NPM1 mutation

Revumenib received its first approval on 15 November 2024 in the USA for the treatment of relapsed or refractory (R/R) acute leukaemia with a KMT2A translocation in adult and paediatric patients 1 year and older. This article summarizes the milestones in the development of revumenib leading to this first approval.

P1, N=28, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

Adult patients with AML demonstrated a higher level of HOXA9 expression, which has a negative impact on the disease-free survival of NPM1-mutated patients (p = 0.055). Therefore, targeting the HOXA9 pathway presents a highly plausible treatment option for NPM1-mutated adult AML patients.

Our study supports the use of MRD response along with FLT3-ITD status in the decision to use post-remission therapy. We demonstrate that older patients and patients with FLT3-ITD-mutated AML have a high relapse rate but can be salvaged, leading to long-term survival.

P3, N=415, Not yet recruiting, Stichting Hemato-Oncologie voor Volwassenen Nederland | Trial primary completion date: May 2028 --> Dec 2029

Intriguingly, Npm1c mutations reversed the intrinsic bias of the clone of origin, with differentiation-primed stem cells giving rise to more primitive malignant states. Thus, we highlight the relevance of single-cell lineage tracing to unravel early events in cancer evolution and posit that different cellular histories carry distinct cancer phenotypic potential.

revealed that allo-SCT in CR1 improved the outcomes (EFS and OS) in Groups 2 and 3, but had no additional impact in Group 1. Age, primary refractory disease and allogenic stem cell transplantation in the first complete response were found to have a prognostic impact on outcomes, Interestingly, no significant association was detected between the poor prognostic cytogenetic abnormalities or the presence of additional mutations in myeloid genes, MDS-related genes or KRAS/NRAS genes and the outcomes in any group of patients.

The VEN + HMAs regimen demonstrated considerable efficacy in the treatment of R/R AML patients, with both response rates and overall survival being influenced by distinct genetic features. These findings provide valuable insights into optimizing personalized treatment strategies for this challenging patient population.

This case emphasizes the importance of genetic profiling in identifying clinically relevant mutation patterns and highlights the potential of genetic insights to inform personalized treatment. It also underscores the need for further studies on the functional implications of unique CEBPA mutations in AML pathogenesis.

Overexpression of RIPK3 was associated with specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation, and may facilitate the leukemic development. Moreover, RIPK3 overexpression was associated poor prognosis, and may guide treatment choice in AML.

New combination regimens (NCRs), adding midostaurin and gemtuzumab ozogamicin (GO) to the 3 + 7 scheme, are commonly used, though there are no data that compare NCRs with intensive induction chemotherapy. The safety profile was similar, except for delayed platelet recovery with FLAI (22 vs. 18 days; p = 0.0024) and higher-grade II-IV gastrointestinal toxicity with NCRs (43% vs. 18.8%; p = 0.0066). Our data suggest the superiority of NCRs over FLAI in low-risk patients, while all outcomes were comparable in intermediate-risk patients, a setting in which only transplants positively impacted on survival.

This study highlights distinct hematopathological patterns of AML with overt DIC, providing a framework for early and precise diagnosis. Recognizing these patterns is critical for tailoring diagnostic and therapeutic approaches to improve outcomes in this high-risk population.

In the case of NPM1 and FLT3 mutations, these differences vanished at the time of complete remission yet readily reemerged upon relapse, indicating the reproducible nature of these genetic interactions. Thus, CH-associated mutations that likely precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse.

The HLA loss did not lead to any predicted missing ligand for educated natural killer (NK) cells expressing inhibitory killer immunoglobulin-like receptors (KIRs) for self-HLA allotypes, thus not affecting NK-mediated immunosurveillance. The present case represents a model of a 'perfect crime' by immunological escape of leukaemic blasts and supports mutated NPM1-derived neopeptides as an attractive target for AML immunotherapy.

Consequently, eIF4A inhibition synergizes with conventional chemotherapy. Together, these results suggest that AML cells rely on BMSCs to maintain an oncogenic translational program required for relapse.

