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BIOMARKER:

MYD88 L265P

i
Other names: MYD88, MYD88 Innate Immune Signal Transduction Adaptor, Myeloid Differentiation Primary Response Protein MyD88, Myeloid Differentiation Primary Response Gene (88), Myeloid Differentiation Primary Response 88, Mutant Myeloid Differentiation Primary Response 88, MYD88D
Entrez ID:
Related biomarkers:
1d
Bruton Tyrosine Kinase Inhibition: an Effective Strategy to Manage Waldenström Macroglobulinemia. (PubMed, Curr Hematol Malig Rep)
The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.
Review • Journal • IO biomarker
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 mutation • MYD88 L265P • BTK C481 • MYD88 wild-type
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Imbruvica (ibrutinib) • Rituxan (rituximab) • cyclophosphamide
17d
Mutational, immune microenvironment, and clinicopathological profiles of diffuse large B-cell lymphoma and follicular lymphoma with BCL6 rearrangement. (PubMed, Virchows Arch)
In conclusion, both BCL6-R-positive FL and BCL6-R-positive DLBCL had a common mutational profile; but also, differences. DLBCL cases had a higher density of microenvironment markers.
Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • BCL2 (B-cell CLL/lymphoma 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • NOTCH1 (Notch 1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • BCL6 (B-cell CLL/lymphoma 6) • KMT2D (Lysine Methyltransferase 2D) • NOTCH2 (Notch 2) • CREBBP (CREB binding protein) • CD163 (CD163 Molecule) • ARID1B (AT-Rich Interaction Domain 1B) • CD36 (thrombospondin receptor) • IL10 (Interleukin 10) • RHOA (Ras homolog family member A) • PIM1 (Pim-1 Proto-Oncogene) • CSF1R (Colony stimulating factor 1 receptor) • HLA-B (Major Histocompatibility Complex, Class I, B) • H1-4 (H1.4 Linker Histone, Cluster Member) • PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) • BTG2 (BTG Anti-Proliferation Factor 2) • LAIR1 (Leukocyte Associated Immunoglobulin Like Receptor 1)
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ATM mutation • MYD88 L265P • BCL6 rearrangement • ARID1B mutation • IL10-L • PIM1 mutation • MYC negative
20d
A Rare Case of Non-IgM Lymphoplasmacytic Lymphoma with Unusual Lack of Immunoglobulin Light Chain Production. (PubMed, Am J Case Rep)
The patient received 6 cycles of rituximab and bendamustine treatment, and no residual marrow involvement was found on the follow-up bone marrow biopsy. CONCLUSIONS We report a non-IgM LPL case featuring no light chain production and no heavy chain secretion, which we believe is the first reported case of this kind in the literature.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • IGK (Immunoglobulin Kappa Locus)
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MYD88 L265P • CXCR4 mutation
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Rituxan (rituximab) • bendamustine
21d
The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma. (PubMed, Leukemia)
Here, we show that KIN-8194, a dual inhibitor of BTK and HCK with in vivo activity against Myd88-L265P-driven diffuse large B-cell lymphoma and Waldenström Macroglobulinemia, has a potent growth inhibitory effect in MCL cell lines and primary MCL cells, irrespective of their sensitivity to BTKi (ibrutinib and acalabrutinib). Taken together, our data demonstrate that KIN-8194 inhibits growth and integrin-mediated adhesion of BTKi-sensitive MCL cells, as well as MCL cells with primary or acquired BTKi resistance. This renders KIN-8194 a promising novel treatment for MCL patients.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • HCK (HCK Proto-Oncogene)
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MYD88 L265P
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Imbruvica (ibrutinib) • Calquence (acalabrutinib) • KIN-8194
24d
Single-cell analysis of MYD88L265P and MYD88WT Waldenström macroglobulinemia patients. (PubMed, Hemasphere)
