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BIOMARKER:

MLL mutation

i
Other names: HTRX1, HTRX, MLL1A, Mixed Lineage Leukemia 1, Myeloid/Lymphoid Or Mixed-Lineage Leukemia Protein 1, CXXC7, MLL1, TRX1, Zinc Finger Protein HRX, Trithorax-Like Protein, ALL-1, Lysine (K)-Specific Methyltransferase 2A, CXXC-Type Zinc Finger Protein 7, Histone-Lysine N-Methyltransferase 2A, Myeloid/Lymphoid Or Mixed-Lineage Leukemia, Lysine Methyltransferase 2A, MLL, Myeloid/Lymphoid Or Mixed-Lineage Leukemia, KMT2A
1m
The Menin story in acute myeloid leukaemia-The road to success. (PubMed, Br J Haematol)
Other HOX and MEIS1 expressing leukaemias may also be sensitive to Menin inhibition. Following the encouraging results as monotherapy in refractory and relapsed AML, the combination of Menin inhibitors with chemotherapeutic agents and other targeted drugs is being investigated clinically.
Review • Journal
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NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1) • PBX3 (PBX Homeobox 3)
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NPM1 mutation • MLL rearrangement • MLL mutation • MLL fusion
1m
KMT2A Mutations and High Prevalence of dMMR-associated Mutational Signatures as Prognostic Indicators in Metastatic Colorectal Cancer. (PubMed, J Cancer)
KMT2A mutations (hazard ratio [HR], 4.47; 95% confidence interval [CI], 1-19.93; P =0.050) and dMMR signature proportions (HR, 3.57; 95% CI, 1.42-8.96; P = 0.007) remained independently associated with PFS after multivariate analysis and the results were further externally validated. These findings may enhance our understanding of this disease and may potentially facilitate the optimization of its treatment approaches.
Journal • BRCA Biomarker • Metastases
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BRAF (B-raf proto-oncogene) • BRCA2 (Breast cancer 2, early onset) • KMT2A (Lysine Methyltransferase 2A)
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MSI-H/dMMR • BRAF mutation • RAS mutation • KMT2A mutation • MLL mutation
2ms
Characteristics and treatment of acute myeloid neoplasms with cutaneous involvement in infants up to 6 months of age: A retrospective study. (PubMed, Pediatr Blood Cancer)
In the largest cohort to date, our study describes the characteristics of infants with cutaneous involvement of myeloid neoplasms including cytomolecular findings and survival rates. Further prospective biologic and clinical studies of these infants with myeloid neoplasms will be required to individualize therapy for this rare patient population.
Retrospective data • Journal
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KMT2A (Lysine Methyltransferase 2A)
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KMT2A rearrangement • MLL rearrangement • MLL mutation
3ms
Donor Stem Cell Transplantation Using α/β+ T-lymphocyte Depleted Grafts From HLA Mismatched Donors (clinicaltrials.gov)
P2, N=9, Terminated, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2024 --> Mar 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Mar 2024; Low accrual
Trial completion date • Trial termination • Trial primary completion date
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TP53 (Tumor protein P53) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • NUP214 (Nucleoporin 214) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • DEK (DEK Proto-Oncogene)
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TP53 mutation • RUNX1 mutation • KMT2A rearrangement • IKZF1 mutation • MLL mutation • Chr t(9;11)
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Rituxan (rituximab) • cyclophosphamide • clofarabine • melphalan • fludarabine IV • thiotepa • busulfan
3ms
Testing the Addition of an Anti-cancer Drug, SNDX-5613, to the Standard Chemotherapy Treatment (Daunorubicin and Cytarabine) for Newly Diagnosed Patients With Acute Myeloid Leukemia That Has Changes in NPM1 or MLL/KMT2A Gene (clinicaltrials.gov)
P1, N=28, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Trial completion date: Feb 2024 --> Dec 2027 | Initiation date: Feb 2024 --> Nov 2024 | Trial primary completion date: Feb 2024 --> Dec 2027
Enrollment open • Trial completion date • Trial initiation date • Trial primary completion date • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • MLL rearrangement • FLT3 wild-type • MLL mutation
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daunorubicin • revumenib (SNDX-5613) • Starasid (cytarabine ocfosfate)
4ms
A Study of BN104 in the Treatment of Acute Leukemia (clinicaltrials.gov)
P1/2, N=90, Recruiting, BioNova Pharmaceuticals (Shanghai) LTD. | Not yet recruiting --> Recruiting
Enrollment open
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NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • KMT2A rearrangement • MLL rearrangement • KMT2A mutation • MLL mutation
5ms
The genetic and immune features of salivary gland secretory carcinoma with high-grade transformation. (PubMed, Oral Dis)
Our findings reveal novel gene alterations involved in the progression of HGT in SCs. Most HGT SCs patients cannot benefit from PD-L1 blocking and may be approached with a distinct treatment strategy including the lymph node dissection and application of molecular target drugs in precision oncology.
