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    BIOMARKER:

    CBL mutation

    i
    Other names: CBL, c-Cbl, CBL2, RNF55, Cbl proto-oncogene, E3 ubiquitin protein ligase
    Entrez ID:
    867
    Related biomarkers:
    Mutation
    15d
    Alpha/Beta T Cell and CD19+ B Cell Depletion in Allogeneic Stem Cell Transplantation in Patients With Malignant Diseases (clinicaltrials.gov)
    P2, N=20, Recruiting, University of Florida | Not yet recruiting --> Recruiting
    Enrollment open
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • CBL mutation • Chr t(9;11)
    1m
    Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm. (PubMed, Blood Adv)
    Compared to a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P <.001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.
    Journal
    |
    TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SETBP1 (SET Binding Protein 1)
    |
    TP53 mutation • NF1 mutation • TET2 mutation • CBL mutation • SETBP1 mutation
    3ms
    AMLM26/T1 INTERCEPT: A multi-arm trial for patients with acute myeloid leukaemia investigating new treatments which target early relapse and changes in disease characteristics - Gilteritinib+ Venetoclax (ACTRN12624000082505)
    P1/2, N=60, Not yet recruiting, Australasian Leukaemia and Lymphoma Group
    New P1/2 trial
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • CBL mutation
    |
    Venclexta (venetoclax) • Xospata (gilteritinib)
    3ms
    Venetoclax Added to Fludarabine + Busulfan Prior to Transplant and to Maintenance Therapy for AML, MDS, and MDS/MPN (clinicaltrials.gov)
    P1, N=100, Recruiting, Jacqueline Garcia, MD | Trial completion date: Dec 2024 --> Feb 2026 | Trial primary completion date: Feb 2024 --> Feb 2025
    Trial completion date • Trial primary completion date • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BCR (BCR Activator Of RhoGEF And GTPase) • BCL2 (B-cell CLL/lymphoma 2) • NPM1 (Nucleophosmin 1) • NF1 (Neurofibromin 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • KMT2A (Lysine Methyltransferase 2A) • 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) • STAG2 (Stromal Antigen 2) • MECOM (MDS1 And EVI1 Complex Locus) • NUP214 (Nucleoporin 214) • GATA2 (GATA Binding Protein 2) • DEK (DEK Proto-Oncogene) • RIT1 (Ras Like Without CAAX 1) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
    |
    TP53 mutation • KRAS mutation • NRAS mutation • RUNX1 mutation • RAS mutation • ASXL1 mutation • CBL mutation • MLL rearrangement • U2AF1 mutation • Chr del(5q) • FLT3 wild-type
    |
    Venclexta (venetoclax) • azacitidine • Inqovi (decitabine/cedazuridine) • fludarabine IV • busulfan
    4ms
    Alpha/Beta T Cell and CD19+ B Cell Depletion in Allogeneic Stem Cell Transplantation in Patients With Malignant Diseases (clinicaltrials.gov)
    P2, N=20, Not yet recruiting, University of Florida
    Trial completion date • Trial initiation date • Trial primary completion date
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3 mutation • CBL mutation • Chr t(9;11)
    4ms
    LNK/SH2B3 as a novel driver in juvenile myelomonocytic leukemia. (PubMed, Haematologica)
    Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
    Journal
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SH2B3 (SH2B Adaptor Protein 3)
    |
    KRAS mutation • NF1 mutation • CBL mutation
    |
    Jakafi (ruxolitinib)
    4ms
    Enasidenib in Combination With Cobimetinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov)
    P1, N=15, Recruiting, City of Hope Medical Center | Phase classification: P1b --> P1 | Trial completion date: Mar 2024 --> May 2025 | Trial primary completion date: Mar 2024 --> May 2025
    Phase classification • Trial completion date • Trial primary completion date • Combination therapy
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
    |
    KRAS mutation • NRAS mutation • IDH2 mutation • NF1 mutation • RAS mutation • CBL mutation • IDH2 R140 • IDH2 R172
    |
    Cotellic (cobimetinib) • Idhifa (enasidenib)
    5ms
    Real-World Experience of Ropeginterferon-Alfa Treatment of PV and ET - Two Centers Experience (ASH 2023)
    Prior to ropeginterferon-alfa, the participants were managed with therapeutic phlebotomies, or cytoreduced with either hydroxyurea, pegylated interferon-alpha 2a ( Pegasys), JAK2 inhibitors, or were newly diagnosed and previously untreated. Ropeginterferon-alfa is effective in PV and ET, however, the dose that achieves CHR is highly individualized, necessitating an incremental titration approach. The patients already in CHR from prior therapy needed relatively lower doses of ropeginterferon-alfa to maintain CHR. Clinical trials are ongoing with an alternate accelerated dosing scheme and results are awaited.