Finally, gene expression analysis showed common transcriptional features between patients compared to the healthy control but also differentially expressed genes between MYD88 L265P and MYD88 WT patients involved in distinct pathways, including NFκΒ, BCL2, and BTK. Overall, our data highlight the intra-tumor clonal heterogeneity in WM with potential prognostic and therapeutic implications.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 L265P • MYD88 wild-type
1m
Nomogram for predicting survival of patients with diffuse large B-cell lymphoma. (PubMed, Ann Hematol)
The present nomograms incorporating IPI factors and the MYD88/CD79B mutation have sufficient discrimination ability, and may effectively predict prognosis in DLBCL patients. The prognostic models we have presented here may help clinicians personalize prognostic assessments and clinical decisions.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD79B (CD79b Molecule)
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MYD88 L265P • CD79B mutation • CD79B mutation
1m
PlentiPlex™ MYD88 Waldenström lymphoma qPCR assay: A highly sensitive method for detection of MYD88 L265P mutation. (PubMed, Int J Lab Hematol)
Our data demonstrate that PlentiPlex™ MYD88 Waldenström lymphoma qPCR assay is a fast, highly sensitive, and specific method for the detection of MYD88 L265P compared with conventional AS-PCR.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 L265P
2ms
Mutational landscape in Waldenström macroglobulinemia evaluated using a next-generation sequencing lymphoma panel in routine clinical practice. (PubMed, Leuk Lymphoma)
NGS performance for the MYD88L265P variant was 96% when compared to qPCR. In conclusion, targeted NGS provided important diagnostic and prognostic information in a routine clinical setting.
Journal • Next-generation sequencing
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TP53 (Tumor protein P53) • ARID1A (AT-rich interaction domain 1A) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD79B (CD79b Molecule) • BIRC3 (Baculoviral IAP repeat containing 3)
|
TP53 mutation • ARID1A mutation • MYD88 L265P
3ms
"Quadruple-hit" primary testicular diffuse large B-cell lymphoma with MYD88 L265P mutation, IGH::MYC, and IRF4- and BCL6-rearrangements. (PubMed, J Hematop)
Gene expression profiling demonstrated an activated B-cell expression profile. This case highlights the genetic complexity of DLBCL arising in the testis and questions the clinical significance of the identified genetic abnormalities.
Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • BCL6 (B-cell CLL/lymphoma 6) • IRF4 (Interferon regulatory factor 4)
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MYD88 mutation • MYD88 L265P • BCL6 rearrangement
3ms
Diagnostic methods for primary vitreoretinal lymphoma: A systematic review. (PubMed, Surv Ophthalmol)
Overall, our systematic review found that an IL-10/IL-6 ratio greater or equal to one may provide the highest sensitivity in identifying patients with PVRL. Future studies are needed to employ multiple diagnostic tools to aid in the detection of PVRL to further establish nuanced guidelines when determining the optimal diagnostic tool to use in diverse patient populations.
Review • Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IGH (Immunoglobulin Heavy Locus) • CD79B (CD79b Molecule) • IL10 (Interleukin 10) • IL6R (Interleukin 6 receptor)
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MYD88 L265P • CD79B mutation • CD79B mutation • MYD88 L265P + CD79B mutation
4ms
The Efficacy and Safety of Zanubrutinib, Dexamethasone and or Not Cyclophosphamide Regimen in Symptomatic Waldenstrom Macroglobulinnemia (ASH 2023)
After 8 cycles, patients with VGPR remission receive Chlorambucil 6mg D1-4,15-18, dexamethasone 20mg D1-4,15-18, cyclophosphamide 300mg, D1-4,15-18 for 4cycles, others receive Zanubrutinib as maintenance. These results demonstrate that zanubrutinib, dexamethasone and or not cyclophosphamide are quickly effective in the treatment of WM, with more deeper response and less toxicity, maybe treatment discontinued by combining with cyclophosphamide after deep remission. Comments*The regimen of ZD: Zanubrutinib 240mg d1-28, dexamethasone 20mg D1-4,15-18. Patients more than 75 years old, Zanubrutinib 160mg d1-28, dexamethasone 10mg D1-4,15-18.
