scholarly journals EBV-tissue positive primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity

Blood ◽  
2020 ◽  
Author(s):  
Maher K Gandhi ◽  
Thanh Hoang ◽  
Soi C Law ◽  
Sandra Brosda ◽  
Kacey O'Rourke ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Hla Class I ◽  
Cns Lymphoma ◽  
Copy Number Loss ◽  
Cell Of Origin ◽  
Systemic Spread

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression, e.g. post-transplant lymphoproliferative disorders (PTLD) or HIV (AIDS-related PCNSL). These cases are poorly characterized, have dismal outcome and are typically Epstein-Barr virus (EBV)-tissue positive. We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. 47 were EBV-tissue negative: 45 EBV(-) HIV(-) PCNSL, 2 EBV(-) HIV(+) PCNSL; and 44 were EBV-tissue positive: 23 EBV(+) HIV(+) PCNSL, 21 EBV(+) HIV(-) PCNSL. As with prior studies, EBV(-) HIV(-) PCNSL had frequent MYD88, CD79B and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin (COO) sub-type. In contrast, these mutations were absent in all EBV-tissue positive cases and ABC frequency was low. Furthermore, copy number loss in HLA-class I/II and antigen presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV(+) HIV(-) PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-tissue positive PCNSL in the immunosuppressed is immunobiologically distinct from EBV(-) HIV(-) PCNSL, and despite expressing an immunogenic virus retains the ability to present EBV-antigens. Results provide a framework for targeted treatment.

scholarly journals Gene expression and angiotropism in primary CNS lymphoma

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3716-3723 ◽  
Author(s):  
James L. Rubenstein ◽  
Jane Fridlyand ◽  
Arthur Shen ◽  
Ken Aldape ◽  
David Ginzinger ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Tumor Cells ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
High Expression ◽  
Cns Lymphoma ◽  
B Cell Lymphomas ◽  
Cns Lymphomas ◽  
Large B Cell

Primary CNS lymphoma is an aggressive form of non-Hodgkin lymphoma whose growth is restricted to the central nervous system. We used cDNA microarray analysis to compare the gene expression signature of primary CNS lymphomas with nodal large B-cell lymphomas. Here, we show that while individual cases of primary CNS lymphomas may be classified as germinal center B-cell, activated B-cell, or type 3 large B-cell lymphoma, brain lymphomas are distinguished from nodal large B-cell lymphomas by high expression of regulators of the unfolded protein response (UPR) signaling pathway, by the oncogenes c-Myc and Pim-1, and by distinct regulators of apoptosis. We demonstrate that interleukin-4 (IL-4) is expressed by tumor vasculature as well as by tumor cells in CNS lymphomas. We also identify high expression in CNS lymphomas of several IL-4-induced genes, including X-box binding protein 1 (XBP-1), a regulator of the UPR. In addition, we demonstrate expression of the activated form of STAT6, a mediator of IL-4 signaling, by tumor cells and tumor endothelia in CNS lymphomas. High expression of activated STAT6 in tumors was associated with short survival in an independent set of patients with primary CNS lymphoma who were treated with high-dose intravenous methotrexate therapy.

scholarly journals Clinical Features and Cell of Origin Subtyping Using Gene Expression Profiling in HIV-Negative Patients with Primary Central Nervous System Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2977-2977
Author(s):  
Talal Hilal ◽  
Alanna Maguire ◽  
Heidi E. Kosiorek ◽  
Lisa M. Rimsza ◽  
Allison C. Rosenthal
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Brain Lesion ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Germinal Center B Cell ◽  
Hiv Negative