Journal • PD(L)-1 Biomarker • IO biomarker
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RET (Ret Proto-Oncogene) • ARID1A (AT-rich interaction domain 1A) • NRG1 (Neuregulin 1) • CD8 (cluster of differentiation 8) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • NOTCH3 (Notch Receptor 3) • GATA6 (GATA Binding Protein 6)
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PD-L1 expression • ARID1A mutation • RET mutation • NOTCH3 mutation • MLL mutation • ETV6 mutation
6ms
Somatic mutations of MLL4/COMPASS induce cytoplasmic localization providing molecular insight into cancer prognosis and treatment. (PubMed, Proc Natl Acad Sci U S A)
Using a preclinical carcinogen model of bladder cancer in mouse, we demonstrate that truncated cytoplasmic MLL4 predicts response to targeted metabolic inhibition therapy for bladder cancer and could be developed as a biomarker for KMT2D-mutated cancers. We also highlight the broader potential for prognosis, patient stratification and treatment decision-making based on KMT2D mutation status in MLL4 truncation-relevant diseases, including human cancers and Kabuki Syndrome.
Journal
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KMT2D (Lysine Methyltransferase 2D)
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KMT2D mutation • MLL mutation
6ms
Enrollment open
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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FLT3 mutation • NPM1 mutation • KMT2A rearrangement • MLL rearrangement • KMT2A mutation • MLL mutation
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cytarabine • Xospata (gilteritinib) • idarubicin hydrochloride • ziftomenib (KO-539) • fludarabine IV
6ms
Phase classification
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • MLL rearrangement • FLT3 wild-type • MLL mutation
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daunorubicin • revumenib (SNDX-5613) • Starasid (cytarabine ocfosfate)
6ms
Trial completion date • Trial primary completion date • Combination therapy
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NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • KMT2A rearrangement • MLL rearrangement • KMT2A mutation • MLL mutation
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Venclexta (venetoclax) • azacitidine • daunorubicin • ziftomenib (KO-539)
6ms
Molecular and immune landscape by cyclin dependent kinase (CDK) 4/6 expression and TP53 mutational status in mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC). (ASCO-GI 2024)
Our comprehensive analysis is the first to show distinct mutational profiles according to TP53 mut status, and differential expression of immune-related genes and TME cell infiltration independent of TP53 mut in CDK4/6 high vs low dMMR/MSI-H CRC. In our series, CDK6 expression correlated with ICI treatment benefit in TP53 mut tumors, warranting further studies to explore the potential of targeting the CDK4/6 axis to enhance ICI efficacy in CRC.
Microsatellite instability • PD(L)-1 Biomarker • MSi-H Biomarker • IO biomarker • Mismatch repair
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PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • MSI (Microsatellite instability) • DNMT3A (DNA methyltransferase 1) • ARID1A (AT-rich interaction domain 1A) • PD-1 (Programmed cell death 1) • KMT2A (Lysine Methyltransferase 2A) • IFNG (Interferon, gamma) • LAG3 (Lymphocyte Activating 3) • CDH1 (Cadherin 1) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • FANCL (FA Complementation Group L) • BMPR1A (Bone Morphogenetic Protein Receptor Type 1A) • CD80 (CD80 Molecule) • CD86 (CD86 Molecule) • HNF1A (HNF1 Homeobox A)
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TP53 mutation • KRAS mutation • MSI-H/dMMR • BRAF mutation • ARID1A mutation • DNMT3A mutation • APC mutation • NF2 mutation • TP53 expression • MLL mutation • CDK4 mutation • CDK6 expression
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MI Tumor Seek™
6ms
LMTK3 gene expression and the molecular landscape of colorectal cancer (CRC). (ASCO-GI 2024)
Our data show a strong association between LMTK3 gene expression and distinct molecular features and TME immune cell infiltration in CRC. These findings suggest that LMTK3 may be an important molecular factor that plays a role in determining the composition of the TME, thus targeting LMTK3 could represent a novel strategy in selected CRC subgroups.