    Clinical • Real-world evidence • Real-world
    |
    DNMT3A (DNA methyltransferase 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • CALR (Calreticulin)
    |
    DNMT3A mutation • TET2 mutation • CBL mutation • JAK2 V617F • JAK2 mutation • CALR mutation
    |
    Pegasys (pegylated interferon α -2a) • hydroxyurea
    5ms
    Analysis of Methylation Level and Clinical Characteristics of Juvenile Myelomonocytic Leukemia (ASH 2023)
    high risk factors such as age at first diagnosis, PTPN11 mutation and compound mutation are significantly correlated with methylation in patients.
    Clinical
    |
    KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
    |
    KRAS mutation • NRAS mutation • NF1 mutation • ALK fusion • ALK mutation • PTPN11 mutation • CBL mutation
    5ms
    Interactions between Iron Overload, Oxidative Stress, and Somatic Mutations in Myelodysplastic Syndromes; Evidence from the Literature (ASH 2023)
    Of 31 mutations found in the IPSS-M, an additional four mutations found in familial predisposing conditions (DDX41, GATA2, CHEK2, SAMD9) were searched as was TET2, for a total of 35 mutations. Fifty-four references were identified. Fifty-three references were preclinical/translational in nature, with one case report (WT1).
    Oxidative stress
    |
    TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • WT1 (WT1 Transcription Factor) • CHEK2 (Checkpoint kinase 2) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • DDX41 (DEAD-Box Helicase 41) • GATA2 (GATA Binding Protein 2) • ERFE (Erythroferrone)
    |
    TP53 mutation • NRAS mutation • TET2 mutation • SF3B1 mutation • CBL mutation • CHEK2 mutation • U2AF1 mutation • STAG2 mutation
    5ms
    Prevalence, Dynamics and Clinical Significance of Clonal Hematopoiesis of Indeterminate Potential (CHIP) in Newly Diagnosed Cancer Patients (ASH 2023)
    A patient with diffuse large B-cell lymphoma and CHIP ( ASXL1, PPM1D, and TP53 variants) developed a TRMN (MDS-MD) 7 months after completing R-CHOP treatment...Finally, and in contrast contrast with our initial hypothesis, we found no evidence of impaired outcomes in the CHIP population. These results emphasize the need for further longitudinal follow-up.
    Clinical
    |
    TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • CHEK2 (Checkpoint kinase 2) • GNAS (GNAS Complex Locus) • PPM1D (Protein Phosphatase Mg2+/Mn2+ Dependent 1D)
    |
    DNMT3A mutation • TET2 mutation • SF3B1 mutation • CBL mutation • SRSF2 mutation • PPM1D mutation
    |
    Rituxan (rituximab)
    5ms
    Research progress of additional pathogenic mutations in chronic neutrophilic leukemia. (PubMed, Ann Hematol)
    The coexistence of these mutated genes and CSF3R mutations, as well as the different evolutionary sequences of clones, deepens the complexity of CNL molecular biology. The purpose of this review is to summarize the genetic research findings of CNL in the last decade, focusing on the common mutated genes in CNL and their clinical significance, as well as the clonal evolution pattern and sequence of mutation acquisition in CNL, to provide a basis for the appropriate management of CNL patients.
