MLL rearrangement

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

P=N/A, N=200, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Oct 2026 --> Feb 2027 | Trial primary completion date: Oct 2025 --> Feb 2026

Overall, we observed synergistic effects on differentiation induction and proliferation inhibition, both in vitro and in vivo. Together, our studies underscore the promise of this combination strategy as a novel therapeutic approach for improving treatment outcomes in patients with these specific genomic alterations.

P2, N=22, Completed, Masonic Cancer Center, University of Minnesota | Active, not recruiting --> Completed

P3, N=5949, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Oct 2026

The fetal barrier to transformation was enforced by the histone methyltransferase MLL3, and it could be overcome by cooperating mutations, such as NrasG12D. Heritable fetal protection against leukemic transformation may contribute to the low incidence of congenital and infant leukemias in humans.

As a synergistic effect of BMI1 and EZH2 has already been demonstrated in other neoplasms, we hypothesize that acquiring an EZH2 mutation might be a crucial proliferation advantage in PICALM::MLLT10 positive cells. This may explain the high percentage of EZH2 mutated cases in this entity, but also supports the hypothesis of BMI1-mediated leukemogenesis.

These discoveries could provide rationale for future strategies to treat MLL-r AML, which has a poor prognosis in children and adults. Delivery of the ELDR RNA could potentially be utilized as an adjunct to LSD1i/ATRA treatment or other currently used chemotherapeutic drugs to develop novel therapies for these AML subtypes.

P2, N=34, Completed, Masonic Cancer Center, University of Minnesota | Active, not recruiting --> Completed | Trial completion date: Dec 2025 --> Mar 2025

At present, there is no report on the efficacy and safety of the MEA regimen consisting of L-MIT combined with etoposide and cytarabine in patients with AML with MLL rearrangement. Gastrointestinal side effects were mild, with no liver or kidney damage, obvious cardiac toxicity, infusion reactions, or skin discoloration. The L-MIT-based MEA regimen showed promising efficacy with a favorable safety profile in patients with MLL-rearranged AML, suggesting that the MEA regimen could be one of the preferred therapeutic options for this population.