Ziftomenib was well tolerated with no new safety concerns in healthy men. Considering the pharmacokinetic profile and manageable safety outcomes, these findings support further clinical investigation of ziftomenib as treatment for AML.

HOXA9 methylation linked to HOXA9 expression correlates with diverse genetic abnormalities of AML, such as normal karyotype, t(15;17), t(8;21), t(16;16) and FLT3, NPM1 and DNMT3A mutations. Moreover, HOXA9 hypomethylation may be associated with adverse prognosis, and may guide treatment choice in AML.

Whereas adverse molecular risk features (HR 4.69, p=0.003) and relapsed/refractory disease (HR 2.83/3.59, p=0.005/0.001) were associated with unfavorable prognosis, administration of post-transplant maintenance improved survival in multivariable analysis (HR 0.48, p=0.06). Our findings suggest that in patients with NPM1mut AML MRD positivity as assessed per qPCR at time of transplant does not impact posttransplant outcomes of NPM1mut AML.

Research over the last two decades has dramatically expanded our understanding of the biology of NPM1mut AML and led to the development of new therapeutic approaches and strategies for monitoring measurable residual disease (MRD). Here, we review NPM1mut AML with a practical focus on the current treatment landscape, the role of MRD in guiding management, and emerging therapies, including menin inhibitors.

Our literature-driven approach identified a robust gene signature that stratifies AML patients into distinct risk groups. The LBS6 score shows promise in redefining initial risk stratification and identifying high-risk AML patients.

P2, N=300, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Nov 2025 --> Jun 2026 | Trial primary completion date: Jan 2025 --> Jun 2025

Using a dataset of 572 WSIs, the largest database with both WSI and genetic mutation information, our model achieved an AUC of 0.90 ± 0.08 for NPM1 and 0.80 ± 0.10 for FLT3-ITD in the testing cohort. Additionally, we found that blasts are pivotal indicators for gene mutation predictions, with their proportions varying between mutated and standard WSIs, highlighting the clinical potential of AML WSI analysis.

Indeed, one Menin inhibitor, Revumenib, was recently approved for the treatment of patients with relapsed or refractory KMT2A-rearranged acute leukemia. However, single agent therapy can lead to resistance. In this Review article we summarize our current understanding about the biology of pathogenic KMT2A-complex function in cancer, specifically leukemia, and give a systematic overview of lessons learned from recent clinical and preclinical studies using Menin inhibitors.

No abstract available

Venetoclax in combination with FOXM1 inhibitor STL001 inhibited BCL2A1 and circumvented venetoclax resistance. Pharmacological inhibition of FOXM1/BCL2A1 axis represents a therapeutic strategy to sensitize AML cells to venetoclax-induced apoptosis.

P1/2, N=135, The First Affiliated Hospital of Soochow University; The First Affiliated Hospital of Soochow University

When focusing on the 470 patients with 2022 ELN favorable-risk NPM1 mut AML, multivariable analysis for event-free survival (EFS) identified age (p < 0.001), DNMT3A R882 (p < 0.001), IDH1 (p = 0.007), and MRG mutations (p = 0.03) as unfavorable factors, cohesin gene co-mutations (p = 0.001) and treatment with gemtuzumab ozogamicin (p = 0.007) as favorable factors...For OS, age (p < 0.001), DNMT3A R882 (p = 0.042), IDH1 (p = 0.045), and KRAS (0.003) mutations were unfavorable factors, sole favorable factor was IDH2 co-mutation (p = 0.037). In 2022 ELN favorable-risk NPM1 mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering NPM1 mut MRD status post cycle 2; DNMT3A R882 and MYC mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the NPM1 mut MRD status.

Treatment included intensive chemotherapy (IC) (36.8%), Low-Intensity Regimen Based on Low-Dose Cytarabine (LDAC-based) (12.6%), hypomethylating agents (HMAs, with/without venetoclax) (35.3%), and supportive care (15.2%). The overall survival (OS) rate was 35.2% at 1 year and 5.6% at 5 years (13.7% for IC, 9.4% for LDAC-based, and 0% for other treatments); with median OS of 8.2 months (10.6 months after IC, 8.8 months after non-IC, 8.9 months after azacitidine/decitabine, 8.2 months after azacitidine-venetoclax, and 1.9 months with supportive care)...The Leukemia-free survival (LFS) rate was 45.8% at 1-year and 13.7% at 5-years (22.4% for IC, 9.4% and 0% for other treatments); with median LFS of 9.5 months (17.3 months after IC, 7.4 months after LDAC-based, and 10.8 months after HMA). This study provides new insights into the management of patients in Colombia, highlighting the need for a highly individualized approach in treating AML in elderly patients.

