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KMT2A (Lysine Methyltransferase 2A)

News alerts, weekly reports and conference planners

Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead. (PubMed, J Hematol Oncol)

More importantly, approval of the combination of the BCl-2 inhibitor, venetoclax, and hypomethylating agents or low dose cytarabine provided unprecedented breakthrough for the frontline treatment of older, unfit AML patients. Recent development of menin inhibitors targeting AML with KMT2A rearrangements or NPM1 mutations could represent a promising new horizon of treatment for patients within these subsets of AML. Our current review will focus on a summary and updates of recent developments of menin inhibitors in the treatment of AML, on the challenges ahead arising from drug resistance, as well as on the opportunities of novel combinations with menin inhibitors.

2 days ago

Review • Journal • IO biomarker

FLT3 (Fms-related tyrosine kinase 3) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • KMT2A rearrangement • MLL rearrangement

Venclexta (venetoclax) • cytarabine

Prioritization of Eleven-Nineteen-Leukemia Inhibitors as Orally Available Drug Candidates for Acute Myeloid Leukemia. (PubMed, J Med Chem)

Subsequent optimization efforts led to the development of SR-C-107 (R), which exhibited strong activity against AML both at the cellular level (CC50 (MOLM-13): 1.25 ± 0.18 μM; CC50 (MV4-11): 0.81 ± 0.15 μM) and in vivo. These findings establish SR-C-107 (R) as a compelling candidate for AML treatment and lay the groundwork for the development of next-generation AML inhibitors.

7 days ago

Journal

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement • MLL rearrangement • MLL fusion

A RUNX1: RUNX1T1 AML with a simultaneous false positive KMT2A rearrangement: FISH interpretation pitfalls. (PubMed, Hematology)

Given that KMT2A FISH probes cover approximately 1 Mb around KMT2A, this subtle shift led to a split-apart signal pattern mimicking a genuine KMT2A rearrangement, resulting in a false positive FISH interpretation. This case highlights a false positive KMT2Ar in primary AML, indicating the need for additional molecular testing for confirmation.

7 days ago

Journal

RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1)

KMT2A rearrangement • MLL rearrangement • RUNX1-RUNX1T1 fusion • MLL fusion

AALL1131: Combination Chemotherapy in Treating Young Patients With Newly Diagnosed High-Risk B Acute Lymphoblastic Leukemia and Ph-Like TKI Sensitive Mutations (clinicaltrials.gov)

P3, N=5949, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

8 days ago

Trial completion date

MLL rearrangement • MLL rearrangement

dasatinib • cytarabine • doxorubicin hydrochloride • cyclophosphamide • etoposide IV • methotrexate • vincristine • daunorubicin • clofarabine • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • thioguanine • Hemady (dexamethasone tablets) • Starasid (cytarabine ocfosfate)

Capturing Fusion in Hematological Malignancies through Targeted RNASeq (AMP 2024)

We have demonstrated the capability of the SureSeq Myeloid Fusion Complete NGS Workflow Solution to detect known rearrangements in AML. We observed 100% concordance with qPCR and FISH for all samples tested. The NGS data permitted single-exon resolution of breakpoints and revealed the presence of multiple breakpoints which would have remained undetected with FISH.

8 days ago

ABL1 (ABL proto-oncogene 1) • BCR (BCR Activator Of RhoGEF And GTPase) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • AFF1 (AF4/FMR2 Family Member 1) • PML (Promyelocytic Leukemia) • MECOM (MDS1 And EVI1 Complex Locus) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • AFDN (Afadin, Adherens Junction Formation Factor) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)

BCR-ABL1 fusion • MLL fusion

SureSeq™ Myeloid Fusion Panel

DNA and RNA NGS for Myeloid Neoplasms Using Oncomine Myeloid Assay GX v2 on GeneXus: An Assessment of Clinical Utility (AMP 2024)

This DNA- and RNA-based 80-gene panel has proven to be a powerful tool for genomic profiling of myeloid neoplasms. The results were provided to hematopathologists/oncologists in timely fashion with the critical information for diagnosis confirmation, and disease classification, as well as assessment of patient response to treatment.