MSi-H Biomarker • IO biomarker
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ER (Estrogen receptor) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • ATM (ATM serine/threonine kinase) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • IFNG (Interferon, gamma) • RNF43 (Ring Finger Protein 43) • SMAD4 (SMAD family member 4) • CD4 (CD4 Molecule) • CDX2 (Caudal Type Homeobox 2) • AMER1 (APC Membrane Recruitment Protein 1)
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TP53 mutation • TMB-H • MSI-H/dMMR • ATM mutation • ASXL1 mutation • APC mutation • RNF43 mutation • SMAD4 mutation • MLL mutation
6ms
Genomic analysis of oesophageal carcinoma (EC) to identify recurrent mutations in histone methyltransferases as a distinctive subset. (ASCO-GI 2024)
This is the largest study to investigate the distinct genomic landscapes between KMT2 -MT and WT EC to date. Our data showed the KMT2 -MT EC has a distinctive genetic profile, indicated by higher TMB, and higher frequency of dMMR/MSI-H and gene mutations involved in DDR and epigenetic regulation. Understanding these molecular characteristics may be informative in the development of effective treatment strategies in KMT2 -MT EC.
Tumor mutational burden • BRCA Biomarker • MSi-H Biomarker • IO biomarker • Genomic analysis • Epigenetic controller • Omic analysis
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TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • MSI (Microsatellite instability) • NF1 (Neurofibromin 1) • KMT2A (Lysine Methyltransferase 2A) • KMT2D (Lysine Methyltransferase 2D) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • KMT2C (Lysine Methyltransferase 2C)
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TMB-H • MSI-H/dMMR • NF1 mutation • MLL mutation
6ms
Integrated analysis of single-cell RNA-seq and bulk RNA-seq reveals RNA N6-methyladenosine modification associated with prognosis and drug resistance in acute myeloid leukemia. (PubMed, Front Immunol)
Notably, patients with the immune dysregulation subtype were sensitive to immunotherapy and chemotherapy. Collectively, our findings suggest that mA modification could be a potential therapeutic target for AML, and the identified subtypes could guide personalized therapy.
Journal • IO biomarker
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RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ELAVL1 (ELAV Like RNA Binding Protein 1) • FMR1 (Fragile X Messenger Ribonucleoprotein 1) • IGF2BP3 (Insulin Like Growth Factor 2 MRNA Binding Protein 3) • YTHDF2 (YTH N6-Methyladenosine RNA Binding Protein 2)
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RUNX1 mutation • KMT2A mutation • MLL mutation
7ms
Maintenance Therapy with Chidamide Decreases the Relapse in Fusion Gene-Positive AML Patients with MRD-Positive or ELN-High Risk (ASH 2023)
They were all maintemanced with chidamide, except one with chidamide plus sorafenib. Maintenance therapy with chidamide might decrease the relapse in fusion gene-positive AML patients with MRD-positive or ELN-high risk, who could not take allo-HSCT, and prolong their survival, with a well toleration.
Clinical • Minimal residual disease
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RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A)
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RUNX1 mutation • MLL rearrangement • MLL rearrangement • MLL mutation
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sorafenib • Epidaza (chidamide)
7ms
Genomic Analyses Unveil the Pathogenesis and Inform on Therapeutic Targeting in KMT2A-PTD AML (ASH 2023)
Given the results obtained with menin inhibitors in KMT2A-rearranged and NPM1-mutated AML, our findings open an opportunity for exploiting a therapeutic vulnerability in all HOX-AML including KMT2A-PTD AML or AML with high MEN1 expression. Since HOX-AML highly express genes according to the HOX differentiation profile, stage-specific surface proteins coded by these genes would be promising targets.