Abstract Objectives: Primary central nervous system lymphoma (PCNSL) is a rare aggressive B-cell lymphoma, particularly in HIV-negative individuals, that represents a clinical challenge due to its location and lack of comprehensive molecular and biologic description. Histopathologic features are that of diffuse large B-cell lymphoma with expression of pan-B-cell markers as well as cell of origin (COO) germinal center B cell (GCB) and post-germinal center B cell (non-GCB) markers. Previous studies using immunohistochemistry (IHC) suggest that the majority of PCNSL cases are non-GCB. However, gene expression profiling has revealed non-GCB to be comprised of two distinct subtypes, namely activated B-cell (ABC) and unclassified (UNC) subtypes that are indistinguishable by IHC. To date COO testing using the highly accurate Lymph2Cx gene expression profiling assay has not been reported in PCNSL. Methods: IRB approval was obtained and HIV negative patients diagnosed with PCNSL, who had given informed consent and for whom archived tumor tissue was available for testing were identified. COO testing was performed using the Lymph2Cx NanoString assay on RNA extracted from formalin-fixed, paraffin embed tissues using our established laboratory protocols. Clinical data including patient demographics, lines of treatment and survival outcomes were collected and correlated with each other and Lymph2Cx COO results. Results: Thirty-two HIV-negative patients diagnosed between January 2005 and June 2015 were included. Median age was 61 years (30-82) and 53% were male. Radiographic information was available for 18/32 patients. Eleven (61%) had a single brain lesion at diagnosis, while 7 (39%) had >1 brain lesion. Lines of systemic therapy were 1 (91%) and 2 (9%). All patients received methotrexate-based induction therapy (44% received methotrexate, rituximab and temozolomide, 16% received single-agent methotrexate, 31% received methotrexate and rituximab, and 9% received the modified Bonn regimen; methotrexate and cytarabine-based induction). A total of 10 patients (31%) received high-dose chemotherapy and autologous stem cell transplant (ASCT) for consolidation. Of the 10 patients that underwent consolidation therapy, 9 underwent ASCT after first line induction, and 1 underwent ASCT after second line therapy. None of the patients received whole-brain radiation therapy. At a median follow-up of 29 months (range of 2-107) median event-free survival (EFS) was 16.3 months (95% CI, 8.8-45.7), and median overall survival (OS) was 41.2 months (95% CI, 28.5-NE). COO testing using the Lymph2Cx assay revealed that 91% (29/32) were ABC, 9% (3/32) were GCB, and none were UNC. Histopathology reports described COO using the Hans algorithm in 11 of the 32 cases. Of the 3 determined to be GCB on Lymph2Cx, 1 was denoted GCB by the Hans algorithm and 2 were not stained to determine COO. Of the 29 determined to be ABC by Lymph2Cx, 9 were denoted non-GCB and 1 was denoted GCB by the Hans algorithm, and 19 were not stained to determine COO. Conclusions: This series of HIV-negative patients with PCNSL showed median survival consistent with previous studies. In this first series using the Lymph2Cx assay, we confirmed that over 90% of PCNSLs are of ABC subtype, which concurs with previous reports that PCNSL tumors are predominately non-GCB by the Hans algorithm. These findings provide biological rationale forthat pharmacologic interventions targeting B-cell receptor signaling to be explored in clinical trials in the majority of patients with PCNSL. Figure. Figure. Disclosures Rimsza: NanoString: Other: Inventor on the patent for the Lymph2Cx assay.

Phase I Study of Dose-Adjusted-Teddi-R with Ibrutinib in Untreated and Relapsed/Refractory Primary CNS Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 472-472 ◽  
Author(s):  
Kieron Dunleavy ◽  
Catherine E. Lai ◽  
Mark Roschewski ◽  
Jennifer N Brudno ◽  
Brigitte Widemann ◽  
...  
Keyword(s):  
Protein Binding ◽  
B Cell ◽  
Brain Mri ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Csf Penetration ◽  
Mixed Response ◽  
Therapeutic Principles