8 days ago

Clinical • Next-generation sequencing

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • 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) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • DDX41 (DEAD-Box Helicase 41) • CALR (Calreticulin) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

FLT3-ITD mutation • NPM1 mutation • U2AF1 mutation • CEBPA mutation • JAK2 V617F

Oncomine Myeloid Assay GX

Lineage Switch from Therapy-Related B Cell Acute Lymphoblastic Leukemia to Pure Erythroid Leukemia Following CD20-Directed Immunotherapy: A Mechanism for Immune Escape? (AMP 2024)

Six weeks later, while receiving the CD20-directed immunotherapies glofitamab and obinutuzumab, another bone marrow biopsy revealed eradication of the B-ALL and new involvement by pure erythroid leukemia (PEL). This patient's B-ALL lacked an IGH::BCL2 fusion resulting from t(14; 18), suggesting it did not arise through transformation of his prior FL/DLBCL. Instead, the B-ALL was likely caused by his extensive exposure to genotoxic chemotherapy drugs – including alkylating agents – for his preceding lymphomas. The shared cytogenetic and molecular features between this patient's B-ALL and PEL imply they are clonally related.

8 days ago

IO biomarker

TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • CD20 (Membrane Spanning 4-Domains A1) • KMT2A (Lysine Methyltransferase 2A)

TP53 mutation • KMT2A rearrangement • MLL rearrangement • BCL2 fusion

TruSight Myeloid Sequencing Panel

Gazyva (obinutuzumab) • Columvi (glofitamab-gxbm)

Evaluation of OGT's SureSeq Myeloid Fusion Complete NGS Workflow Solution V2 for Partner-Agnostic Fusion Gene Detection in Acute Leukemias (AMP 2024)

We demonstrated the capability of OGT's SureSeq Myeloid Fusion Complete NGS Workflow Solution V2 to achieve 100% accurate detection for novel and canonical translocations. By allowing concurrent detection of multiple known and novel rearrangements, NGS assays offer an economical and efficient alternative to routine cytogenetic approaches.

8 days ago

Next-generation sequencing

ABL1 (ABL proto-oncogene 1) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • MECOM (MDS1 And EVI1 Complex Locus) • HOXD8 (Homeobox D8)

KMT2A rearrangement • MLL rearrangement

SureSeq™ Myeloid Fusion Panel

15d

Addition of Inotuzumab Ozogamicin to Melphalan Plus Fludarabine Reduced-Intensity Conditioning Regimen of Allogeneic Transplantation in Patients with Acute Lymphoblastic Leukemia and Aggressive Lymphoid Malignancies: A Phase II Prospective Trial (ASH 2024)

We recently demonstrated that INO can be added safely to a non-myeloablative conditioning of bendamustine, fludarabine, and rituximab in patients with indolent lymphoid malignancies who required an allogeneic hematopoietic transplantation (HCT) (Am J Hematol 2024)...Patients who received transplants from MUDs received an additional dose of methotrexate 5 mg/m2 on day +11 and 1 mg/kg of rabbit anti-thymocyte globulin IV on days -1 and -2 before HCT...The patient who was in CR2 at transplant had Ph+ ALL and was maintained on ponatinib after HCT. Key prior therapies in ALL patients included blinatumomab (n=5) and INO (n=5)... Our conclusions are limited by the small number of patients due to slow accrual. However, our data suggest that INO is safe when combined with a melphalan plus fludarabine HCT conditioning regimen. The survival outcomes are encouraging and need to be validated in a larger number of patients.