The clinical promise of Revumenib in genetically defined AML highlights its potential role in shaping the future treatment landscape. This mini-review underscores the need for ongoing trials to define optimal dosing, safety protocols, and combination therapies, with the ultimate goal of establishing Revumenib as a standard of care for high-risk AML subsets.

Based on the case and relevant literatures, we explored the relationships between AML and NPM1/ DNMT3A/IDH2 gene mutations and t(5;12)(q31;p13), as well as their values in treatment and prognosis for AML.

P1/2, N=40, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2025 --> Jan 2027 | Trial primary completion date: Jan 2025 --> Jan 2027

MDS patients are prone to gene mutation, and the increasing number of mutations and the presence of TP53, NPM1 and TET2 gene mutation may be factors affecting the prognosis.

Our study supports the use of MRD response along with FLT3-ITD status in the decision to use post-remission therapy. We demonstrate that older patients and patients with FLT3-ITD-mutated AML have a high relapse rate but can be salvaged, leading to long-term survival.

The findings highlight the patients exhibiting the CD34-HLA-DR- immunophenotype as a unique AML subgroup with specific clinical and molecular traits, notably a predisposition to DIC, which affecting prognosis. This finding has implications for risk stratification and potential targeted therapies for AML management.

Menin inhibitors have emerged as a promising therapeutic approach, targeting key genetic drivers of AML such as KMT2A rearrangements and NPM1 mutations. Here, we review the clinical value of menin inhibitors, highlighting their mechanism of action, efficacy, safety, and potential to transform AML treatment.

Of the remaining 10 cases, 4 uncharacteristically had no detectable molecular genetic abnormalities. Our data show that, if a presumptive MDS shows a nonprimitive blast phenotype, caution is needed to rule out AML with recurrent genetic abnormality with an oligoblastic presentation, high-risk myeloid neoplasms with double-hit TP53 mutation with abnormal erythroid proliferation, and MDS with molecular-genetic and clinical features more akin to AML.

Functionally, this results in enhanced sensitivity of leukemic blasts to T cell-mediated cytotoxicity in allogeneic and autologous settings. Our data indicate that JNJ-75276617 provides a potential therapeutic approach whereby not only proliferation is impaired and differentiation is induced, but whereby therapeutic benefit might also be achieved by reactivating the antigen presentation machinery.

The NPM1 mutant undergoes changes at the C-terminus of the protein that leads to its delocalization in the cytoplasm of the leukemic cells. Here, we focus also on its biological functions discussing the murine models of NPM1 mutations and the various mechanisms that occur at cytoplasmic and nuclear levels to promote and maintain NPM1-mutated AML.

Patients in the high-risk group for these factors experienced significantly poor outcomes, which were closely associated with aDC, CD8 T cells, and TH17 cells. In summary, SYTL4 overexpression is linked to poor prognosis and immune infiltration in AML, with the constructed risk model intended as a prognostic evaluation tool for AML patients.

Improved survival was observed with transplantation in groups DP2, DP7, and DP9. These findings highlight the role of genomic classifications in guiding personalized treatment strategies, ultimately enhancing the understanding and management of myeloid neoplasms.

To our knowledge, this work is the largest study to explore the up-to-date undefined role of allo-HSCT in patients with triple-mutated AML. Our real-world data suggest that allo-HSCT could overcome the poor prognosis of DNMT3AmutNPM1mutFLT3-ITDmut in AML.

Current best practices for the diagnosis, classification, prognostication, and treatment of AML call for the assessment of the presence and absence of numerous genomic alterations. Therefore, in contrast to single-gene or small-panel molecular testing, the F1H platform can simplify such assessment via a CGP approach.