    Review • Journal
    |
    DNMT3A (DNA methyltransferase 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • CSF3R (Colony Stimulating Factor 3 Receptor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • SETBP1 (SET Binding Protein 1) • GATA2 (GATA Binding Protein 2)
    |
    CBL mutation • SRSF2 mutation • U2AF1 mutation • CSF3R mutation
    5ms
    GENE FUSIONS ARE A PUTATIVE MECHANISM THAT DIMINISHES SENSITIVITY TO VENETOCLAX-HYPOMETHYLATING AGENTS COMBINATION IN ACUTE MYELOID LEUKEMIA (SIE 2023)
    Appealing patterns of resistance emerged from genomic analysis: the “activating like� signature may help define a specific target among tyrosine kinase inhibitors, while “self-renewal like� patients may benefit from histone deacetylase inhibitors (as we previously published). HOXA genes overexpression open a novel therapeutic options for selected patients.
    FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR1 (Fibroblast growth factor receptor 1) • JAK2 (Janus kinase 2) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • ETV6 (ETS Variant Transcription Factor 6) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CSF3R (Colony Stimulating Factor 3 Receptor) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • MECOM (MDS1 And EVI1 Complex Locus) • NSD1 (Nuclear Receptor Binding SET Domain Protein 1) • BAX (BCL2-associated X protein) • LTBP1 (Latent-transforming growth factor beta-binding protein 1) • CCND2 (Cyclin D2) • DDX5 (DEAD-Box Helicase 5) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B) • PER1 (Period Circadian Clock 1) • TBL1XR1 (TBL1X Receptor 1)
    |
    NRAS mutation • CBL mutation • MECOM rearrangement • PDGFRB mutation
    |
    TruSight RNA Pan-Cancer Panel
    |
    Venclexta (venetoclax)
    6ms
    Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms. (PubMed, Leuk Lymphoma)
    STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.
    Journal
    |
    RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • SRSF2 (Serine and arginine rich splicing factor 2) • CSF3R (Colony Stimulating Factor 3 Receptor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1) • CUX1 (cut like homeobox 1)
    |
    ASXL1 mutation • SF3B1 mutation • CBL mutation • SRSF2 mutation • U2AF1 mutation • STAG2 mutation • SETBP1 mutation
    6ms
    Influence of Co-Mutational Patterns in Disease Phenotype and Clinical Outcomes of Chronic Myelomonocytic Leukemia (ASH 2023)
    These data suggest that somatic mutations in CMML have unique patterns of clustering that define disease phenotype and influence disease outcomes.
    Clinical • Clinical data
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • ETV6 (ETS Variant Transcription Factor 6) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • SETBP1 (SET Binding Protein 1) • BCORL1 (BCL6 Corepressor Like 1)
    |
    TP53 mutation • BRAF mutation • NRAS mutation • DNMT3A mutation • RUNX1 mutation • ASXL1 mutation • TET2 mutation • EZH2 mutation • CBL mutation • SRSF2 mutation • U2AF1 mutation • CEBPA mutation • WT1 mutation • Chr del(7q) • ETV6 mutation
    6ms
    Phase II Study Assessing Safety and Preliminary Efficacy of High Dose Intravenous Ascorbic Acid in Patients with TET2 Mutant Clonal Cytopenias (ASH 2023)
    We report the final safety and efficacy analysis of HI-AA in PTs with TET2MT CCUS. The trial data suggest that HI-AA is safe and well tolerated. Although there were no significant responses by IWG MDS criteria, alleviation in severity of cytopenias in a subset of PTs (n=3) along with correlative epigenetic changes in enhancer regions, needs further exploration.
