News - CBL mutation - LARVOL VERI

Sitravatinib in patients with solid tumors selected by molecular alterations: results from a Phase Ib study. (PubMed, Future Oncol)

Most treatment-emergent adverse events were mild-to-moderate in severity. The study closed before the planned number of patients were enrolled in all cohorts. Sitravatinib had a manageable safety profile with modest signals of clinical activity in patients with molecularly selected solid tumors.Clinical trial registration: www.clinicaltrials.gov identifier is NCT02219711.

3 days ago

P1 data • Journal

PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • AXL (AXL Receptor Tyrosine Kinase) • KDR (Kinase insert domain receptor) • DDR2 (Discoidin domain receptor 2) • NTRK (Neurotrophic receptor tyrosine kinase)

MET mutation • RET rearrangement • CBL mutation

sitravatinib (MGCD516)

A prospective clinical study to evaluate the efficacy of dexitabine in maintenance therapy after hematopoietic stem cell transplantation in juvenile myelomonocytic leukemia (ChiCTR2400091166)

P=N/A, N=40, Not yet recruiting, The Seventh Affiliated Hospital, Sun Yat-sen University; The Seventh Affiliated Hospital, Sun Yat-sen University

8 days ago

New trial

KRAS (KRAS proto-oncogene GTPase) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)

KRAS mutation • NRAS mutation • NF1 mutation • PTPN11 mutation • CBL mutation

19d

ADVL1521: Trametinib in Treating Patients With Relapsed or Refractory Juvenile Myelomonocytic Leukemia (clinicaltrials.gov)

P2, N=10, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2025

19 days ago

Trial completion date

NF1 (Neurofibromin 1) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11)

NF1 mutation • RAS mutation • PTPN11 mutation • CBL mutation

Mekinist (trametinib) • omipalisib (GSK2126458)

2ms

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=45, Recruiting, Australasian Leukaemia and Lymphoma Group | Not yet recruiting --> Recruiting

2 months ago

Enrollment open

FLT3 (Fms-related tyrosine kinase 3)

FLT3 mutation • CBL mutation

Venclexta (venetoclax) • Xospata (gilteritinib)

2ms

Genomic Landscape of Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Central Study. (PubMed, Int J Mol Sci)

In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.

2 months ago

Journal

TP53 (Tumor protein P53) • 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)

TP53 mutation • RUNX1 mutation • ASXL1 mutation • CBL mutation • SRSF2 mutation

2ms

CBL mutations in chronic myelomonocytic leukemia often occur in the RING domain with multiple subclones per patient: Implications for targeting. (PubMed, PLoS One)

Furthermore, we noted an increased percentage of CMML CD34+ stem and progenitor cells expressing CD116 and CD131 in all CBL mutant cases and increased CD116 receptor density compared to healthy controls, similar to CMML overall. In summary, our data demonstrate that CBL mutations are associated with distinct molecular and clinical features in CMML and are potentially targetable with CD116-directed immunotherapy.

2 months ago

Journal • IO biomarker

KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • TET2 (Tet Methylcytosine Dioxygenase 2) • CD34 (CD34 molecule)

KRAS mutation • NRAS mutation • TET2 mutation • CBL mutation

2ms

Case of B-acute lymphoblastic leukaemia with t(1;19)(q23;p13.3) TCF3::PBX1 and co-occurring CBL mutation in an elderly patient. (PubMed, BMJ Case Rep)

She was treated with modified Ph-negative EWALL induction (Vincristine, Idarubicin, dexamethasone) and achieved a complete remission. However, she subsequently experienced an early relapse and was refractory to targeted therapy with blinatumomab. After treatment with inotuzumab ozogamicin, she achieved a second complete remission...It demonstrates that patients with ostensibly favourable prognostic factors may experience poor response rates to traditional chemotherapy as well as targeted salvage agents. It also illustrates the challenges of treating B-ALL in the elderly population.

2 months ago

Journal

CBL (Cbl proto-oncogene) • TCF3 (Transcription Factor 3) • PBX1 (PBX Homeobox 1)

CBL mutation

Blincyto (blinatumomab) • Besponsa (inotuzumab ozogamicin) • vincristine • idarubicin hydrochloride

2ms

Early drivers of clonal hematopoiesis shape the evolutionary trajectories of de novo acute myeloid leukemia. (PubMed, medRxiv)

Thus, early CH-associated mutations that precede malignant transformation subsequently shape the evolutionary trajectories of AML through diagnosis, therapy, and relapse. DNMT3A , TET2 and ASXL1 mutations persist through AML-directed therapy Distinct CH-related mutations shape the evolutionary trajectories of AML from diagnosis through relapse.

2 months ago

Journal

FLT3 (Fms-related tyrosine kinase 3) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • SRSF2 (Serine and arginine rich splicing factor 2)

FLT3 mutation • NPM1 mutation • DNMT3A mutation • ASXL1 mutation • TET2 mutation • CBL mutation • SRSF2 mutation • FLT3 mutation + NPM1 mutation

7ms

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

7 months ago

Enrollment open

FLT3 (Fms-related tyrosine kinase 3)

FLT3 mutation • CBL mutation • Chr t(9;11)

8ms

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.

8 months ago

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

10ms

P1/2, N=60, Not yet recruiting, Australasian Leukaemia and Lymphoma Group

10 months ago

New P1/2 trial

FLT3 (Fms-related tyrosine kinase 3)

FLT3 mutation • CBL mutation

Venclexta (venetoclax) • Xospata (gilteritinib)

10ms

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

10 months ago

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

11ms

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

11 months ago

Trial completion date • Trial initiation date • Trial primary completion date

FLT3 (Fms-related tyrosine kinase 3)

FLT3 mutation • CBL mutation • Chr t(9;11)

11ms

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.

11 months ago

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)

11ms

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

11 months ago

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)

12ms

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.

12 months ago

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

12ms

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).

12 months ago

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

12ms

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.

12 months ago

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

12ms

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.

12 months ago

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)

12ms

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.

12 months ago

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

1year

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 â€œactivating likeâ€� signature may help define a specific target among tyrosine kinase inhibitors, while â€œself-renewal likeâ€� patients may benefit from histone deacetylase inhibitors (as we previously published). HOXA genes overexpression open a novel therapeutic options for selected patients.

1 year ago

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)

1year

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.

1 year ago

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

1year

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.

1 year ago

Clinical • P2 data

RUNX1 (RUNX Family Transcription Factor 1) • TET2 (Tet Methylcytosine Dioxygenase 2)

TET2 mutation • CBL mutation

1year

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.

1 year ago

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

1year

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.

1 year ago

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

1year

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.

1 year ago

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)

1year

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.

1 year ago

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

1year

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.

1 year ago

Clinical • P1/2 data • Combination therapy

FLT3 (Fms-related tyrosine kinase 3)

FLT3-ITD mutation • FLT3 mutation • CBL mutation

azacitidine • Vanflyta (quizartinib)

1year

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.

1 year ago

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

1year

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.

1 year ago

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

1year

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.

1 year ago

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

1year

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.

1 year ago

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

1year

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.

1 year ago

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

1year

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.

1 year ago

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)