15 days ago

Clinical • P2 data

TP53 (Tumor protein P53) • KMT2A (Lysine Methyltransferase 2A) • IKZF1 (IKAROS Family Zinc Finger 1) • CD22 (CD22 Molecule) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B) • HLA-C (Major Histocompatibility Complex, Class I, C)

TP53 mutation • CD22 expression • IKZF1 mutation • KMT2A mutation • MLL mutation

clonoSEQ

Rituxan (rituximab) • Iclusig (ponatinib) • cyclophosphamide • Blincyto (blinatumomab) • methotrexate • Besponsa (inotuzumab ozogamicin) • bendamustine • melphalan • fludarabine IV

15d

Comprehensive Genomic Profiling (CGP) of Acute Lymphoblastic Leukemias with Foundation One Heme Identifies Actionable Genomic Alterations and Biomarkers (ASH 2024)

This analysis of 2,637 samples comprising a variety of molecular subtypes of ALL demonstrated that the F1H assay detects pathogenic genomic alterations with diagnostic, prognostic, and therapeutic significance. As both the treatment landscape and disease classification system in ALL have continued to evolve over time, CGP assays such as F1H can play a critical role in clinical decision making by simultaneously assessing the presence and absence of numerous actionable genomic alterations and biomarkers with a single assay.

15 days ago

KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • CRLF2 (Cytokine Receptor Like Factor 2) • IKZF1 (IKAROS Family Zinc Finger 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • PAX5 (Paired Box 5) • TCF3 (Transcription Factor 3) • P2RY8 (P2Y Receptor Family Member 8) • PBX1 (PBX Homeobox 1) • ABL2 (ABL Proto-Oncogene 2, Non-Receptor Tyrosine Kinase)

TP53 mutation • KRAS mutation • NRAS mutation • PTEN mutation • CDKN2A deletion

FoundationOne® Heme CDx

15d

KMT2A (MLL1) Rearrangements in Hematolymphoid Malignancies: A Genomic Landscape Study (ASH 2024)

Rearrangements in the KMT2A gene in AML are common and may emerge as a new target of therapy for AML patients. This genomic landscape study reveals significant differences in import GA associated with AML in KMT2Ara and KMT2Anra cases.

15 days ago

Tumor mutational burden

KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • WT1 (WT1 Transcription Factor)

KRAS G12C • KMT2A rearrangement • KRAS G12 • MLL rearrangement • MLL rearrangement • MLL mutation

FoundationOne® Heme CDx

15d

Enhanced Flow Cytometry and Next Generation Sequencing Assays for Residual B Lymphoblastic Leukemia (B-ALL) Reveal a Subset with Discordant Results Due to Leukemic Changes Post-Therapy (ASH 2024)

There is an excellent overall concordance between the NGS and enhanced MFC assays to a limit of detection of 0.001% using routine clinical samples from a pediatric oncology service where anti-CD19 immunotherapy is frequently administered. MFC is able to identify a subset of discordant cases with clear residual disease that is not identifiable by NGS due to changes in clonal sequence (NGS false negatives). Conversely, NGS identifies a subset of discordant cases that likely represent persistent clonal sequences in myelomonocytic populations whose relationship to relapse risk remains to be determined (potentially NGS false positives).

15 days ago

Next-generation sequencing • IO biomarker • Discordant

KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2) • CD73 (5'-Nucleotidase Ecto) • CD123 (Interleukin 3 Receptor Subunit Alpha) • CD22 (CD22 Molecule) • CD24 (CD24 Molecule) • IL3RA (Interleukin 3 Receptor Subunit Alpha) • NRP1 (Neuropilin 1) • CD81 (CD81 Molecule)

CRLF2 rearrangement

clonoSEQ

15d

Clearance of Very Low Levels of Measurable Residual Disease with Blinatumomab Significantly Improves Outcomes in B-Cell Acute Lymphoblastic Leukemia (ASH 2024)

Non-responders to blinatumomab have poor outcomes (2-year RFS: 25%) but may be salvaged by ASCT. The relatively low rate of NGS MRD negativity with blinatumomab monotherapy (31% in Ph- B-ALL) highlights the need for combination therapies in B-ALL.