    Clinical • P2 data
    |
    RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2)
    |
    TET2 mutation • CBL mutation
    6ms
    Signaling Pathway Mutations Cooperate with the PICALM/MLLT10 Fusion in a Knock-in AML Mouse Model (ASH 2023)
    We aim to functionally validate these findings by establishing mouse models that harbor the C/A fusion as well as mutations in Ptpn11 and other signal transduction genes. These murine models will be immensely valuable for gaining a deeper insight into PICALM/MLLT10-mediated leukemogenesis, studying cooperating mutations and for testing new targeted therapies.
    Preclinical
    |
    KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • PAX5 (Paired Box 5) • IKZF3 (IKAROS Family Zinc Finger 3) • HOXA9 (Homeobox A9) • MEIS1 (Meis Homeobox 1) • SOX9 (SRY-Box Transcription Factor 9) • SPI1 (Spi-1 Proto-Oncogene) • GATA1 (GATA Binding Protein 1) • AFF2 (AF4/FMR2 family member 2) • ZEB1 (Zinc Finger E-box Binding Homeobox 1) • MLLT10 (MLLT10 Histone Lysine Methyltransferase DOT1L Cofactor)
    |
    KRAS mutation • PTPN11 mutation • CBL mutation • CD19 expression
    6ms
    Molecular Landscape of c-CBL Mutation in Adults' Myeloid Malignancies (ASH 2023)
    In sum, our study of the molecular landscape of c-CBL mutations highlights that these lesions occur mainly during disease development with majority of the cases carrying subclonal hits with a weaker effect on disease phenotype and prognosis. Such mutations can be present in both primary and secondary AML (in contrast with previous reports) and additive effects can be observed when c-CBL mutations co-occur with more than one RAS gene in these disease groups. In some cases, especially in non-canonical mutations, c-CBL could also act as ancestral event and as an independent leukemic driver.
    Clinical
    |
    KRAS (KRAS proto-oncogene GTPase) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NF1 (Neurofibromin 1) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2) • CSF3R (Colony Stimulating Factor 3 Receptor)
    |
    FLT3 mutation • Chr del(11q) • TET2 mutation • CBL mutation • SRSF2 mutation
    6ms
    Novel Mechanisms of Venetoclax Resistance in Acute Myeloid Leukemia Based on Genomic Rearrangements (ASH 2023)
    Through deep transcriptomic characterization combined with conventional diagnostics, this analysis uncovered novel mechanisms of VEN resistance while confirming established ones. The distinct gene expression patterns may help tailor targeted therapies, with patients showing the "activating-like" signature potentially benefiting from tyrosine kinase inhibitors and those with the "self-renewal like" signature possibly responding well to histone deacetylase inhibitors. Furthermore, HOXA gene overexpression presents an exciting therapeutic opportunity for selected patients.
    IO biomarker
    |
    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR (Fibroblast Growth Factor Receptor) • JAK2 (Janus kinase 2) • MCL1 (Myeloid cell leukemia 1) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • ETV6 (ETS Variant Transcription Factor 6) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CSF3R (Colony Stimulating Factor 3 Receptor) • NUP98 (Nucleoporin 98 And 96 Precursor 2) • MECOM (MDS1 And EVI1 Complex Locus) • NSD1 (Nuclear Receptor Binding SET Domain Protein 1) • BAX (BCL2-associated X protein) • LTBP1 (Latent-transforming growth factor beta-binding protein 1) • CCND2 (Cyclin D2) • DDX5 (DEAD-Box Helicase 5) • BCL11B (BAF Chromatin Remodeling Complex Subunit BCL11B) • PER1 (Period Circadian Clock 1) • GSDMC (Gasdermin C) • TBL1XR1 (TBL1X Receptor 1)
    |
    NRAS mutation • CBL mutation • MCL1 expression • NRAS G13 • MECOM rearrangement • PDGFRB mutation
    |
    TruSight RNA Pan-Cancer Panel
    |
    Venclexta (venetoclax)
    6ms
    Clinical Characteristics and Outcomes of Therapy-Related Chronic Myelomonocytic Leukemia: Analysis of a Large Cohort (ASH 2023)
    Patients with tCMML have a higher proportion of chromosome 7 abnormalities and a lower incidence of NRAS and CBL mutations. Although responses to HMA were similar, patients with tCMML with a previous exposure to chemotherapy are associated with a lower survival, especially patients classified as CPSS-Mol intermediate-1.