Clinical
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CXCR4 (Chemokine (C-X-C motif) receptor 4)
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MYD88 L265P • CXCR4 mutation
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Rituxan (rituximab) • cyclophosphamide • Brukinsa (zanubrutinib) • Leukeran (chlorambucil) • fludarabine IV • Mustargen (mechlorethamine)
4ms
CXCR4 S338X Promotes Resistance to Second Generation BTK Inhibitor and BCL-2 Inhibitor in WM Cells (ASH 2023)
The aim of this study was to further investigate the effect of CXCR4 S338X on BTK inhibitors (ibrutinib and zanubrutinib) and a BCL-2 inhibitor (venetoclax) resistance. The above data demonstrate the role of CXCR4 S338X mutation in drug resistance and suggest the necessity to develop therapeutic strategies to address this issue and overcome this therapeutic barrier in WM. Data on more cell lines and downstream signaling will be presented at the meeting.
IO biomarker
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CASP8 (Caspase 8) • CASP9 (Caspase 9) • ANXA5 (Annexin A5)
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MYD88 L265P • CXCR4 mutation • CXCR4 S338X • CXCR4 expression
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Brukinsa (zanubrutinib)
4ms
RCHOP Plus High-Dose Methotrexate As First-Line Therapy in Large B-Cell Lymphoma with Testis Involvement (ASH 2023)
PTL may benefit from HD-MTX in preventing relapse, while alternative treatments should be explored for DLBCL-T. Future studies should consider PTL and DLBCL-T as separate entities to better understand their characteristics and optimize treatment strategies.
Clinical • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • PD-1 (Programmed cell death 1) • BCL6 (B-cell CLL/lymphoma 6) • CD79B (CD79b Molecule) • B2M (Beta-2-microglobulin) • CREBBP (CREB binding protein) • CARD11 (Caspase Recruitment Domain Family Member 11) • EP300 (E1A binding protein p300) • TCF3 (Transcription Factor 3) • PIM1 (Pim-1 Proto-Oncogene) • IRF4 (Interferon regulatory factor 4) • CD58 (CD58 Molecule) • PRDM1 (PR/SET Domain 1) • NFKBIE (NFKB Inhibitor Epsilon)
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PD-L1 expression • MYD88 mutation • MYD88 L265P • PD-1 expression • BCL2 expression • MYC expression • CD79B mutation • PIM1 mutation
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Rituxan (rituximab)
4ms
The Incidence, Clinical Application and Prognostic Significance of MYD88 and CXCR4 Mutation in Chinese Patients with Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia (ASH 2023)
NGS was the most sensitive method for detecting CXCR4 mutation. MYD88 mutation had prognostic significance in BTKi-based therapy, while CXCR4 mutation indicated higher tumor burden and inferior survival in BTKi-based therapy.
Clinical
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
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MYD88 mutation • MYD88 L265P • CXCR4 mutation • MYD88 mutation + CXCR4 mutation • MYD88 L265P + CXCR4 mutation • MYD88 wild-type
4ms
A Phase 4, Observational Study Evaluating the Efficacy and Safety of the Bruton Tyrosine Kinase Inhibitor (BTKi) Zanubrutinib in Patients with Waldenström Macroglobulinemia (WM) (ASH 2023)
Background and Significance: Zanubrutinib, a next-generation, selective BTKi, is approved for treatment of WM based on data from the phase 3 ASPEN study (NCT03053440), in which zanubrutinib showed a favorable benefit-risk profile vs ibrutinib, a first-generation BTKi, in patients with symptomatic WM (Tam CS, et al. MRR, VGPR+ rate, and ORR will be presented with 95% CIs, and median DOR will be estimated with the Kaplan-Meier method. The study is currently open for enrollment.
Clinical • Observational data • P4 data
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 mutation • MYD88 L265P • MYD88 wild-type
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Imbruvica (ibrutinib) • Brukinsa (zanubrutinib)
4ms
Next-Generation Sequencing of Vitreoretinal Lymphoma by Vitreous Liquid Biopsy: Diagnostic Potential and Genotype/Phenotype Correlation. (PubMed, Invest Ophthalmol Vis Sci)
Overall, NGS of the vitreous demonstrated high sensitivity among conventional diagnostic tests. VRL and CNSL appeared to have both shared and distinct genetic variations, which may suggest site-specific variations from a common origin.