15 days ago

IO biomarker

TP53 (Tumor protein P53) • ABL1 (ABL proto-oncogene 1) • KMT2A (Lysine Methyltransferase 2A)

TP53 mutation

clonoSEQ

Blincyto (blinatumomab)

15d

Genomic Complexity Correlates with the Degree of Marrow Independence of Malignant Plasma Cells in the Context of Extramedullary Disease (ASH 2024)

Several patients with prior melphalan exposure have SBS99 evident in several biopsies, consistent with single cell expansion from MM cells surviving transplant and subsequently seeding in multiple sites... PMD and EMD demonstrate multiple features of genomic complexity when compared with BM-based myeloma, which include emerging copy number aberrations, mutational burden and complex structural variants. EMD are more complex in general than PMD, while IMD shows only trends to increased genomic aberration compared with BM. Ongoing analyses include an expansion in WGS samples, and correlation of genomic features with clinical response to therapy.

15 days ago

Tumor mutational burden • BRCA Biomarker

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA2 (Breast cancer 2, early onset) • DNMT3A (DNA methyltransferase 1) • NF1 (Neurofibromin 1) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • KMT2C (Lysine Methyltransferase 2C) • FAT1 (FAT atypical cadherin 1)

TP53 mutation • KRAS mutation • NRAS mutation • DNMT3A mutation

MSK-IMPACT Heme

melphalan

15d

Early Achievement of Deep Measurable Residual Disease (MRD) Negativity Identifies Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) Who Have Excellent Long-Term Outcomes and Do Not Benefit from Allogeneic Stem Cell Transplant, Irrespective of Baseline High-Risk Cytomolecular Features (ASH 2024)

Frontline therapy was hyper-CVAD-based ± immunotherapy (e.g. inotuzumab ozogamicin and/or blinatumomab) in 43% (n=69), mini-hyper-CVD-based ± immunotherapy in 28% (n=45), and chemotherapy-free in 29% (n=47, all of whom were Ph+). Early achievement of NGS MRD negativity identifies pts with excellent outcomes after frontline therapy. Importantly, no relapses were observed in pts with HR cytogenetic/molecular features who achieved early NGS MRD negativity, suggesting that early MRD dynamics should be included in ALL risk stratification systems. Pts with HR Ph- ALL who achieve deep MRD negativity within the first 6 months of frontline therapy do not appear to benefit from allogeneic SCT.

15 days ago

Clinical • IO biomarker • Minimal residual disease

TP53 (Tumor protein P53) • KMT2A (Lysine Methyltransferase 2A)

TP53 mutation

clonoSEQ

Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin)

15d

CD19-CAR T Cells As Definitive Consolidation for Older Adults with B-Cell Acute Lymphoblastic Leukemia in First Complete Remission: A Pilot Study (ASH 2024)

Ten (77%) pts received blinatumomab as part of initial therapy...Among pts who completed the DLT period (n=11), 7 (64%) experienced transient grade (G) 1 cytokine release syndrome (CRS) that resolved with tocilizumab +/- corticosteroid... The use of CAR-T in older adults with B-ALL in CR1 appears safe with no observed ICANS or ≥G2 CRS. CAR T cells had a robust expansion in the blood and CSF despite the low antigen setting. We have observed preliminary durable remissions and pts maintained function and cognition on day 100 post CAR-T.

15 days ago

Clinical • CAR T-Cell Therapy

CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • KMT2A (Lysine Methyltransferase 2A) • EP300 (E1A binding protein p300) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1) • ZNF384 (Zinc Finger Protein 384)

CDKN2A deletion

clonoSEQ

Blincyto (blinatumomab) • Actemra IV (tocilizumab)

17d

Umbilical Cord Blood Transplantation Using a Myeloablative Preparative Regimen for Hematological Diseases (clinicaltrials.gov)

P=N/A, N=200, Recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

17 days ago

Trial completion date • Trial primary completion date

KMT2A (Lysine Methyltransferase 2A) • IKZF1 (IKAROS Family Zinc Finger 1)

MLL rearrangement • MLL rearrangement

cyclophosphamide • fludarabine IV • cyclosporin A microemulsion

20d

A dual role for PSIP1/LEDGF in T cell acute lymphoblastic leukemia. (PubMed, Sci Adv)

In cell lines, PSIP1 down-regulation leads to a reduction of COX20, an assembly factor of the cytochrome c oxidase in the mitochondria, and to a reduction in mitochondrial respiration. This indicates that PSIP1 can exert a dual role in the context of T-ALL, either as a tumor suppressor gene during tumor initiation or as a dependency factor in tumor maintenance.