    Clinical
    |
    TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2)
    |
    TP53 mutation • NRAS mutation • TET2 mutation • CBL mutation
    6ms
    Risk Stratified Treatment for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase 1/2 Non-Randomized Study of Trametinib and Azacitidine with or without Chemotherapy (ASH 2023)
    Trametinib is FDA-approved for the treatment of adults with advanced melanoma with BRAF V600E or V600K mutations and in children with Ras-mutant solid tumors in combination with dabrafenib...High-risk patients will receive trametinib administered once-daily for 28 days in combination with azacitidine, fludarabine, and cytarabine (aza/FLA) administered daily for five days per cycle...The study is open to accrual at all TACL consortium sites. We acknowledge the TACL Consortium's scientific contribution to and participation in this study, including participating member institutions, investigators, research teams, and the TACL Operations Center.
    Clinical • P1/2 data • Tumor mutational burden
    |
    KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SH2B3 (SH2B Adaptor Protein 3)
    |
    BRAF V600E • KRAS mutation • NRAS mutation • BRAF V600 • BRAF V600K • NF1 mutation • RAS mutation • CBL mutation
    |
    Mekinist (trametinib) • Tafinlar (dabrafenib) • cytarabine • azacitidine • fludarabine IV
    6ms
    Molecular Classification of Chronic Myelomonocytic Leukemia: Results of the Analysis of an International Cohort of 2,471 Patients (ASH 2023)
    15% of patients showed clear overlapping features with other myeloid neoplasms, thus providing the rational to refine the boundaries among different clinical entities. A molecular classification of CMML may provide a basis to define a next-generation prognostic tool and improve clinical decision-making.
    Clinical
    |
    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) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • SETBP1 (SET Binding Protein 1) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
    |
    TP53 mutation • KRAS mutation • NPM1 mutation • DNMT3A mutation • TET2 mutation • CBL mutation • SRSF2 mutation • JAK2 mutation
    6ms
    Results of Phase I/II Study of Azacitidine in Combination with Quizartinib for Patients with Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms with FLT3 or CBL Mutations (ASH 2023)
    Therapy with azacitidine in combination with quizartinib for pts with higher-risk MDS and MDS/MPN with FLT3 or CBL mutations has acceptable toxicity profile and is associated with promising responses mainly among FLT3-mutant pts.
    Clinical • P1/2 data • Combination therapy
    |
    FLT3 (Fms-related tyrosine kinase 3)
    |
    FLT3-ITD mutation • FLT3 mutation • CBL mutation
    |
    azacitidine • Vanflyta (quizartinib)
    6ms
    Error-Corrected Next-Generation Sequencing Provides a Comprehensive Overview of the Subclonal Mutation Landscape and Its Prognostic Implications in Juvenile Myelomonocytic Leukemia (ASH 2023)
    We successfully performed error-corrected NGS to assess comprehensive subclonal secondary mutational profiles, including very low VAF variants. The presence of subclonal mutations, particularly in RAS pathway genes, was associated with poor OS. These findings provide important information for appropriate risk stratification, which will contribute to the implementation of precision medicine for patients with JMML.
    Next-generation sequencing
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • JAK3 (Janus Kinase 3) • SETBP1 (SET Binding Protein 1) • SH2B3 (SH2B Adaptor Protein 3) • ZRSR2 (Zinc Finger CCCH-Type, RNA Binding Motif And Serine/Arginine Rich 2)
    |
    KRAS mutation • RAS mutation • CBL mutation • JAK3 mutation • ZRSR2 mutation
    6ms
    Overexpression of the Signaling Integrator Gab2 Accelerates AML Development in Mice with Dnmt3aR878H and Npm1cA Mutations (ASH 2023)
    These data nominate GAB2 overexpression as a factor that may be relevant for the progression of founding clones with DNMT3A and NPM1 mutations to overt AML. Additional studies to define its protein interactome in preleukemic cells, its mechanism of action, and how leukemia-causing mutations in DNMT3A and NPM1 shape the fitness landscape to select for GAB2 overexpression are underway.