Journal • Liquid biopsy • Next-generation sequencing • Biopsy
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IGH (Immunoglobulin Heavy Locus) • ETV6 (ETS Variant Transcription Factor 6) • IL6 (Interleukin 6) • IL10 (Interleukin 10) • PIM1 (Pim-1 Proto-Oncogene) • IGLL5 (Immunoglobulin Lambda Like Polypeptide 5)
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MYD88 mutation • MYD88 L265P
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LymphoTrack® Dx IGH Assay • LymphoTrack® Dx IGK Assay
4ms
IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies. (PubMed, Front Immunol)
These data suggest that the anti-leukemic activity of IRAK-4 inhibition can be exploited in relapsed/refractory (R/R) AML/MDS. In this review article, we discuss the currently available pre-clinical and clinical data of emavusertib, a selective, orally bioavailable IRAK-4 inhibitor in the treatment of R/R B-cell lymphomas and myeloid malignancies.
Review • Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SF3B1 (Splicing Factor 3b Subunit 1) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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SF3B1 mutation • MYD88 L265P • U2AF1 mutation
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emavusertib (CA-4948)
4ms
Anterior segment involvement in vitreoretinal lymphoma: clinical manifestations, molecular findings and in vivo confocal microscopy. (PubMed, Br J Ophthalmol)
Anterior segment manifestations are often present in VRL and include dendritiform and dust-like keratic precipitates. IVCM in VRL can identify different patterns associated with keratic precipitates. MYD88 L265P mutation in the aqueous humour of VRL patients can also be found in eyes without significant anterior segment involvement.
Preclinical • Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 L265P
5ms
Clinical Characteristics, Treatment Approach and Long-Term Outcomes of 678 Patients with Symptomatic Waldenstrom's Macroglobulinemia: Comprehensive Insights from a Spanish Registry of IgM Gammapathies (ASH 2023)
The main first-line treatment regimens received were: chlorambucil (37%), dexamethasone, rituximab and cyclophosphamide (DRC)(21%), rituximab monotherapy (13%), bendamustine/rituximab (BR) (9.1%), Bruton tyrosine kinase (BTK) inhibitors (7%), and bortezomib, dexamethasone and rituximab (BDR) (5.5%). There were no significant differences in OS between different times of diagnosis. This Spanish registry for SWM contributes to advancing knowledge and the continual enhancement of treatment strategies for WM.
Clinical
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • PRAME (Preferentially Expressed Antigen In Melanoma)
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MYD88 L265P • CXCR4 mutation
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Rituxan (rituximab) • bortezomib • cyclophosphamide • bendamustine • Leukeran (chlorambucil)
5ms
Lymphoplasmacytic Lymphoma: An Atypical Presentation with IgG Monoclonal Gammopathy (ASH 2023)
He received one cycle of CyBorD (Cyclophosphamide, Bortezomib, Dexamethasone), followed by seven cycles of KCD (Carfilzomib, Cyclophosphamide, Dexamethasone) and Rituximab...The patient was treated with Acalabrutinib, and his anemia, epistaxis, and coagulopathy resolved...In contrast to our patient, who has LPL with IgG Monoclonal gammopathy, approximately 95 percent of LPL patients have IgM Monoclonal gammopathy, which corresponds with WM. As a result, clinicians should be on the lookout for LPL that lacks an IgM Monoclonal Paraprotein.
IO biomarker
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CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • CD38 (CD38 Molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • NCAM1 (Neural cell adhesion molecule 1) • CD5 (CD5 Molecule) • SDC1 (Syndecan 1) • MME (Membrane Metalloendopeptidase) • ITGAX (Integrin Subunit Alpha X) • FCER2 (Fc Fragment Of IgE Receptor II)
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CD20 positive • MYD88 mutation • MYD88 L265P • CXCR4 mutation • CD38 positive • SDC1 positive
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Rituxan (rituximab) • bortezomib • cyclophosphamide • Calquence (acalabrutinib) • carfilzomib
5ms
Trial in Progress: An Open-Label Expansion Trial Evaluating the Safety, PK/PD, and Clinical Activity of Emavusertib (CA-4948) + Ibrutinib in R/R Primary CNS Lymphoma (ASH 2023)
Key exclusion criteria: intraocular PCNSL without brain lesion or CSF involvement or significant co-morbidity. Key clinical assessments include brain imaging, CSF- and ocular examinations.