20 days ago

Journal

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

21d

Chidamide Combined with (+) -JQ-1 to Kill MLL-Rearrangement Acute Myeloid Leukemia Cells by Disrupting the DNA Damage Response Pathway (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi)

Chidamide combined with (+)-JQ-1 can inhibit the proliferation of MLL-r AML cells, inhibit the initiation of protective self-repair of these leukemia cells by inhibiting the DNA damage response pathway, and ultimately increase the apoptosis of these cells, but non- MLL-r AML cells have no similar results.

21 days ago

Journal • IO biomarker

BCL2 (B-cell CLL/lymphoma 2) • KMT2A (Lysine Methyltransferase 2A) • CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A) • CHEK1 (Checkpoint kinase 1) • BAX (BCL2-associated X protein) • CASP3 (Caspase 3) • BRD4 (Bromodomain Containing 4) • TP53BP1 (Tumor Protein P53 Binding Protein 1)

MLL rearrangement • MLL rearrangement • BCL2 expression • BAX expression

JQ-1 • Epidaza (chidamide)

22d

NUP98 fusion proteins and KMT2A-MENIN antagonize PRC1.1 to drive gene expression in AML. (PubMed, Cell Rep)

We show that PRC1.1 loss leads to resistance to small-molecule Menin-KMT2A inhibitors in vivo. Therefore, a critical function of oncofusion proteins that hijack Menin-KMT2A activity is antagonizing repressive chromatin complexes.

22 days ago

Journal

KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2)

25d

CRLF2-rearranged B-cell ALL with extramedullary lineage switch to AML following CD19-targeted therapy. (PubMed, J Immunother Cancer)

To our knowledge, these are the first cases of LS to be reported in patients with CRLF2 rearranged acute lymphoblastic leukemia. In addition to raising awareness that this genetic mutation may associate with lineage plasticity, our cases illustrate the importance of multi-modal disease surveillance in the diagnosis of LS.

25 days ago

Journal

KMT2A (Lysine Methyltransferase 2A) • CRLF2 (Cytokine Receptor Like Factor 2)

KMT2A rearrangement • MLL rearrangement • CRLF2 rearrangement

27d

Menin-mll protein-protein interaction inhibitors: a patent review (2021-present). (PubMed, Expert Opin Ther Pat)

Therefore, new drug discovery strategy should be considered in advance. The expert opinion was proposed from several aspects, such as developing diverse chemical structures, discovering covalent inhibitors, designing small molecular PROTACs, and targeting the amino acids mutations for next-generation inhibitors.

27 days ago

Review • Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • KMT2A mutation

29d

CR109124: A Study of Bleximenib in Combination With Acute Myeloid Leukemia (AML) Directed Therapies (clinicaltrials.gov)

P1, N=200, Recruiting, Janssen Research & Development, LLC | N=150 --> 200

29 days ago

Enrollment change • Combination therapy

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

Venclexta (venetoclax) • cytarabine • azacitidine • daunorubicin • idarubicin hydrochloride • bleximenib (JNJ-6617)

29d

Low PD-L1 expression, MAP2K2 alterations, and enriched HPV gene signatures characterize brain metastases in head and neck squamous cell carcinoma. (PubMed, J Transl Med)

HNSCC patients with BM frequently have oropharyngeal primary sites and are HPV+. Common molecular alterations in BM samples, including targetable PIK3CA and ATM, were identified. MAP2K2 alterations were enriched and densities of immune cells were low, highlighting potential targets for further research and immunotherapy considerations.