Genomic analysis
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • CD276 (CD276 Molecule) • SRSF2 (Serine and arginine rich splicing factor 2) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • PML (Promyelocytic Leukemia) • CD34 (CD34 molecule) • STAG2 (Stromal Antigen 2) • CD14 (CD14 Molecule) • LILRB4 (Leukocyte Immunoglobulin Like Receptor B4) • MEN1 (Menin 1) • CD1D (CD1d Molecule) • CD86 (CD86 Molecule) • HOXB2 (Homeobox B2) • NKX2-3 (NK2 Homeobox 3)
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NPM1 mutation • TET2 mutation • KMT2A rearrangement • MLL rearrangement • SRSF2 mutation • U2AF1 mutation • STAG2 mutation • MLL mutation • MLL translocation • KMT2A expression • KMT2A-PTD • CD1D expression
7ms
Test then erase? Current status and future opportunities for Measurable Residual Disease testing in Acute Myeloid Leukemia. (PubMed, Acta Haematol)
The treatment options for patients with AML have expanded for specific molecular subsets such as FLT3 and IDH1/2 mutated AML, with development of novel agents for NPM1 mutated or KMT2A rearranged AML ongoing, but also due to effective venetoclax-combinations. Evidence regarding highly sensitive molecular MRD detection methods for specific molecular subgroups, in the context of these new treatment approaches, will likely shape the future of AML care.
Review • Journal
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • MLL rearrangement • KMT2A mutation • MLL mutation
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Venclexta (venetoclax)
7ms
Predictive biomarkers of response and survival following immunotherapy with a PD-L1 inhibitor benmelstobart (TQB2450) and antiangiogenic therapy with a VEGFR inhibitor anlotinib for pretreated advanced triple negative breast cancer. (PubMed, Signal Transduct Target Ther)
Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450 (70% vs. 11%, P < 0.001) and a significantly longer median PFS (11.0 vs. 2.9 months, P < 0.001) than patients with other scenarios. Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.
Journal • Tumor mutational burden • PD(L)-1 Biomarker • IO biomarker • Metastases
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PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • KMT2C (Lysine Methyltransferase 2C)
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TP53 mutation • TMB-H • PIK3CA mutation • MLL mutation • MLL3 mutation
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Focus V (anlotinib) • benmelstobart (APL-502)
7ms
Haploidentical (Half-matched) Related Donor Stem Cell Transplantation Using Killer Immunoglobulin-like Receptors in Addition to Normal Selection Factors to Determine the Best Donor (clinicaltrials.gov)
P=N/A, N=44, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Aug 2024 --> Nov 2023 | Trial primary completion date: Aug 2024 --> Nov 2023
Trial completion • Trial completion date • Trial primary completion date
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1)
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TP53 mutation • FLT3 mutation • RUNX1 mutation • ASXL1 mutation • IKZF1 mutation • MLL mutation
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cyclophosphamide • melphalan • fludarabine IV • mesna • thiotepa • Neupogen (filgrastim)
7ms
How I treat refractory and relapsed acute myeloid leukemia. (PubMed, Blood)
Gilteritinib is approved by the Food and Drug Administration (FDA) and European Medicines Agency for patients with relapsed FLT3 mutated AML, while targeted therapy for relapsed IDH1/2 mutated AML has only FDA approval. Patients who are refractory or relapse after azacitidine and venetoclax (AZA/VEN) have a dismal outcome...Examples of ongoing developments include menin inhibitors, a targeted therapy for patients with mutated NPM1 or KMT2A rearrangements, antibodies targeting the macrophage immune checkpoint CD47 as well as triple combinations involving AZA/VEN. The latter cause significant myelosuppressive effects, which make it challenging to find the right schedule and dose.
