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GENE:

KMT2A (Lysine Methyltransferase 2A)

News alerts, weekly reports and conference planners

Menin inhibitors in the treatment of acute myeloid leukemia. (PubMed, Blood)

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.

2 days ago

Journal

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

NPM1 mutation • KMT2A rearrangement • MLL rearrangement

Case Report: A case of infantile acute hyperleukocytic leukemia treated by leukapheresis. (PubMed, Front Pediatr)

The infant recovered after the high-dose methotrexate chemotherapy. These results demonstrate that leukapheresis is a feasible treatment option for acute hyperleukocytic leukemia in infants with ALL.

3 days ago

Journal

KMT2A (Lysine Methyltransferase 2A) • AFF1 (AF4/FMR2 Family Member 1)

methotrexate • methotrexate IV

The Significance of Detecting an Unusual Myeloblast Immunophenotype in a Presumptive Clinical Diagnosis of Myelodysplastic Syndromes. (PubMed, Arch Pathol Lab Med)

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.

4 days ago

Journal

TP53 (Tumor protein P53) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • CD33 (CD33 Molecule) • CD34 (CD34 molecule) • ANPEP (Alanyl Aminopeptidase, Membrane)

TP53 mutation • NPM1 mutation • MLL rearrangement

Bleximenib, the novel menin-KMT2A inhibitor JNJ-75276617, impairs long-term proliferation and immune evasion in acute myeloid leukemia. (PubMed, Haematologica)

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.

6 days ago

Journal

DNMT3A (DNA methyltransferase 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1) • MLLT3 (MLLT3 Super Elongation Complex Subunit)

NPM1 mutation • MLL rearrangement

bleximenib (JNJ-6617)

Protocol for CRISPR-Cas9-mediated induction of KMT2A rearrangements in cell line and umbilical cord blood hematopoietic stem and progenitor cells. (PubMed, STAR Protoc)

We describe steps for patient-specific single guide RNA (sgRNA) design, optimized sgRNA in vitro transcription, detailed purification of hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood (UCB), and CRISPR-Cas9 editing of the test cell line K562 as well as UCB HSPCs. The provided methodology is donor independent.

7 days ago

Preclinical • Journal

KMT2A (Lysine Methyltransferase 2A)

KMT2A rearrangement • MLL rearrangement

Synergistic Strategies for KMT2A-Rearranged Leukemias: Beyond Menin Inhibitor. (PubMed, Cancers (Basel))

By integrating these diverse strategies, we propose a comprehensive therapeutic paradigm that targets multiple points of the leukemic transcriptional and epigenetic network. These combination approaches aim to disrupt key oncogenic pathways, reduce resistance, and enhance treatment efficacy, ultimately providing more durable remissions and improved survival for patients with KMT2A-rearranged leukemias.

9 days ago

Review • Journal

KMT2A (Lysine Methyltransferase 2A) • BRD4 (Bromodomain Containing 4) • DOT1L (DOT1 Like Histone Lysine Methyltransferase)

MLL rearrangement • MLL fusion

Patient-Specific Circulating Tumor DNA for Monitoring Response to Menin Inhibitor Treatment in Preclinical Models of Infant Leukemia. (PubMed, Cancers (Basel))

Notably, ctDNA analysis proved to be a superior predictor of MRD compared to PB assessment alone, especially in instances of low disease burden. These findings highlight the potential of ctDNA as a sensitive biomarker for monitoring treatment response and detecting MRD in infant MLL-r ALL.

9 days ago

Preclinical • Journal • Circulating tumor DNA

KMT2A (Lysine Methyltransferase 2A)

MLL rearrangement

11d

Progressive chromatin rewiring by ETO2::GLIS2 revealed in a human iPSC model of pediatric leukemia initiation. (PubMed, Blood)

Importantly, DLX3 knock-out abrogated leukemia initiation in this ETO2::GLIS2 iPSC model. Collectively, characterization of a novel human iPSC-derived AMKL model revealed hijacking of the osteogenic homeobox transcription factor DLX3 as an essential early step in chromatin changes and leukemogenesis driven by the ETO2::GLIS2 fusion oncogene.