29 days ago

Journal • Gene Signature • PD(L)-1 Biomarker • IO biomarker

PD-L1 (Programmed death ligand 1) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • KMT2A (Lysine Methyltransferase 2A) • MAP2K2 (Mitogen-activated protein kinase kinase 2) • TSC1 (TSC complex subunit 1) • FOXP3 (Forkhead Box P3)

PD-L1 expression • TSC1 mutation • PD-L1-L

Recent Developments and Evolving Therapeutic Strategies in KMT2A-Rearranged Acute Leukemia. (PubMed, Cancer Med)

Studies indicate that KMT2A rearrangements are present in over 70% of infant leukemia cases, approximately 10% of adult AML cases, and numerous instances of secondary acute leukemias, making it a disease of critical concern to clinicians and researchers alike. The future of KMT2A-r acute leukemia research is characterized by an expanding knowledge of the disease's biology, with an emphasis on personalized therapies, immunotherapies, genomic advancements, and innovative therapeutic combinations. The overarching aim is to enhance patient outcomes, lessen the disease burden, and elevate the quality of life for those affected. Ongoing research and clinical trials in this area continue to offer promising opportunities for refining treatment strategies and improving patient prognosis.

1 month ago

Review • Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

Testing the Addition of the Anti-cancer Drug Venetoclax and/or the Anti-cancer Immunotherapy Blinatumomab to the Usual Chemotherapy Treatment for Infants With Newly Diagnosed KMT2A-rearranged or KMT2A-non-rearranged Leukemia (clinicaltrials.gov)

P2, N=171, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2027 --> Dec 2028 | Initiation date: Oct 2024 --> Jan 2025 | Trial primary completion date: Dec 2027 --> Dec 2028

1 month ago

Trial completion date • Trial initiation date • Trial primary completion date • Combination therapy

MCL1 (Myeloid cell leukemia 1) • KMT2A (Lysine Methyltransferase 2A) • BCL2L1 (BCL2-like 1)

BCL2 expression

Venclexta (venetoclax) • cytarabine • doxorubicin hydrochloride • cyclophosphamide • Blincyto (blinatumomab) • methotrexate • vincristine • daunorubicin • leucovorin calcium • Oncaspar liquid (pegaspargase) • mercaptopurine • Asparlas (calaspargase pegol-mknl) • Rylaze (asparaginase erwinia chrysanthemi (recombinant)-rywn) • thioguanine • Hemady (dexamethasone tablets) • Starasid (cytarabine ocfosfate) • prednisolone

Tumor immune microenvironment dynamics and outcomes of prognosis in non-muscle-invasive bladder cancer. (PubMed, Cancer Sci)

Analyses of recurrent tumors after BCG therapy revealed that tumor immune activity was widely maintained before and after treatment, and high FGFR3 expression was detected after recurrence in tumors initially classified into the cold cluster. Collectively, we revealed the dynamics of the tumor microenvironment in BC as a whole and identified candidate molecules as therapeutic targets for recurrent NMIBC, e.g., after BCG therapy.

1 month ago

Journal • PD(L)-1 Biomarker • IO biomarker

TP53 (Tumor protein P53) • FGFR3 (Fibroblast growth factor receptor 3) • CD20 (Membrane Spanning 4-Domains A1) • RB1 (RB Transcriptional Corepressor 1) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • KMT2A (Lysine Methyltransferase 2A) • LAG3 (Lymphocyte Activating 3) • KDM6A (Lysine Demethylase 6A) • CD163 (CD163 Molecule) • TIGIT (T Cell Immunoreceptor With Ig And ITIM Domains 2) • CD44 (CD44 Molecule) • IDO1 (Indoleamine 2,3-dioxygenase 1) • CD68 (CD68 Molecule) • FOXP3 (Forkhead Box P3) • ENTPD1 (Ectonucleoside Triphosphate Diphosphohydrolase 1)

CD44 expression • FGFR3 expression • ENTPD1 expression

Molecular characterization and biomarker identification in paediatric B-cell acute lymphoblastic leukaemia. (PubMed, J Cell Mol Med)

Baseline plasma ctDNA exhibited high mutational concordance with the paired BM samples and was significantly associated with chemotherapy efficacy. These findings suggest that ctDNA and BM profiling offer promising prognostic insights for paediatric B-ALL management.

