KMT2A mutation

Currently, most leukemias are effectively treated with immunotherapies (highly effective monoclonal antibodies targeting CD19 [blinatumomab], or CD22 [inotuzumab ozogamicin]), BCR::ABL1 tyrosine kinase inhibitors (TKIs; e.g., dasatinib, ponatinib), Bruton TKIs (e.g., ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, olutasidenib, and enasidenib), FLT3 inhibitors (e.g., midostaurin, quizartinib, and gilteritinib), menin inhibitors (revumenib, ziftomenib), and chimeric antigen receptor T-cell therapies. Herein, we provide a high-level overview of prominent clinical developments across all leukemias. In contemporary times, harnessing the benefits of novel targeted therapies and the evolving treatment landscape bolster the optimistic view that most, if not all, leukemias are curable.

Targeted therapies have improved outcomes in molecularly defined subsets of AML, with menin, IDH and FLT3 inhibitors representing major advances. However, TP53-mutated AML continues to carry a dismal prognosis, underscoring the need for more effective therapeutic strategies. Continued biomarker-driven research, novel drug combinations, and mechanistic insights will be essential to further refine AML treatment and improve long-term survival across disease subsets.

P1/2, N=66, Active, not recruiting, Institut de Recherches Internationales Servier (I.R.I.S.) | Trial completion date: Jun 2027 --> Dec 2027 | Trial primary completion date: Jun 2026 --> Dec 2026

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.

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.

Among these components, MLL mutations frequently co-occur with CHD1 mutations in various cancers, suggesting a shared pathway in cancer development. These findings underscore the importance of chromatin remodeler condensation as a regulatory hub in various cellular processes and tumor suppression.

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.

P1/2, N=66, Active, not recruiting, Institut de Recherches Internationales Servier (I.R.I.S.) | Recruiting --> Active, not recruiting | N=266 --> 66

This study described the clinical features, mutation landscape and TCR rearrangement profile in a relatively larger PRCA cohort, which may contribute to the clear perception of PRCA and the development of more potent treatment approaches.

The present study systematically reviewed biological functions of the menin protein and its application in targeted therapy for specific AML subtypes. Notably, menin inhibitors have demonstrated potential in KMT2A/NPM1-mutant leukemia, however, the off-target effects, resistance mechanisms and a lack of biomarkers due to the extensive nature of their binding interface remains to be elucidated.

P1, N=420, Recruiting, Kura Oncology, Inc. | N=212 --> 420 | Trial completion date: May 2027 --> Apr 2030 | Trial primary completion date: May 2026 --> Apr 2030