NPM1 mutation

Notably, intra-clonal co-localization of NPM1 with IDH1 or TET2 was associated with improved outcomes, whereas co-localization with WT1 predicted dismal prognosis. These results demonstrate that quantitative and structural dimensions of clonality refine the biological and prognostic landscape of NPM1-mutated AML beyond mutational status alone.

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.

Therapeutic strategies targeting XPO1 and Menin, which have shown promise in NPM1c-AML, may also hold potential for NPM1-r AML. Continued research is essential to further elucidate the biology of this rare AML subtype and to establish optimized treatment strategies.

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

The combination of ziftomenib 600 mg with venetoclax/azacitidine was well tolerated with deep and durable clinical activity in R/R NPM1-m AML. This trial was registered at www.ClinicalTrials.gov as #NCT05735184.

CRc rates were higher with venetoclax-based intensive (88.2%) or non-intensive (63.6%) CMT than with CMT alone (p = 0.001). In conclusion, this study offers a potential treatment paradigm for AML patients with co-occurring FLT3-ITD, NPM1 and DNMT3A mutations.

Selinexor, an exportin 1 inhibitor to impede NPM1MU export from nucleus, enhances FTO degradation and reduces macrophage M2 polarization. This work reveals that FTO-creatine signaling plays an oncogenic role in NPM1MU AML, guiding more effective therapy strategies and clinical benefits for this distinctly leukemic entity.

Currently, several small-molecule menin inhibitors are being tested in combination with conventional therapies. This publication reviews the recent progress in investigating the clinical evidence of menin inhibitors (revumenib, ziftomenib, bleximenib, enzomenib, BMF-219, emilumenib) toward aggressive leukemias, guides future study and optimal treatment for patients with this type of leukemia.

Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Next, we show that inhibitors of SETD2 (EZM0414) and menin (Revumenib) have synergistic efficacy against MLL-fusion and NPM1-mut leukemia and make prominent induction of cell cycle arrest, differentiation, and apoptosis. Finally, we clarify that the combined-drug treatment delays MLL-fusion leukemia progression in vivo. Taken together, these findings establish the simultaneously blocking of transcription elongation and initiation by epigenetic inhibitors as a promising therapeutic strategy for these aggressive leukemias.

Microclones and macroclones (low and high AR) were independently associated with increased relapse risk (sHR 1.50 [95% CI 1.18-1.91], 1.98 [1.50-2.62], and 2.33 [1.69-3.22], respectively) after adjustment for age, white blood cell count, other gene mutations, midostaurin treatment, and allogeneic hematopoietic stem cell transplantation...These findings challenge current risk stratification models and support the integration of NGS-based FLT3-ITD detection into the diagnostic and prognostic workflow for AML. Prospective trials addressing the management of patients with FLT3-ITD microclones are warranted, as is their consideration in future ELN guidelines.

Multivariate analysis showed that the Charlson comorbidity index (CCI) (OR=10.540, P=0.003), platelet count (OR=10.980, P=0.001), coagulopathy (OR=7.126, P=0.005), CD34(-)/HLA-DR(-) immunophenotype (OR=6.416, P=0.002), and infection (OR=59.080, P<0.001) were independent risk factors for ED in NPM1(mut) AML patients. Severe infection and bleeding were the main risk factors for ED in NPM1(mut) AML patients, and the CD34(-)/HLA-DR(-) immunophenotype should be considered in risk stratification and clinical management of patients with NPM1(mut) AML to guide early intervention.