Clinical • PK/PD data • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • IRAK4 (Interleukin 1 Receptor Associated Kinase 4)
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MYD88 L265P
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Imbruvica (ibrutinib) • emavusertib (CA-4948)
5ms
Modified Staging System for Waldenström Macroglobulinemia (MSS-WM): A Multi-Institutional Externally Validated Prognostic Model for Active/Symptomatic Waldenström Macroglobulinemia (ASH 2023)
We also validated MSS-WM using competing risk analysis (p=0.001) and in the cohort of rituximab treated patients (p<0.0001)... Our proposed model, MSS-WM, is a simple, clinically useful, externally validated model that reliably risk stratifies previously untreated patients with active WM into four groups that have distinct outcomes based on the composite scores derived from the patients' age, serum albumin and serum LDH at diagnosis.
Clinical
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B2M (Beta-2-microglobulin)
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MYD88 L265P • MYD88 wild-type
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Rituxan (rituximab)
5ms
PIM1 Point Mutations Increase Migration of Diffuse Large B-Cell Lymphoma (DLBCL) Cells (ASH 2023)
PIM1 mutations did not affect the proliferation of DLBCL cells and did not increase resistance to doxorubicin, excluding the proliferation rate or treatment resistance as a cause of the poor prognosis associated with PIM1 mutations...Finally, in transwell assays, PIM1 mutant cells exhibited markedly increased migratory potential. Taken together, these studies indicate that PIM1 mutants are not likely associated with differential drug responses, but rather facilitate tumor dissemination and are thus associated with inferior prognosis in DLBCL patients harboring PIM1 mutations.
Tumor mutational burden
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TMB (Tumor Mutational Burden) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • IFNG (Interferon, gamma) • CD79B (CD79b Molecule) • STAT3 (Signal Transducer And Activator Of Transcription 3) • PIM1 (Pim-1 Proto-Oncogene) • IL15 (Interleukin 15)
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MYD88 mutation • MYD88 L265P • CD79B mutation • CD79B mutation • PIM1 mutation • MYD88 mutation + CD79B mutation
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doxorubicin hydrochloride
5ms
CD19-Targeting CAR T-Cell Therapy in Transformed Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma: A Descar-T and US Collaborative Study (ASH 2023)
We retrospectively identified patients with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in the French DESCAR-T registry (NCT04328298) and 2 US centers. This study shows a high efficacy of anti-CD19 CAR T-cell therapy in R/R tWM with no unexpected toxicity. Longer follow-up is needed to confirm the long-term efficacy of CAR T-cells in tWM.