1 month ago

Journal

CD8 (cluster of differentiation 8) • KMT2A (Lysine Methyltransferase 2A) • TRIM29 (Tripartite Motif Containing 29)

The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency. (PubMed, J Hematol Oncol)

Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.

1 month ago

Journal

KMT2A (Lysine Methyltransferase 2A) • KAT6A (Lysine Acetyltransferase 6A) • MLLT3 (MLLT3 Super Elongation Complex Subunit)

MLL rearrangement

Clinical features and long-term outcomes of pediatric patients with de novo acute myeloid leukemia in China with or without specific gene abnormalities: a cohort study of patients treated with BCH-AML 2005. (PubMed, Hematology)

Not achieving complete remission after induction 2 was found to be an independent prognostic factor for OS and EFS. These findings indicate that genetic abnormalities could be considered stratification factors, predict patient outcomes, and imply the application of targeted therapy.

1 month ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • NUP214 (Nucleoporin 214) • CBFB (Core-Binding Factor Subunit Beta 2) • DEK (DEK Proto-Oncogene)

FLT3-ITD mutation • KIT mutation • KMT2A rearrangement • MLL rearrangement • DEK-NUP214 rearrangement

2ms

A simplified and robust risk stratification model for stem cell transplantation in pediatric acute myeloid leukemia. (PubMed, Cell Rep Med)

Moreover, by incorporating the FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) allelic ratio, the pAML SCT model is refined, enhancing its ability to effectively select suitable candidates. We develop a simple and robust risk stratification model for pAML patients undergoing SCT, to aid in risk stratification and inform pretransplant decision-making at CR1 stage.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

2ms

Design and development of a series of 4-(piperazin-1-yl)pyrimidines as irreversible menin inhibitors. (PubMed, Eur J Med Chem)

This effect of 37 is not involved in proteasomal degradation, and may directly affect the synthesis of menin protein, which offers a significant advantage in addressing acquired resistance to menin inhibitors. Further study showed that compound 37 has prolonged anti-leukemic action and exhibits promising in vivo efficacy, making it a valuable probe for further menin-MLL interaction studies.

2 months ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • MLL rearrangement • MLL rearrangement • MLL fusion

2ms

Selective inhibition of HDAC class IIA as therapeutic intervention for KMT2A-rearranged acute lymphoblastic leukemia. (PubMed, Commun Biol)

Finally, LMK-235 appeared to exert minimal anti-leukemic effects in vivo in combination with the BCL-2 inhibitor venetoclax, but not enough to prolong survival in treated mice. In conclusion, class IIA HDAC isoforms represent attractive therapeutic target in KMT2A-rearranged ALL, although clinical applications require the development of more stable and efficient specific HDAC inhibitors.

2 months ago

Journal

KMT2A (Lysine Methyltransferase 2A) • HDAC5 (Histone Deacetylase 5) • HDAC4 (Histone Deacetylase 4) • HDAC7 (Histone Deacetylase 7)

MLL rearrangement

Venclexta (venetoclax)

2ms

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial. (PubMed, Lancet Oncol)

Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing.

2 months ago

P1 data • Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A)

NPM1 mutation • KMT2A rearrangement • MLL rearrangement • MLL mutation

ziftomenib (KO-539)

2ms

MBD2 regulates the progression and chemoresistance of cholangiocarcinoma through interaction with WDR5. (PubMed, J Exp Clin Cancer Res)

MBD2 promotes the progression and chemoresistance of CCA through interactions with WDR5. MM-102 can effectively block this process and increase the sensitivity of CCA to cisplatin.