Journal
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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FLT3 mutation • NPM1 mutation • KMT2A rearrangement • MLL rearrangement • MLL mutation
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine
7ms
Intestinal-Type Adenocarcinoma in Head and Neck: Dissecting Oncogenic Gene Alterations Through Whole Transcriptome and Exome Analysis. (PubMed, Mod Pathol)
This changed the activity of multiple genes/gene clusters, supporting oncogenicity mostly via pathways of signaling, dedifferentiation, proliferation, migration, immune and inflammatory deregulation, indicating a truly epigenetic event as the root cause for the heterogeneous diversity of these enteric types of cancer. The data of this study form the basis for understanding cell fate determination and cellular homeostasis in the normal respiratory mucosa at different anatomic sites and show the contribution of different mucosal components to the etiology/molecular pathology of ITAC.
Journal
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KMT2C (Lysine Methyltransferase 2C)
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KMT2C mutation • MLL mutation • MLL3 mutation
7ms
Acute Myeloid Leukemia Arising from Myelodysplastic Syndromes. (PubMed, Clin Lab Med)
Recent data suggest that, in addition to previously described translocations, NPM1 mutations and KMT2A rearrangements are also AML-defining genetic alterations that lead to rapid disease progression, even if they present initially with less than  20% blasts. While some adult patients <20% blasts can be treated effectively with intensive AML-type chemotherapy, in the future, treatment of individual patients in this MDS/AML group will likely be dictated by genetic, biological, and patient-related factors rather than an arbitrary blast percentage.
Review • Journal
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NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • KMT2A rearrangement • MLL rearrangement • MLL mutation
8ms
Combined Single Cell Flow Cytometry and Imaging Analyses Reveal Immunomodulatory Effects Exerted By Targeted Phospho-SYK Inhibitors with Elevated Sensitivity in NPM1 Mutated AML (ASH 2023)
Entospletinib (ENTO) and lanraplenib (LANRA) are inhibitors of spleen tyrosine kinase (SYK); the latter is a next-generation SYK inhibitor and is currently being evaluated in combination with gilteritinib (GILT) in patients with relapsed or refractory FLT3-mutated AML (NCT05028751)...Two different AML patient cohorts were assessed by ex vivo treatment with ENTO, LANRA and combinations of LANRA (trametinib, gilteritinib (GILT), aPD-1) over a range of time points (2h, 4h, 3d and 9d) and readouts for cellular phenotype (e.g., differentiation state, immune cell populations) and functional readouts (pSYK, viability) for each cohort were analyzed by HP-FC and sc-MI and associated with available mutation information (bulk gene and single cell RNA sequencing)...These support studies investigating the use of pSYK inhibitors in combination with other therapies to reduce tumor burden, and as an improved line of treatment for AML. Acknowledgements: We are appreciative of the patients and families for their time and participation.
Immunomodulating
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FLT3 (Fms-related tyrosine kinase 3) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • mTOR (Mechanistic target of rapamycin kinase) • SYK (Spleen tyrosine kinase)
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IDH1 mutation • IDH2 mutation • FLT3 mutation • NPM1 mutation • FLT3 mutation + NPM1 mutation • MLL mutation • SYK mutation
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Mekinist (trametinib) • Xospata (gilteritinib) • entospletinib (GS-9973) • lanraplenib (GS-9876)
8ms
Deciphering the Role of RAS Pathway Mutations in the Biology of Human Acute Myeloid Leukemia Using In Vivo Models (ASH 2023)
Some SMO inhibitors have been tested in clinical trial and Glasdegib is FDA approved in combination with low dose cytarabine in elderly patients. Given the success of generating these two point mutations, we are currently generating more RAS pathway mutations, including other KRAS mutations, PNTP11 and NF1 mutations. Conclusion These experiments showed: 1) It is possible to induce 2 oncogenic hits in human primary cells and get leukemia in vivo; 2) the KRAS G13D and NRAS G12D mutations shorten the latency of the disease and 3) increase the LSC frequency in secondary mice; 4) a possible involvement of the Hh pathway on stemness/LSC in RAS mutated cells; 5) our experimental approach is robust and very promising to decipher the RAS pathway in human MLL leukemias.