CAR T-Cell Therapy • IO biomarker
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CXCR4 (Chemokine (C-X-C motif) receptor 4)
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MYD88 L265P • CXCR4 mutation • MYD88 L265P + CXCR4 mutation
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Yescarta (axicabtagene ciloleucel) • Kymriah (tisagenlecleucel-T)
5ms
Remodeling of the Immune Microenvironment By Oncogenic MYD88 Dictates Immunotherapy Responses across Indolent and Aggressive B-Cell Lymphomas (ASH 2023)
Accordingly, anti-CD40 therapy disrupted B/T-cell interactions and increased ibrutinib activity...These data highlight that a TP53-driven DP-LME may limit immunotherapy activity in DLBCL, providing a scientific explanation to the poor outcome of DLBCL patients with TP53 alterations to CD19-directed CAR T cells (Shouval-JCO-2021). Collectively, our study defines the cellular origins and the stepwise genetic alterations of indolent and aggressive lymphomas with MYD88L265P, dissects distinct immunological paths underlying progression driven by oncogenic MYD88, and builds proof-of-concept for advancing precision immunotherapy in B-cell lymphomas.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD8 (cluster of differentiation 8) • IL2RA (Interleukin 2 receptor, alpha) • IL10 (Interleukin 10) • FOXP3 (Forkhead Box P3) • PRDM1 (PR/SET Domain 1) • CD40LG (CD40 ligand) • CXCR3 (C-X-C Motif Chemokine Receptor 3)
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TP53 mutation • TP53 deletion • MYD88 mutation • MYD88 L265P • BCL2 expression
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Imbruvica (ibrutinib)
5ms
An In Vivo PiggyBac Insertional Mutagenesis Screen Reveals Oncogenic Lesions Cooperating with Myd88L265P (ASH 2023)
The formation of these complexes depended on active BTK, as treatment with the BTK inhibitor ibrutinib reduced complex formation to levels found in Cd79b WT lymphomas. Consequently, we investigated the effects of ibrutinib treatment in Cd79b-mutant and wildtype MCD DLBCL mouse models and found Cd79b-mutant lymphomas to be significantly more sensitive to ibrutinib treatment than their Cd79b WT counterparts.
Preclinical • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • ETV6 (ETS Variant Transcription Factor 6) • BCL2L1 (BCL2-like 1) • CD79B (CD79b Molecule) • PLCG2 (Phospholipase C Gamma 2) • SDC1 (Syndecan 1) • SYK (Spleen tyrosine kinase) • MALT1 (MALT1 Paracaspase) • PIM1 (Pim-1 Proto-Oncogene) • PRDM1 (PR/SET Domain 1) • TBL1XR1 (TBL1X Receptor 1)
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MYD88 mutation • BCL2 overexpression • MYD88 L265P • CD79B mutation • CD79B mutation • PLCG2 mutation • MYD88 overexpression
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Imbruvica (ibrutinib)
5ms
Polatuzumab Vedotin, Zanubrutinib and Rituximab Achieved Rapid and Deep Response in Previously Untreated Frail and Elderly Diffuse Large B-Cell Lymphoma Patients (ASH 2023)
R-miniCHOP, a reduced intensity regimen of R-CHOP, is currently the standard of care for this population, yet with limitation due to toxicities (Frédéric Peyrade et al., Lancet Oncol, 2011). Chemo-free regimens combining Bruton kinase inhibitors, rituximab and lenalidomide showed fewer toxicities, but compromised on efficacy in elderly DLBCL in multiple previous reports (Pengpeng Xu et al., Lancet Healthy Longev, 2022; Haiyan Yang et al., ASH 2022)... Based on these results in our study, ZPR regimen showed rapid and deep response in previously untreated frail and elderly DLBCL patients with manageable safety profiles. We registered and initiated a phase 2b trial (NCT05940064) to further evaluate the efficacy and safety of ZPR regimen as first-line treatment for this population. Ongoing treatment and follow up of these twelve patients will also be further updated.
Clinical
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 L265P
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Rituxan (rituximab) • lenalidomide • Brukinsa (zanubrutinib) • vincristine • Polivy (polatuzumab vedotin-piiq)
5ms
Whole Exome Sequencing Analysis of Diffuse Large B-Cell Lymphoma That Progressed to Central Nervous System (ASH 2023)
A total of 44 patients with DLBCL who developed sCNSL after receiving standard rituximab-containing chemotherapy between 2009 and 2020 were identified from five institutions... Our study confirmed that MCD was a major genetic subtype of DLBCL that developed sCNSL. We identified recurrently mutated genes that were common in both sCSNL and PCNSL but not in the general DLBCL cohort; these genes may be associated with CNS progression. Validation of our results and investigation of the functions of these genes will help to understand the mechanisms of CNS relapse and develop more accurate markers to predict sCNSL.
