Clinically, EVI1 overexpression is one of the most robust independent indicators of poor prognosis, associated with therapy resistance and reduced overall survival. This review provides a detailed discussion of the mechanisms underlying EVI1's activation, its complex molecular functions in hematopoietic transformation, and its profound clinical implications in hematological malignancies.

Modulators targeting DOT1L have been developed for more than a decade, and compounds such as competitive inhibitors, protein-protein interaction (PPI) inhibitors, and degraders block DOT1L's pathogenic functions through various pharmacological mechanisms. Challenges and opportunities are discussed in this perspective, aiming to provide valuable insights for the future design of DOT1L modulators.

Compared to each drug alone, co-treatment with SNDX-5613 (revumenib) and FHD-286 or OTX015 and FHD-286 significantly reduced the in vivo AML burden and improved survival of the immune depleted mice, without inducing significant toxicity, in the xenograft models of MITR and MI-resistant PD MLL1-r AML cells. These findings highlight novel, targeted, drug combinations that overcome MI resistance in AML cells with MLL1-r or mtNPM1.

By incorporating MRD-guided dynamic risk stratification and optimized drug regimens, the CCCG-ALL-2015 protocol significantly improved the quality of induction remission, reduced adverse events, and improved the long-term survival in adolescents (aged 10-18 years) with ALL. The MRD status at the end of induction therapy is a critical prognostic indicator and provides important guidance for individualized therapy.

In addition, the combination of MAT and RSL3 can dramatically reduce the population of bone marrow CD45+ cells in AML xenograft mouse. In conclusion, MAT can synergistically promote non-toxic-dose RSL3 induced ferroptosis by modulating the p53 pathway in AML with MLL translocation, which may potentially enable the clinical application of ferroptosis inducers in further.

The 3-year overall survival rates and event-free survival (EFS) rates were 80.7% and 69.4%, respectively. Multivariate Cox regression analysis revealed that gene MLL rearrangement (excluding MLL-AF9) (HR=3.071, 95%CI: 1.024-9.205) and positive molecular MRD after Induction Course Ⅱ therapy (HR=5.571, 95%CI: 1.244-24.957) were risk factors for EFS in pediatric AML patients.

We evaluate the latest data on various menin inhibitors-both as monotherapy and in combinations-emphasizing their efficacy and safety profiles. As new evidence continues to accumulate with recent drug approvals and ongoing randomized, phase 3 studies, menin inhibitors are rapidly becoming a component of the AML treatment paradigm for relapsed/refractory and likely newly diagnosed disease.

P2, N=31, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

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.

P1/2, N=32, Active, not recruiting, Bambino Gesù Hospital and Research Institute | Recruiting --> Active, not recruiting | Trial primary completion date: Mar 2025 --> Mar 2027

This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat...In vivo, the combination produced potent antileukemic effects in both MOLM-13 and MLL-r patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in MLL-r AML.

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Completed --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2026