11 days ago

Journal

KMT2A (Lysine Methyltransferase 2A) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • CD34 (CD34 molecule) • GLIS2 (GLIS Family Zinc Finger 2)

13d

Next-generation sequencing RNA fusion panel for the diagnosis of haematological malignancies. (PubMed, Pathology)

These findings confirm the unique utility of the NGS-based RNA fusion panel as a diagnostic tool to identify gene rearrangements that drive haematological malignancies. It can identify novel and rare gene rearrangements to assist with diagnosis, prognostication and treatment decisions.

13 days ago

Journal • Next-generation sequencing

ABL1 (ABL proto-oncogene 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • RUNX1 (RUNX Family Transcription Factor 1) • KMT2A (Lysine Methyltransferase 2A) • ETV6 (ETS Variant Transcription Factor 6) • CREBBP (CREB binding protein) • AFF1 (AF4/FMR2 Family Member 1) • FIP1L1 (Factor Interacting With PAPOLA And CPSF1) • KAT6A (Lysine Acetyltransferase 6A) • MLLT3 (MLLT3 Super Elongation Complex Subunit)

13d

Mayo Genetic Risk Models for Newly Diagnosed Acute Myeloid Leukemia Treated With Venetoclax + Hypomethylating Agent. (PubMed, Am J Hematol)

The Mayo genetic risk models offer pre-treatment and response-based prognostic tools for ND-AML treated with Ven-HMA. The current study underscores the prognostically indispensable role of achieving CR/CRi and ASCT.

13 days ago

Journal

KRAS (KRAS proto-oncogene GTPase) • KMT2A (Lysine Methyltransferase 2A)

Venclexta (venetoclax)

14d

BMT-06: Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) (clinicaltrials.gov)

P2, N=27, Recruiting, University of Illinois at Chicago | Trial completion date: Nov 2024 --> Dec 2026 | Trial primary completion date: Nov 2024 --> Dec 2026

14 days ago

Trial completion date • Trial primary completion date • Post-transplantation

RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • HLA-DQB1 (Major Histocompatibility Complex, Class II, DQ Beta 1) • HLA-B (Major Histocompatibility Complex, Class I, B)

RUNX1 mutation • ASXL1 mutation • MLL rearrangement • MLL rearrangement • MLL translocation

cyclophosphamide • fludarabine IV

15d

MLL/WDR5 complex recruits centriolar satellite protein Cep72 to regulate microtubule nucleation and spindle formation. (PubMed, Sci Adv)

Last, we show that MLL and WDR5 recruit Cep72 to the centrosome. Our studies provide insight into an undiscovered role of MLL at the centrosome and elucidate how centriolar satellite proteins like Cep72 can be recruited to the centrosome.

15 days ago

Journal

KMT2A (Lysine Methyltransferase 2A) • CEP72 (Centrosomal Protein 72) • WDR5 (WD Repeat Domain 5)

19d

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

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.

19 days ago

IO biomarker

TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BCL2 (B-cell CLL/lymphoma 2) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • SRSF2 (Serine and arginine rich splicing factor 2) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • BCOR (BCL6 Corepressor) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2) • NUP214 (Nucleoporin 214) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • MRTFA (Myocardin Related Transcription Factor A) • RBM15 (RNA Binding Motif Protein 15)

TP53 mutation • NPM1 mutation • KMT2A rearrangement • MLL rearrangement • U2AF1 mutation • CEBPA mutation • MLL mutation • NPM1 W288

FoundationOne® Heme CDx

20d

YAP1::KMT2A-rearranged sarcomas harbor a unique methylation profile and are distinct from sclerosing epithelioid fibrosarcoma and low-grade fibromyxoid sarcoma. (PubMed, Virchows Arch)

DNA methylation analysis further showed that YAP1::KMT2A-rearranged sarcomas formed a distinct cluster, which was clearly separate from both conventional SEF and low-grade fibromyxoid sarcoma (LGFMS). These results suggest that YAP1::KMT2A-rearranged sarcomas likely represent a unique sarcoma subtype with propensity for aggressive behavior.