IO biomarker • Whole exome sequencing
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CD79B (CD79b Molecule) • MUC16 (Mucin 16, Cell Surface Associated) • PIM1 (Pim-1 Proto-Oncogene) • FAT4 (FAT Atypical Cadherin 4) • BTG2 (BTG Anti-Proliferation Factor 2)
|
MYD88 L265P • BCL2 expression • MYC expression • CD79B mutation
|
Rituxan (rituximab)
5ms
Ibrutinib and Venetoclax in Symptomatic, Treatment-Naive Patients with Waldenström Macroglobulinemia (ASH 2023)
In symptomatic, treatment-naive patients with WM, the combination of ibrutinib and venetoclax was shown to be highly effective with a VGPR rate of 42% and a 24-month PFS rate of 76%, despite stopping therapy early due to unexplained ventricular arrhythmia. VGPR attainment might predict longer PFS after EOT, and PFS was similar in patients who received <12 vs. ≥12 months of therapy.
Clinical • IO biomarker
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
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TP53 mutation • MYD88 L265P • CXCR4 mutation
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Venclexta (venetoclax) • Imbruvica (ibrutinib)
5ms
Ethnic Diversity in Presentation of Waldenström Macroglobulinaemia and IgM Mgcs in the United Kingdom- a Real-World Data Analysis (ASH 2023)
Analysis of the national registry for WM shows that ethnic minorities comprise 10% of WM/IgM MGCS, present with WM at a younger age, a lower M-protein and with a higher proportion of MYD88-wild type cases which may suggest different disease biology. There was no difference in overall survival in our cohort. Limitations include the retrospective analysis of real-world data and incomplete documentation of baseline data.
Clinical • Real-world evidence • Real-world
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CXCR4 (Chemokine (C-X-C motif) receptor 4)
|
MYD88 mutation • MYD88 L265P • CXCR4 mutation • MYD88 wild-type
5ms
Genetic Knockin Approaches to Reconstructing DLBCL-Subtypes from Human Germinal Center B-Cells (ASH 2023)
Previous approaches to model DLBCL starting from germinal center B-cells were based on lentiviral overexpression of mutant oncogenes. Thereby, tonsillar germinal center B-cells with lentiviral BCL2 and BCL6 overexpression did not form lymphomas in NSG mice, however, were permissive to malignant transformation by MYC. Building on this previous work, we propose an improved model for preclinical testing for genetically defined DLBCL subtypes.
IO biomarker
|
BCL2 (B-cell CLL/lymphoma 2) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • BCL6 (B-cell CLL/lymphoma 6) • CD79B (CD79b Molecule) • IL7R (Interleukin 7 Receptor) • CD40LG (CD40 ligand) • IL21 (Interleukin 21) • TSLP (Thymic Stromal Lymphopoietin)
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MYD88 L265P • CD79B mutation • BCL6 overexpression
5ms
Quantitative MYD88 L265P Analysis Represents a Powerful Tool for Assessing Disease Response and Evaluating Clinical Trial Performance in Waldenstrom's Macroglobulinemia (ASH 2023)
As such, we performed a comprehensive study of qMYD88 L265P response assessment utilizing BM and PB CD19-selected tissue across 5 prospective clinical studies in WM: Ixazomib, Dexamethasone and Rituximab (IDR; NCT02400437) Ibrutinib monotherapy (IBR; NCT02604511); Venetoclax monotherapy (VEN; NCT02677324); Ibrutinib plus Ulocuplomab (IBR/ULO; NCT03225716); and Ibrutinib plus Venetoclax (IBR/VEN; NCT04273139). In contrast, minimal changes in BM and PB MYD88 L265P ΔCt from baseline were observed at best response for most major responders on IBR or IBR/ULO, including individuals who achieved very good partial responses denoted by >90% decrease in IgM by IWWM-11 criteria. In this first prospective evaluation of BM and PB qMYD88 L265P response assessment, we show that both BM and PB L265P qMYD88 analysis can provide more accurate assessment of treatment related changes in disease burden over the current standard of IgM response assessment alone, and can be used to more robustly evaluate clinical trial performance by identifying treatments or regimens that produce more meaningful tumor reductions in WM patients.