    Preclinical
    |
    FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CD34 (CD34 molecule)
    |
    NPM1 mutation • KIT mutation • DNMT3A mutation • PTPN11 mutation • CBL mutation • DNMT3A mutation + NPM1 mutation • FLT3 expression • PAK1 overexpression
    6ms
    Lenzilumab in Addition to Azacitidine Improves Complete Response Rates in Chronic Myelomonocytic Leukemia (ASH 2023)
    Interim analysis of the PREACH-M trial demonstrated that GM-CSF neutralization with LENZ/AZA, for the treatment of CMML with RAS-pathway mutations resulted in 55% CR, achieved early in treatment, durability up to 18 months, thus far, and no unexpected serious adverse events. These data suggest CMML is driven by a non-redundant cytokine that responds to immunotherapy. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.
    Clinical • IO biomarker
    |
    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • TET2 (Tet Methylcytosine Dioxygenase 2) • CSF2 (Colony stimulating factor 2)
    |
    KRAS mutation • NRAS mutation • RAS mutation • TET2 mutation • CBL mutation
    |
    azacitidine • LENZ (lenzilumab)
    6ms
    Cytokine and Mutation Profiling Reveal Patterns of Complete Remission Rates with Lenzilumab Combination Therapy in Chronic Myelomonocytic Leukemia (ASH 2023)
    Introduction: Chronic myelomonocytic leukemia (CMML) is characterized by accumulation of classical CD14+CD16- inflammatory monocytes driven in part by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a pro-inflammatory cytokine. CMML is a disorder of profound innate immune activation, driven by GM-CSF and other pro-inflammatory cytokines. Early treatment with LENZ/AZA, a precision immunotherapeutic approach, leads to a) efficacy in INNATE-1 that exceeds historical CR rates for hypomethylating agents1,2; and b) evolving efficacy in INNATE-2, in which pro-inflammatory activity is more robust. Xu Y, Guo R, Miao M, Zhang G, Lan J, Jin J. Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study.
    Clinical • Combination therapy • IO biomarker
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    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • SRSF2 (Serine and arginine rich splicing factor 2) • WT1 (WT1 Transcription Factor) • CD14 (CD14 Molecule) • CSF2 (Colony stimulating factor 2) • PHF6 (PHD Finger Protein 6) • IL17A (Interleukin 17A) • CX3CL1 (C-X3-C Motif Chemokine Ligand 1) • IL1B (Interleukin 1, beta) • CRP (C-reactive protein)
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    KRAS mutation • RAS mutation • CBL mutation • SRSF2 mutation • WT1 mutation • PHF6 mutation
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    azacitidine • LENZ (lenzilumab)
    6ms
    Correlation between Peripheral Blood and Bone Marrow Somatic Mutations Among Patients with Suspected or Established Myelodysplastic Syndromes from the National MDS Study (ASH 2023)
    PB can be used to reliably identify somatic mutations in patients with suspected or established MDS and related conditions. Linear correlation between PB and BM VAFs showed, unsurprisingly, that BM mutations with higher VAFs are more likely to be detected. If PB is positive, this method of variant detection may be used potentially to diagnose and monitor.
    Clinical
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    DNMT3A (DNA methyltransferase 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • ETNK1 (Ethanolamine Kinase 1)
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    ASXL1 mutation • CBL mutation • SRSF2 mutation
    6ms
    A Large Cohort Study of 412 Patients with SRSF2/TET2 Co-Mutated Myeloid Neoplasms: The Molecular Landscape and Clinical Outcomes (ASH 2023)
    SRSF2 and TET2 co-mutations occurred in various myeloid diseases, including CMML, AML transformed from CMML, other types of AML, MDS, and MPN. RUNX1, ASXL1, and CBL, were commonly mutated and associated with lower OS compared to patients with only SRSF2 and TET2 mutations. When comparing OS for patients diagnosed with low-grade diseases (CMML or MDS), ASXL1 mutation was associated with an increased risk of death.