2 months ago

Journal

KMT2A (Lysine Methyltransferase 2A) • ABCB1 (ATP Binding Cassette Subfamily B Member 1) • WDR5 (WD Repeat Domain 5)

cisplatin

2ms

Somatic mutation of targeted sequencing identifies risk stratification in advanced ovarian clear cell carcinoma. (PubMed, Gynecol Oncol)

Mutations in genes, including MUC16, ATM, NOTCH3, KMT2A, and CTNNA1, were associated with the poor prognosis of advanced OCCC. The risk stratification according to these genes demonstrated acceptable prediction power of prognosis and platinum response, suggesting the potential to be a novel target for precision medicine.

2 months ago

Journal • Metastases

KMT2A (Lysine Methyltransferase 2A) • MUC16 (Mucin 16, Cell Surface Associated) • NOTCH3 (Notch Receptor 3) • CTNNA1 (Catenin Alpha 1)

ATM mutation • MUC16 mutation • NOTCH3 mutation

2ms

Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia. (PubMed, Hemasphere)

Human KMT2A-r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels...Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • STAT5A (Signal Transducer And Activator Of Transcription 5A) • NKG2D (killer cell lectin like receptor K1)

RAS mutation • KMT2A rearrangement • MLL rearrangement • NRAS G12D • NRAS G12 • FLT3 N676K • MLL mutation • KMT2A expression

Farydak (panobinostat)

2ms

Pre-transplantation levels of lysine (K)-specific methyltransferase 2A (KMT2A) partial tandem duplications can predict relapse of acute myeloid leukemia patients following haploidentical donor hematopoietic stem cell transplantation. (PubMed, Blood Sci)

In multivariable analysis, KMT2A-PTD ≥1% before HID HSCT was the only independent risk factor for relapse (hazard ratio [HR]: 4.90; 95% CI: 1.22-19.59; P = .025). Thus, pre-transplantation levels of KMT2A-PTD could predict relapse in AML patients following HID HSCT.

2 months ago

Journal • Pre-transplantation

KMT2A (Lysine Methyltransferase 2A)

KMT2A-PTD

2ms

Pretransplant MRD detection of fusion transcripts is strongly prognostic in KMT2A-rearranged acute myeloid leukemia. (PubMed, Blood)

Pre-transplant detection of KMT2Ar MRD ≥0.001% by quantitative PCR was associated with significantly inferior post-transplant survival (2-year RFS 17% vs 59%; p=0.001) and increased cumulative incidence of relapse (2-year CIR 75% vs 25%, p=0.0004).

2 months ago

Journal • Pre-transplantation

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

2ms

Histone methyltransferase KMT2A: Developmental regulation to oncogenic transformation. (PubMed, J Biol Chem)

In 2002, Allis and colleagues first characterized the lysine methyltransferase activity of the mammalian KMT2A (MLL1), a paradigm shifting discovery that brings epigenetic dysregulation into focus for many human diseases that carry KMT2A mutations. This review will discuss the current understanding of the multifaceted roles of KMT2A in development and disease, which has paved the way for innovative and upcoming approaches to cancer therapy.

2 months ago

Review • Journal • Epigenetic controller

KMT2A (Lysine Methyltransferase 2A)

KMT2A mutation • MLL mutation

2ms

Trial Evaluating MGTA-456 in Patients With High-Risk Malignancy (clinicaltrials.gov)

P2, N=22, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Trial completion date: Jun 2024 --> Jun 2025

2 months ago

Trial completion date

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha)

FLT3-ITD mutation • NPM1 mutation • MLL rearrangement • MLL rearrangement • CEBPA mutation • FLT3 wild-type

cyclophosphamide • melphalan • fludarabine IV • busulfan • spanlecortemlocel (MGTA-456)

2ms

Pitfalls in Diagnosis: JMML versus KMT2A Rearranged Juvenile AML. (PubMed, Case Rep Hematol)

This case highlights the challenges of diagnosing KMT2A-rearranged monocytic AML and the importance of careful morphological assessment in partnership with cytogenetic and molecular diagnostics to distinguish between KMT2A-rearranged AML and JMML. Moreover, the emerging role of molecular monitoring in AML is highlighted.

2 months ago

Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement