CD79B mutation

In conclusion, our study highlights a high prevalence of MYD88 and CD79B mutations in PSDLBCL, identifying an aggressive MCD-like subtype with a distinct relapse pattern. This molecular subclassification can be helpful for both prognostic prediction and therapeutic strategy in patients with PSDLBCL.

Although the efficacy of carfilzomib was difficult to confirm due to its toxicity in our models, ibrutinib showed comparable efficacy to a standard combination of chemotherapy drugs. Together, our data provide a new culture method for IVLBCL PDX cells and a rationale for translating ibrutinib to clinical use in IVLBCL patients.

Eighteen patients with high MYC/BCL-2 expression responded better to zanubrutinib (ORR = 61 vs. 29%, p = 0.02). Our results support assessing CD79B mutations, co-expressor DLBCL, and TCL1A expression status to identify patients with DLBCL who will benefit from zanubrutinib.

P2, N=66, Recruiting, BeiGene | Trial primary completion date: Jun 2024 --> Dec 2024

In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable PFS and OS compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while in the non-MCD subtype, they exhibited significantly inferior OS. There was no significant disparity in PFS and OS of MYD88-CD79Bco-mut between the MCD and non-MCD subtypes. The presence of PIM1mut within the MYD88-CD79Bco-mut group correlated with better PFS, which may result from an intricate interplay of immune processes and tumor microenvironment alterations.

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.

We have reviewed the complex role of CD79a/CD79b in multiple aspects of normal B cell biology and how is the normal BCR signaling affected by lymphoid neoplasms associated CD79A/CD79B mutations. We have also summarized important unresolved questions and highlighted issues that remain to be explored for better understanding of CD79a/CD79b-mediated signal transduction and the eventual identification of additional therapeutically targetable BCR signaling vulnerabilities.

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.

The BTK inhibitor-mediated disruption of these signaling complexes translated into a selective ibrutinib sensitivity of lymphomas harboring combined Cd79b and Myd88 mutations. Altogether, this in-depth cross-species comparison provides a framework for the development of molecularly targeted therapeutic intervention strategies in DLBCL.

Background: TP53-mutated DLBCL may be refractory to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)...Of 7 pts, 5 pts received OR-CHOP, 2 OR-CHOP plus lenalidomide... These data supported that OR-CHOP-based regimens had favorable anti-tumor activity and manageable safety profile in pts with TP53-mutated DLBCL. BTKi related off-target AEs were rarely observed. More prospective studies are warranted to validate our findings.

To the best of our knowledge, this is the first study exploring the molecular genetics of bone marrow large B cell lymphoma with HLH. Our study suggesting bone marrow large B cell lymphoma with HLH showed frequent MYD88/CD79B and PD-L1 alterations. Our study provided clues for the pathogenesis of bone marrow large B cell lymphoma with HLH and identified potential druggable targets for future clinical trials.

Collectively, our results indicate combined modality therapy including rituximab-containing immunochemotherapy and consolidative breast RT is a promising approach for PB-DLBCL, while HD-MTX is useful for preventing CNS relapse.

PVRL, as well as secondary vitreoretinal lymphomas after PCNSL or extracerebral DLBCL, have high mutation frequencies in characteristically mutated genes in PCNSL or MCD/cluster 5 type DLBCL. Supporting diagnostics, mutation detection can also be performed on cell-free DNA from the vitreous supernatant.

Blood 2020, Varano et al. Nature 2017), which converge on a common phenotype and high-grade morphology (Figure 1B).

Introduction: In the POLARIX study, polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL; NCT03274492; Tilly et al. In this exploratory biomarker analysis, we recapitulated that pts with molecularly defined DLBCL subtypes, including EZB and MCD by LymphGen and DZsig+ by RNAseq, have poor outcomes with R-CHOP therapy. In pts with the EZB and MCD subtypes, Pola-R-CHP appeared to improve 2-year PFS compared with R-CHOP. Pts with GCB DLBCL who were DZsig+ significantly benefited from Pola-R-CHP vs R-CHOP.

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.

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.

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.

DLBCL NOS has a characteristic mutational profile that depends on the primary organ. In particular, the mutational signature of DLBCL in the breast and ileocecal area was heterogeneous compared with that of other DLBCL NOS. Further research is needed to determine whether primary DLBCL in the breast and ileocecal area can be classified as an independent subtype.

These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.

A prognostic risk scoring system was also established for PCNSL, which included Karnofsky performance status and six mutated genes (BRD4, EBF1, BTG1, CCND3, STAG2, and TMSB4X). Collectively, this study comprehensively reveals the genomic landscape of newly diagnosed Chinese PCNSLs, thereby enriching the present understanding of the genetic mechanisms of PCNSL.

Randomized trials incorporating polatuzumab vedotin, ibrutinib, or lenalidomide as part of initial therapy have shown persistent rates of CNS invasion...Dose-intense regimens like rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate, ifosfamide, etoposide, and cytarabine (R-CODOX-M/ IVAC)5 , intensified R-CHOP with etoposide (R-MegaCHOEP) or rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone with consolidation (R-ACVBP)5 include highdose cytarabine, ifosfamide, and methotrexate, and/or incorporate autologous stem cell transplantation...1). Acknowledgments Adam Olszewski is a Scholar in Clinical Research of The Leukemia and Lymphoma Society.

Genetic alterations in genes involved in immune escape (HLA, CD274/PDL1LG2) were predominantly unique in primary and relapse samples and thus considered late genetic events. Together, this study indicates that primary and relapsed LBCL-IP follow an early parallel evolutionary pattern where the CPC contains genetic alterations that support prolonged survival/proliferation and retention in a memory B-cell state, followed by germinal center re-entry, aSHM and immune escape.

