KMT2A (Lysine Methyltransferase 2A)

P1/2, N=263, Active, not recruiting, Kura Oncology, Inc. | Recruiting --> Active, not recruiting

However, no clear additional DFS advantage was observed among those ultimately transplanted. These findings support frontline integration of blinatumomab and warrant prospective evaluation of transplantation strategies in this setting.

Notably, within the RAS-mutant subgroup, the presence of co-occurring oncogenic alterations was associated with more advanced T status (T3-T4, p = 0.0181) at diagnosis and lower biochemical cure rates (p = 0.02) at the follow-up compared with tumors harboring isolated RAS mutations, supporting the clinical relevance of extended genomic profiling in RAS-mutant sMTC. Overall, these findings highlight additional oncogenic alterations potentially involved in tumor progression and suggest that extended targeted profiling may provide clinically relevant information on molecular heterogeneity in sMTC, particularly within RAS-mutant tumors.

However, the prognosis of older KMT2A-r AML patients remains poor and could be improved by drug combination studies including Menin inhibitors. Many encouraging observations derived from ongoing clinical trials with Menin inhibitors need to be confirmed through randomized clinical trials.

Additionally, we describe a complex RAS mutation cohort (Comp-RAS) characterized by two distinct RAS mutations or high variant allele frequency (VAF) RAS mutations that collectively account for 13.5% (n=90) of patients with RAS mutations. Patients with complex KRAS mutations, and those with complex RAS mutations in the KMT2A-r cohort, had a distinctly adverse outcome, and data demonstrates that Comp-RAS status drives adverse outcomes for those with KRAS mutations in the whole AML cohort.

P3, N=1300, Recruiting, Kura Oncology, Inc.

CRISPR base editor screening previously predicted several MEN1 (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance...Co-crystal structures of menin bound to each menin inhibitor suggest resistance mechanisms related to how each inhibitor engages the KMT2A binding pocket of menin. Orthogonal in vitro and in vivo MEN1 mutation generation under therapeutic pressure suggest the MEN1 mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors.

It underscores the critical importance of promptly recognizing this hyperacute syndrome in young patients presenting with unexplained neurological symptoms and profound hematologic abnormalities. Early multidisciplinary management and awareness of high-risk genetic profiles are essential, although the prognosis in such scenarios remains exceedingly poor.

Ultimately, RAS mutations drive monocytic differentiation of LSCs and venetoclax (VEN) resistance through BCL-2 family rewiring. Beyond AML, they are hallmark genetic lesions in juvenile myelomonocytic leukemia (JMML) and present in 15%-20% of pediatric acute lymphoblastic leukemia (ALL) cases. Here, we propose a comprehensive pathogenic model and targeted therapeutic framework focusing on RAS, MCL-1, BCL2L1 to overcome drug resistance and improve patient outcomes.

P1, N=0, Withdrawn, Children's Oncology Group | N=29 --> 0 | Not yet recruiting --> Withdrawn

P2, N=71, Recruiting, Memorial Sloan Kettering Cancer Center

We evaluated RAS/MAPK targeting using the MEK1/2 inhibitor selumetinib in combination with the menin inhibitor revumenib. Our preclinical study suggests a potential targeted treatment combination for KMT2A-r and RAS pathway mutant leukemia, but one which will require further optimization. COG completed clinical trials AAML03P1, AAML0531, AAML1031 and C2961.