Preclinical
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KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTCH1 (Patched 1) • CD34 (CD34 molecule)
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KRAS mutation • NRAS mutation • KRAS G12D • KRAS wild-type • NF1 mutation • KRAS G13D • RAS mutation • RAS wild-type • KRAS G12 • MLL rearrangement • PTCH1 mutation • KRAS G13 • NRAS G12D • NRAS G12 • NRAS G13 • MLL mutation • NRAS G13D • KMT2A expression • KRAS overexpression • KRAS expression
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cytarabine • Daurismo (glasdegib)
8ms
Survival Outcomes Associated with Molecular and Cytogenetic Alterations in AML Patients Treated with Hypomethylating Agent and Venetoclax (ASH 2023)
In addition, we demonstrated that NPM1 mutation remains favorable in patients treated with HMA + Ven. Our findings help contribute to the ever-growing, complex molecular and genomic profiling of AML patients.
Clinical • Tumor mutational burden
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TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • SRSF2 (Serine and arginine rich splicing factor 2)
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TP53 mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • RUNX1 mutation • SRSF2 mutation • KMT2A mutation • MLL mutation
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Venclexta (venetoclax)
8ms
Menin Inhibitor Induced Menin Protein Degradation Contributes to Menin Inhibitor Efficacy (ASH 2023)
Taken together our data suggests that MI induce degradation is an essential and designable feature of MI design/efficacy. Our data also suggests that degradation evasive mutations in MEN1 could be an alternative resistance mechanism to contend with going forward in clinical trials.
Clinical
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KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1) • MEN1 (Menin 1) • UBR5 (Ubiquitin Protein Ligase E3 Component N-Recognin 5)
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MLL mutation
8ms
Covalent Menin Inhibitor Bmf-219 in Patients with Relapsed or Refractory (R/R) Acute Leukemia (AL): Preliminary Phase 1 Data from the Covalent-101 Study (ASH 2023)
Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups.
Clinical • P1 data
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NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • NSD1 (Nuclear Receptor Binding SET Domain Protein 1) • SETBP1 (SET Binding Protein 1) • NUP214 (Nucleoporin 214)
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MLL mutation • KMT2A-PTD • MLL-PTD
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decitabine • BMF-219
8ms
Phase 1/2 First-in-Human Study of the Menin-MLL Inhibitor DSP-5336 in Patients with Relapsed or Refractory Acute Leukemia (ASH 2023)
Of these 4 pts, all had received prior intensive induction chemotherapy as well as a venetoclax-based regimen, and 3 had received prior allo-transplant. DSP-5336 has been well tolerated with no DLTs to date in heavily pretreated R/R AML patients with NPM1c and MLLr AML. Importantly, no cardiac signals (including no QTcF prolongation) have been observed. PK studies have not identified a significant drug-drug interaction with azoles.
Clinical • P1/2 data
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TP53 (Tumor protein P53) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • HOXA9 (Homeobox A9) • ITGAM (Integrin, alpha M) • MEIS1 (Meis Homeobox 1) • PBX3 (PBX Homeobox 3)
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TP53 mutation • NPM1 mutation • KMT2A rearrangement • MLL rearrangement • MLL mutation
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Venclexta (venetoclax) • DSP-5336
8ms
Impact of KMT2A-PTD Mutational Subgroups on Outcome of AML Patients after Induction Therapy and Allogeneic Hematopoietic Cell Transplantation (ASH 2023)
Therefore, some KMT2A-PTD variants could be potentially implemented in AML risk stratification. However, prospective studies and larger patient numbers are needed.
Clinical
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NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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NPM1 mutation • KMT2A mutation • MLL mutation • KMT2A-PTD
8ms
Cladribine Combined with Homoharringtonine and Cytarabine Achieves a High Remission Rate in Adult Patients with De Novo Acute Myeloid Leukemia, Especially for Adverse-Risk Group: A Prospective, Single Center, Single-Arm, Phase 2 Study (ASH 2023)
We propose the CHA regimen as a novel, effective, and safe chemotherapy regimen for newly diagnosed adult AML patients with remarkable potency in treating adverse-risk group patients, especially those with KMT2A rearrangements and RAS mutations that are otherwise resistant to BCL-2 inhibitor-based therapies, but a limited effect on FLT3 mutated AML patients.