20 days ago

Journal

KMT2A (Lysine Methyltransferase 2A) • EWSR1 (EWS RNA Binding Protein 1) • YAP1 (Yes associated protein 1) • FUS (FUS RNA Binding Protein) • MUC4 (Mucin 4, Cell Surface Associated) • CREB3L1 (CAMP Responsive Element Binding Protein 3 Like 1)

MLL rearrangement • MUC4 expression

21d

HMX3 is a critical vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia. (PubMed, Leukemia)

Strikingly, HMX3 silencing in KMT2A::MLLT3 patient cells resulted in cell cycle arrest, monocytic differentiation and apoptosis. Thus, the neuronal transcription factor HMX3 is a leukemia-specific vulnerability in KMT2A::MLLT3 AML.

21 days ago

Journal

MYC (V-myc avian myelocytomatosis viral oncogene homolog) • KMT2A (Lysine Methyltransferase 2A) • CREBBP (CREB binding protein) • CD34 (CD34 molecule) • MECOM (MDS1 And EVI1 Complex Locus) • KAT6A (Lysine Acetyltransferase 6A) • MLLT3 (MLLT3 Super Elongation Complex Subunit)

MLL rearrangement

23d

TIFAB Modulates Metabolic Pathways in KMT2A::MLLT3-Induced AML Through HNF4A. (PubMed, Blood Adv)

Conversely, Hnf4a knockdown attenuates TIFAB-mediated enhancement of LSPC function. These findings highlight the critical role of the TIFAB-HNF4A axis in KMT2A::MLLT3-induced AML and uncover a novel regulator in leukemia biology.

23 days ago

Journal

KMT2A (Lysine Methyltransferase 2A) • HOXA9 (Homeobox A9) • MEIS1 (Meis Homeobox 1) • MLLT3 (MLLT3 Super Elongation Complex Subunit) • HNF1A (HNF1 Homeobox A) • USP1 (Ubiquitin Specific Peptidase 1)

25d

Pyoderma gangrenosum-like neutrophilic dermatosis as an adverse effect of menin-KMT2A inhibitor therapy for acute myeloid leukaemia. (PubMed, Ann Hematol)

A 71 years old woman received the MENi revumenib (REV) for relapsed/refractory NPM1m AML...However, to our knowledge, this is the first report ever of MENi induced PG-like ND and cutaneous involvement of DS. This report highlights the fact that ND such as PG, as a manifestation of DS, are a possibly severe adverse effect of MENi.

25 days ago

Journal • Adverse events

KMT2A (Lysine Methyltransferase 2A)

Revuforj (revumenib)

28d

Targeting chromatin modifying complexes in acute myeloid leukemia. (PubMed, Stem Cells Transl Med)

This review explores recent discoveries of how leukemic cells hijack these complexes and their interactions with other chromatin regulators to promote disease progression. We also discuss inhibitors targeting these complexes that have demonstrated therapeutic efficacy in preclinical and clinical studies and propose novel therapeutic combinations targeting the KMT2A and PRC1/2 broader interacting networks to overcome issues of resistance to existing monotherapies.

28 days ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEIS1 (Meis Homeobox 1)

NPM1 mutation • MLL rearrangement

29d

BRAF V600E-Mutant Acute Myeloid Leukemia: A Case Series and Literature Review of a Rare Entity. (PubMed, Genes (Basel))

Although it is uncertain whether the complex karyotype and somatic mutations observed in case 1 and KMT2A rearrangement and variants identified in case 2 may have either independently or cooperatively conferred a poor prognosis, we contend that additional comprehensive studies are needed to further understand the pathophysiology and prognosis of BRAF mutations in AML. We further posit whether patients with BRAF V600E-mutant AML may benefit from the combined use of BRAF inhibitors and/or RAS-pathway-targeting regimens, which are currently FDA-approved for the treatment of BRAF V600-mutant solid tumors and BRAF-mutant histiocytic neoplasms.

29 days ago

Review • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • KMT2A (Lysine Methyltransferase 2A) • TET2 (Tet Methylcytosine Dioxygenase 2) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)

BRAF V600E • BRAF V600 • TET2 mutation • KMT2A rearrangement • KRAS G12A • KRAS G12 • MLL rearrangement • MLL rearrangement

29d

Targeting Menin in Acute Myeloid Leukemia: Therapeutic Advances and Future Directions. (PubMed, Cancers (Basel))

These agents, both as monotherapies and in combination with synergistic drugs, are undergoing preclinical and clinical evaluation with promising early results. With the growing literature around menin inhibitors in AML, we discussed the biology of menin, its mechanism of action, its interacting partners in leukemia, possible inhibitors, their implications, synergistic drugs, and future therapeutic strategies in this review.