Clinical
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CD20 (Membrane Spanning 4-Domains A1) • MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • SYK (Spleen tyrosine kinase)
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MYD88 mutation • MYD88 L265P
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Venclexta (venetoclax) • Imbruvica (ibrutinib) • Rituxan (rituximab) • Ninlaro (ixazomib)
5ms
Plasma Circulating Tumor DNA (ctDNA) as an Alternative to Tissue DNA for Genotyping of DLBCL: Results from the POLARIX Study (ASH 2023)
Introduction: In the POLARIX study (NCT03274492), polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL; Tilly et al. Our analyses demonstrated that the mutation landscape of ctDNA in DLBCL characterized by the AVENIO ctDNA NHL assay resembles that of tumor tissue determined by WES. Patients with molecular subtypes defined by WES or ctDNA had similar PFS outcomes. Overall, these findings support the use of plasma ctDNA as an alternative to tumor tissue for the genotyping of DLBCL.
IO biomarker • Circulating tumor DNA
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TP53 (Tumor protein P53) • BCL2 (B-cell CLL/lymphoma 2) • NOTCH1 (Notch 1) • BCL6 (B-cell CLL/lymphoma 6) • TET2 (Tet Methylcytosine Dioxygenase 2) • KMT2D (Lysine Methyltransferase 2D) • CD79B (CD79b Molecule) • NOTCH2 (Notch 2) • TNFAIP3 (TNF Alpha Induced Protein 3) • DCHS1 (Dachsous Cadherin-Related 1) • TP53BP1 (Tumor Protein P53 Binding Protein 1)
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TP53 mutation • NOTCH1 mutation • TET2 mutation • KMT2D mutation • EZH2 mutation • MYD88 L265P • CD79B mutation • BCL6 rearrangement • CD79B mutation • NOTCH2 mutation • BCL2 rearrangement • BCL6 translocation • MYD88 L265P + CD79B mutation • TP53BP1 mutation • BCL2 translocation
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Rituxan (rituximab) • doxorubicin hydrochloride • cyclophosphamide • vincristine • Polivy (polatuzumab vedotin-piiq)
5ms
Targeting MyD88: Therapeutic mechanisms and potential applications of the specific inhibitor ST2825. (PubMed, Inflamm Res)
Targeting MyD88 is a novel therapeutic strategy, and scientific research is presently focused on the development of MyD88 inhibitors. The peptidomimetic compound ST2825 is a widely studied small-molecule inhibitor of MyD88. Thus, ST2825 may be a potential therapeutic small-molecule agent for modulating host immune regulation in inflammatory diseases and inflammatory therapy.
Review • Journal
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 L265P
5ms
RITZ: Comparison Between Rituximab Plus Zanubrutinib Versus Rituximab Monotherapy in Untreated SMZL Patients (clinicaltrials.gov)
P3, N=120, Not yet recruiting, International Extranodal Lymphoma Study Group (IELSG) | Trial completion date: Sep 2028 --> Feb 2029 | Initiation date: Sep 2023 --> Feb 2024 | Trial primary completion date: Sep 2028 --> Feb 2029
Trial completion date • Trial initiation date • Trial primary completion date
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor) • CCND1 (Cyclin D1) • BCL6 (B-cell CLL/lymphoma 6) • IL2RA (Interleukin 2 receptor, alpha) • MME (Membrane Metalloendopeptidase) • ITGAE (Integrin Subunit Alpha E) • ISG20 (Interferon Stimulated Exonuclease Gene 20)
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MYD88 L265P • CCND1 expression • IL2RA expression
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Rituxan (rituximab) • Brukinsa (zanubrutinib)
6ms
Observational Study Evaluating the Efficacy and Safety of Zanubrutinib in Participants With Waldenström Macroglobulinemia (clinicaltrials.gov)
P=N/A, N=111, Recruiting, BeiGene | Not yet recruiting --> Recruiting | Initiation date: Sep 2023 --> Mar 2023
Enrollment open • Trial initiation date
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MYD88 (MYD88 Innate Immune Signal Transduction Adaptor)
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MYD88 mutation • MYD88 L265P • MYD88 wild-type
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Brukinsa (zanubrutinib)