    Clinical • Clinical data
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    KRAS (KRAS proto-oncogene GTPase) • TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • JAK2 (Janus kinase 2) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2) • STAG2 (Stromal Antigen 2) • SETBP1 (SET Binding Protein 1) • CUX1 (cut like homeobox 1)
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    TP53 mutation • KRAS mutation • RUNX1 mutation • ASXL1 mutation • TET2 mutation • CBL mutation • SRSF2 mutation • STAG2 mutation
    6ms
    Genetic Mutation and Outcome of Venetoclax-Based Therapy in Newly Diagnosed AML in the Real World: Hokkaido Leukemia Net Study (ASH 2023)
    Based on these results, we were able to stratify the prognosis by dividing the patients into three groups according to the presence of high-sensitivity mutations, complex karyotype and/or TP53 mutations (Figure 2). Conclusion VEN-based therapy abrogates the efficacy of NCCN2017 stratification, however, the genetic mutation profile of the initial disease successfully stratified prognosis.
    Clinical • Real-world evidence • Real-world
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    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) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • CEBPA (CCAAT Enhancer Binding Protein Alpha)
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    TP53 mutation • KRAS mutation • IDH2 mutation • NPM1 mutation • DNMT3A mutation • CBL mutation • CEBPA mutation
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    Venclexta (venetoclax)
    6ms
    Venetoclax (VEN) Improves Response Rates but Not Survival in Patients with Chronic Myelomonocytic Leukemia (CMML) Treated with Hypomethylating Agents (HMA): A Multicenter, Propensity Score Analysis (ASH 2023)
    For HMA combination partner, 46 (52%) were treated with azacitidine, 35 (39%) with decitabine, and 8 (9%) with both during their VEN course. The current sample size of CMML-BT may limit detection of OS differences between treatment groups. The role of VEN to reduce blasts and serve as a bridge to alloSCT, particularly after HMA failure, requires further investigation in larger studies in both the CMML and CMML-BT populations.
    Clinical
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    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • RUNX1 (RUNX Family Transcription Factor 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • SRSF2 (Serine and arginine rich splicing factor 2)
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    KRAS mutation • NRAS mutation • NF1 mutation • RAS mutation • CBL mutation • SRSF2 mutation
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    Venclexta (venetoclax) • azacitidine • decitabine
    6ms
    Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: A Report from the Children's Oncology Group (ASH 2023)
    Upfront therapies typically include high-dose cytarabine or azacitidine, but the only definitive treatment is hematopoietic stem cell transplantation (HSCT). We conducted an open label, phase 2 trial of trametinib in children with relapsed or refractory JMML. This is the first completed study of a MEK inhibitor in any hematologic malignancy in children. The trial met its primary objective and demonstrated a 50% objective response rate with 70% of patients bridging to a successful HSCT or completing the maximum 12 cycles permitted on study.
    Clinical
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    KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)
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    KRAS mutation • NRAS mutation • NF1 mutation • RAS mutation • CBL mutation • MAP2K1 expression
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    Mekinist (trametinib) • cytarabine • azacitidine
    6ms
    Azacitidine and Quizartinib for the Treatment of Myelodysplastic Syndrome or Myelodysplastic/Myeloproliferative Neoplasm With FLT3 or CBL Mutations (clinicaltrials.gov)
    P1/2, N=58, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024
    Trial completion date • Trial primary completion date • Combination therapy
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    TP53 (Tumor protein P53) • FLT3 (Fms-related tyrosine kinase 3) • ASXL1 (ASXL Transcriptional Regulator 1)
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    TP53 mutation • FLT3-ITD mutation • ASXL1 mutation • CBL mutation
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    azacitidine • Vanflyta (quizartinib)