29 days ago

Review • Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • MEN1 (Menin 1)

30d

Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma. (PubMed, Leukemia)

The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.

30 days ago

Journal

ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • KMT2A (Lysine Methyltransferase 2A) • KMT2C (Lysine Methyltransferase 2C) • MDM4 (The mouse double minute 4) • KMT2B (Lysine Methyltransferase 2B) • JUNB (JunB Proto-Oncogene AP-1 Transcription Factor Subunit)

ALK positive • ALK rearrangement

KMT2A facilitates the epithelial-to-mesenchymal transition and the progression of ovarian cancer. (PubMed, Mol Cell Biochem)

Furthermore, KMT2A knockdown inhibited TGF-β-induced EMT in OC and reduced the phosphorylation levels of Smad2. Taken together, these observations demonstrate that KMT2A could promote the malignant behavior of OC by activating TGF-β/Smad signaling pathway and may be a potential prognostic biomarker and therapeutic target for OC.

1 month ago

Journal

KMT2A (Lysine Methyltransferase 2A) • TGFB1 (Transforming Growth Factor Beta 1)

Ailanthone targets the KMT2A-MEN1 complex to suppress lung metastasis of osteosarcoma. (PubMed, Phytomedicine)

This work showed that AIL targets the KMT2A-MEN1 complex and inhibits SSP to suppress OS lung metastasis. Notably, AIL exhibits new mechanisms of action, distinct from those of existing anti-OS drugs. On the basis of these findings, we proposed a novel strategy to treat OS by targeting epigenetic enzymes and cancer metabolism.

1 month ago

Journal

KMT2A (Lysine Methyltransferase 2A)

A rare case of pediatric T-cell acute lymphoblastic leukemia with myeloid mimicry. (PubMed, Discov Oncol)

Her favorable response to conventional therapy underscores the importance of molecular phenotyping in the treatment of this disease. The continued use of NGS to gather relevant molecular data is crucial for further understanding the molecular phenotype and prognosis of such atypical ALL cases.

1 month ago

Journal

NRAS (Neuroblastoma RAS viral oncogene homolog) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • KMT2A (Lysine Methyltransferase 2A) • WT1 (WT1 Transcription Factor)

NRAS mutation • EZH2 mutation • NRAS overexpression • WT1 overexpression

AUGMENT-101: A Study of Revumenib in R/R Leukemias Including Those With an MLL/KMT2A Gene Rearrangement or NPM1 Mutation (clinicaltrials.gov)

P1/2, N=413, Recruiting, Syndax Pharmaceuticals | Trial completion date: Dec 2024 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2027

1 month ago

Trial completion date • Trial primary completion date

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

NPM1 mutation • MLL rearrangement • MLL rearrangement • NUP98 rearrangement

Revuforj (revumenib) • Tybost (cobicistat)

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.

1 month 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.

1 month 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.

1 month 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

1 month 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.

1 month 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.

1 month 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.

1 month 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.

1 month 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

2ms

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)...The survival outcomes are encouraging and need to be validated in a larger number of patients. Currently, post-transplant cyclophosphamide has been implemented to lessen the risk of GVHD.

2 months 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

2ms

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

Conclusions : 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.

2 months 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

2ms

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

Conclusions : 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.

2 months 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

2ms

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.

2 months ago

IO biomarker

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

TP53 mutation

clonoSEQ

Blincyto (blinatumomab)

2ms

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)

NGS detects very low-level (<0.001%) residual clonal sequences in 22% of patients and the clinical significance remains a matter of investigation. These data suggest that MFC and NGS are complementary and provide more powerful insight into the biology and clinical outcome of B-ALL than either assay alone.

2 months 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

2ms

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...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.

2 months 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

MSK-IMPACT Heme

melphalan

2ms

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...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.

2 months 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)

2ms

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+). 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.

2 months ago

Clinical • IO biomarker • Minimal residual disease

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

TP53 mutation

clonoSEQ

Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin)

2ms

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

2 months 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