Taken together, we refined existing Myd88 p.L252p and BCL2-driven MCD/C5 DLBCL mouse models by co-expressing the Cd79b p.Y195H mutation. Cd79b-mutant murine lymphomas exhibited increased BCR activation levels, resulting in an increased sensitivity towards BTK inhibition, when compared to Cd79b wt control tumors. These findings indicate that patients with CD79B ITAM mutations might be particularly sensitive to BTK inhibitor treatment.

In conclusion, we identified three molecular subtypes of DEL, unveiled distinct genetic, transcriptional, and microenvironmental properties, and highlighted epigenetic therapeutic approaches for targeting histone acetylation in DEL.

This is the first reporting molecular classification and their clinical significance in PCNS-DLBCL of Asian population. MCD subtype was prevalent but has no prognostic power in PCNS-DLBCL. Further larger study is needed.

P2, N=66, Recruiting, BeiGene | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Jun 2024

In patients with DEL, the overall response rate of R-EPOCH regimen was higher than that of RCHOP or RCHOP-like regimen (81.5% vs 63.4%, P=0.004) . DEL is a group of aggressive lymphomas with relatively poor PFS. The R-EPOCH regimen may improve the overall prognosis of patients.

We assessed whether high BCL2/MYC co-expression by RNA sequencing could identify a patient subset responsive to ibrutinib using baseline biopsies from the PHOENIX trial (NCT01855750), which evaluated the addition of ibrutinib to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-GCB DLBCL. Consequently, high BCL2/MYC co-expression identifies a subset of non-GCB DLBCL that may be preferentially responsive to ibrutinib and warrants further investigation. ClinicalTrials.gov NCT01855750.

Following standard first-line R-CHOP (or equivalent), patients must have received 2nd-line salvage therapy with or without autologous stem cell transplant (ASCT), and/or CAR-T therapy, unless ineligible for 2nd-line salvage, ASCT, or CAR-T. Exploratory endpoints include pharmacokinetic, biomarker assessments, and investigator-assessed ORR, DoR, PFS, and CR rate. Result s of this study will help to define the optimal dose and provide confirmatory efficacy and safety data of mivavotinib in patients with non-GCB DLBCL, including MYD88/CD79b-mutated DLBCL to guide further expansion in these biomarker-defined cohorts.

The different mutational patterns in different studies highlight the heterogeneity of PCNSL. However, existing research on the molecular genetics of PCNSL is still limited, and further research into PCNSL is required to clarify the genetic characteristics of PCNSL.

We explored the feasibility of using a combination of two common hotspot mutations in MYD88 and CD79B in PCNSL and PTL plasma samples to aid in diagnosis and disease monitoring. The data presented show that the value of ddPCR for hotspot mutations in plasma of PCNSL and PTL patients is limited.

Addition of ULK1 complex inhibitor (MRT68921) augmented the anti-tumor activity of Ibrutinib in HT, Oci-Ly1, Oci-Ly18 and SUDHL-6 GCB cell lines and activated caspase dependent apoptosis...Younes, A., et al., Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma...Davies, A., et al., Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol, 2019. 20(5): p. 649-662.

In the classical FUO cases with suspected malignant lymphoma, 57% and 35% had malignant lymphoma and IVLBCL, respectively. Compared to the classical diagnostic methods, liquid biopsy can be used to detect lymphoma-specific genetic mutations at an earlier stage, being clinically useful for the early diagnosis of difficult-to-diagnose malignant B-cell lymphomas.

Zanubrutinib (160 mg po bid) plus R-CHOP (ZR-CHOP) was administered in TN cohort, and Zanubrutinib (160 mg po bid) combined with investigator-determined conventional salvage chemotherapy (CSC, including ICE, DHAP, GDP, or GemOx, +/- rituximab) was administered in R/R cohort. CD79A/CD79B mutation was frequent in DLBCL patients, especially in R/R cases. Zanubrutinib combined with immunochemotherapy showed encouraging activity and acceptable tolerance in pts with CD79A/CD79B-mutant DLBCL. TP53 mutation seemed to be a detrimental factor.

Most patients (89.4%) received chemotherapy, the most common of which was CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like regimens. About 77.4% of patients received rituximab combined with chemotherapy...Combined with β2-microglobulin and ECOG score, it can be used to accurately predict the prognosis of PBL patients. For patients with a high risk of progression or relapse, we may need more active treatment options to improve the prognosis of patients.

Multivariate analysis showed that age above 76 years, advanced stage, higher incidence of central nervous system involvement, and hypoalbuminemia were independent factors for poor prognosis in CD5+ DLBCL patients. In summary, CD5+ DLBCL displays poor prognosis, distinctive clinicopathologic characteristics and predominant genetic features of activated B-cell-like and MCD subtypes with worse survival outcome.

Our results confirm the relevance of mutations in B-cell receptor/nuclear factor-κB signaling and immune escape pathways in IVLBCL and identify novel driver alterations. The similar mutational profile in tumors with extravascular dissemination suggests that these cases may also be considered in the spectrum of IVLBCL.

Alt i alt viser resultaterne, at den histologiske undertype er en vigtig prognostisk faktor for lymfomer i øjenregionen. Derudover fremhaever resultaterne vigtigheden af undersøgelsen af MYC/BCL2 faenotypen og implementeringen af MYD88 mutationsundersøgelsen i rutinediagnostikken af storcellede B-celle lymfomer i øjenregionen.