Clinical • P2 data • IO biomarker
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TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • MCL1 (Myeloid cell leukemia 1) • KMT2A (Lysine Methyltransferase 2A)
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TP53 mutation • FLT3 mutation • RAS mutation • KMT2A rearrangement • MLL rearrangement • MLL mutation • KMT2A rearrangement + RAS mutation
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cytarabine • cladribine • Synribo (omacetaxine mepesuccinate)
8ms
Komet-008: A Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-Rearranged or NPM1-Mutant Relapsed/Refractory Acute Myeloid Leukemia (ASH 2023)
Preclinical data have demonstrated ziftomenib's ability to target multiple types of menin-dependent AML clones, and that the antitumor activity of ziftomenib and other menin inhibitors in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models of KMT2A-r and NPM1-m AML is enhanced by the addition of FLT3 inhibitors such as gilteritinib and quizartinib. Secondary endpoints include preliminary efficacy (including MRD-negative responses and number of patients able to receive stem cell transplant) and pharmacokinetics. Exploratory end points include biomarkers for efficacy and resistance and pharmacodynamic biomarkers potentially related to the activity of ziftomenib when combined with SOC treatments in adults with R/R AML with NPM1-m or KMT2A-r.
Clinical • P1 data
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FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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FLT3 mutation • NPM1 mutation • MLL rearrangement • MLL mutation
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Xospata (gilteritinib) • Vanflyta (quizartinib) • ziftomenib (KO-539)
8ms
Conserved and Unique Regulatory Mechanisms of RUNX1 in Hematopoietic Stem/Progenitor Cell Subpopulations in Both Normal Hematopoiesis and FPD/AML Development (ASH 2023)
We used two complementary mouse models: a conditional RUNX1 knockout mouse, i,e, Mx-Cre; Runx1flox/flox, and a tetracycline-inducible FPD/AML patient derived RUNX1 S291fsX300 mutation knock-in crossed to a MLL-PTD knock-in mouse, i.e. MLL-PTD; RUNX1 S291fsX300..."Correction" of the RUNX1S291fsX300 mutation by doxycycline withdraw reversed the FPD phenotype as well as the cellular distribution changes in HSCs, GMPs and MEPs...RUNX1 plays a universal role in the systemic developmental program of various HSPC subpopulations but appears to engage in unique lineage specific factors to deliver subpopulation-specific functions such as mega-K cell fate-priming of HSCs, inflammatory program in GMPs, and bone marrow location signals in MEPs. Ongoing analyses of the FPD/AML mouse genomic data in this context are expected to reveal contributions of patient RUNX1 mutations to the disease development.
Clinical
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FLT3 (Fms-related tyrosine kinase 3) • NOTCH1 (Notch 1) • RUNX1 (RUNX Family Transcription Factor 1) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • CD34 (CD34 molecule) • CXCL12 (C-X-C Motif Chemokine Ligand 12) • ALDH1A1 (Aldehyde Dehydrogenase 1 Family Member A1) • IRF4 (Interferon regulatory factor 4) • ETS1 (ETS Proto-Oncogene 1) • PDGFB (Platelet Derived Growth Factor Subunit B) • TNFRSF11A (TNF Receptor Superfamily Member 11a) • TNFSF4 (TNF Superfamily Member 4) • FUT7 (Fucosyltransferase 7) • ITGA2B (Integrin Subunit Alpha 2b)
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RUNX1 mutation • MLL mutation • MLL-PTD
8ms
Rapid NGS Detection of Gene Mutations and Fusions in Myeloid Neoplasms (AMP 2023)
We have validated an 80-gene DNA/RNA NGS panel for detection of both mutations and fusions, and thus offer a rapid comprehensive NGS test for myeloid neoplasms with an average TAT of five calendar days. More clinical data and comments will be added at the meeting presentation.
Next-generation sequencing
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DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • AFDN (Afadin, Adherens Junction Formation Factor)
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MLL mutation
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Oncomine Myeloid Assay GX
8ms
Trial initiation date • Combination therapy
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FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)
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FLT3-ITD mutation • FLT3 mutation • NPM1 mutation • MLL rearrangement • FLT3 wild-type • MLL mutation
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daunorubicin • revumenib (SNDX-5613) • Starasid (cytarabine ocfosfate)