KMT2A (Lysine Methyltransferase 2A)

P2, N=90, Not yet recruiting, SWOG Cancer Research Network

P1, N=23, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: May 2026 --> May 2027 | Trial primary completion date: May 2026 --> May 2027

Combination therapy with MI plus hypomethylating agent and venetoclax produced higher CR (43.3% vs 19.5%; p = 0.002) and CR+CRh rates (48.6% vs 25.8%; p = 0.007) than monotherapy...Differentiation syndrome occurred in 14.6%, and treatment-related mortality in 5.0%. MI-based therapy demonstrates meaningful activity in heavily pretreated AML, with deeper responses observed using combination strategies.

Conventional karyotyping and targeted FISH probes were employed to identify recurrent and rare chromosomal abnormalities, with a special emphasis on inv(16) (p13.1q22), MLL rearrangements, and complex karyotypes. Our findings highlight the indispensable role of integrating cytogenetics and FISH in routine diagnostic workflows, especially in cases with cryptic rearrangements or subclonal abnormalities, thereby underscoring their clinical and prognostic significance.

Here, we define a clinically actionable strategy that functionally targets PLK1 by combining inhibition of the AAA+ ATPase p97/valosin-containing protein (VCP) with the hypomethylating agent decitabine (DAC). In vivo, CB-5339/DAC is well tolerated, significantly prolongs survival, reduces leukemic burden, and suppresses PLK1 in bone marrow blasts. Together, these data establish p97 inhibition as a rational means to exploit replication and proteotoxic stress in AML and provide strong rationale for clinical evaluation of CB-5339 plus DAC in high-risk disease.

Findings from our study show that KMT2A-amplified MPAL is associated with complex karyotypes, TP53 abnormalities, and an inferior outcome. Our data may help refine MPAL risk stratification.

Further cell assay experiments confirmed that cells expressing individual fusion genes were more sensitive to the suggested drugs, and the key downstream genes were affected by our drugs. FusionTarget provides a unique foundation for developing therapeutics targeting fusion proteins.

SGC-iMLLT strongly inhibited MLL-AF4-driven leukaemia growth in vitro and in vivo, did not alter in vitro colony forming potential of human HSPCs or affect long-term in vivo function of mouse HSPCs. SGC-iMLLT may have a promising therapeutic window in the treatment of MLL-AF4-driven leukaemias.

Although combination chemotherapy remains essential for high-risk GTN, exposure to high cumulative doses of etoposide confers a risk of secondary t-MNs. Long-term hematologic surveillance and less leukemogenic strategies are warranted.

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