Abstract Introduction: Primary central nervous system lymphoma (PCNSL) is a rare type of diffuse large B-cell lymphoma (DLBCL). It closely resembles activated B-cell (ABC) DLBCL and most cases have B cell receptor (BCR) and MyD88 mutations. Ibrutinib is an inhibitor of BTK that targets BCR signaling and is active in patients with relapsed/refractory (R/R) ABC DLBCL. Methods: Ibrutinib was incorporated into a novel regimen called DA-TEDDI-R (temozolomide, etoposide, doxil, dexamethasone, ibrutinib and rituximab) (with intraventricular cytarabine). DA-TEDDI-R was designed around therapeutic principles for systemic DLBCL and CNS penetration. Methotrexate was excluded due to potential antagonism with ibrutinib based on preliminary in vitro experiments. Untreated or R/R PCNSL patients were eligible and received ibrutinib in cohorts (560-1120 mg/day PO) for 14-days in a "window" prior to cycle 1 of DA-TEDDI-R (with pre and post-brain MRI/FDG-PET), followed by DA-TEDDI-R with ibrutinib (days 1-10) q21 days x 6. Plasma and CSF PKs of ibrutinib and its metabolite PCI-45227 were analyzed. CSF penetration (AUCCSF: AUCPLASMA) was corrected for human plasma protein binding: parent: 97.3%, metabolite: 91%. CSF PKs of TEDDI drugs and molecular analysis of FFPE biopsies are ongoing. Results: Eleven patients have enrolled; 6 were R/R (median 3 (1-5) prior treatments) and 5 were previously untreated. Eleven completed the ibrutinib window and 5 patients completed and 2 remain on DA-TEDDI-R; Ibrutinib dosing was 560 mg in patients 1-6; 700 mg in patients 7-10; and 840 mg in patient 11. No patient had dose limiting toxicity determined on cycle 1 of DA-TEDDI-R. There were 3 on-study deaths: from progressive disease, infection and ventricular arrhythmia. Ibrutinib PK was completed in patients 1-10 (Table). When corrected for protein binding, CSF penetration was 21.4-100% for ibrutinib and 48-120% for its metabolite. CSF concentrations > IC50were maintained for a median of 4 hours and 8.5 hours at the 560 mg and 700 mg doses, respectively. With ibrutinib alone, 7 of 8 evaluable patients achieved partial responses, and 1 patient had a mixed response. After DA-TEDDI-R, all 5 patients achieved complete remission of which 4 (all R/R) are in remission at 1+, 2+, 3+, and 6+ months, and 1 (previously untreated) patient relapsed at 3 months. Conclusions: Ibrutinib is active in PCNSL and achieves meaningful CSF concentrations. DA-TEDDI-R is a novel treatment for PCNSL and leverages molecular and therapeutic principles developed for the curative treatment of ABC DLBCL. Accrual continues. Table. Plasma Ibrutinib PK CSF Ibrutinib PK CSF penetration Hours above IC50(0.5nM) Dose 560 mg Cmax(nM) Tmax(h) AUC0-10 (nM•h) T½(h) Cmax(nM) Tmax(h) AUC0-last (nM•h) AUCCSF : AUCPlasma (%) AUCCSF :AUCPlasmaCorrected (%) Plasma CSF 1 502 1 1232 10.2 1.99 2 7.7 (10h) 0.6 23.7 24 4 2 145 2 471 4.6 0.69 2 2.4 (6h) 0.5 21.4 24 2 3 77 2 347 3.1 1.28 2 4.4(6hr) 1.3 55.8 24 4 4 72 1 202 2.6 1.54 4 5.5 (10hr) 2.7 100 24 8 5 162 2 624 8.5 2.0 2 9.2 (10hr) 1.5 54.9 24 10 6 99 1 404 6.3 0.71 2 3.4 (4hr) 1.2 45 24 4 Median 122 1.5 437 5.5 1.4 2 5 1.3 50 24 4 Range 75-502 1-2 202-1232 2.6-10.2 0.7-2 2-4 2.4 9.2 21.4-100 24 2-10 Dose 700mg 7 581 1 2340 5.3 11.1 2 48.6 (24) 1.7 (10) 63 (10) 24 10 8 411 2 1565 2.4 1.63 2 11.9 (10) 0.8 28.1 10 10 9 164 2 865 3.8 0.69 4 3.9(10) 0.45 16.7 24 3 10 577 2 1648 5.4 2.36 2 11.0(10) 0.67 24.8 24 7 Median 494 2 1606 4.6 1.98 2 11.5(10) 0.74 26.5 24 8.5 Range 164-581 1-2 865-2340 2.4-5.4 0.69-11.1 2-4 3.9-48.6 0.45-1.7 16.7-63 10-24 3-10 Disclosures Staudt: Pharmacyclics LLC, an AbbVie Company: Patents & Royalties, Research Funding; NIH: Patents & Royalties.

scholarly journals Pathway analysis of primary central nervous system lymphoma

Blood ◽  
2008 ◽  
Vol 111 (6) ◽  
pp. 3200-3210 ◽  
Author(s):  
Han W. Tun ◽  
David Personett ◽  
Karen A. Baskerville ◽  
David M. Menke ◽  
Kurt A. Jaeckle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Pathway Analysis ◽  
Metastatic Cancer ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Significant Differential Expression ◽  
A Genome

Abstract Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true “CNS signature” because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

First Results of the Acsé Pembrolizumab Phase II in the Primary CNS Lymphoma (PCNSL) Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-16
Author(s):  
Khe Hoang-Xuan ◽  
Roch Houot ◽  
Carole Soussain ◽  
Marie Blonski ◽  
Anna Schmitt ◽  
...  
Keyword(s):  
Objective Response ◽  
Primary Cns Lymphoma ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Moderate Activity ◽  
Multicentric Study ◽  
First Results ◽  
Duration Of Response

Background: AcSé Pembrolizumab is a Phase 2, open-label, single-arm, multi-cohort, multicentric study investigating the efficacy and safety of pembrolizumab monotherapy in patients with advanced rare cancers (NCT03012620). Here, we report the first results of Pembrolizumab in the cohort of Primary Central Nervous System Lymphoma (PCNSL). Methods: Main inclusion criteria were: relapsed or refractory PCNSL after one or several lines of treatment including high dose Methotrexate based chemotherapy, pathologically confirmed diffuse large B cell lymphoma, age>18, HIV negative, concurrent steroid medication at a dose no greater than prednisone 20 mg/day or equivalent. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycles for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to IPCG at 84 day after the start of treatment. Secondary endpoints included best response (ORR), duration of response, progression-free survival (PFS), overall survival (OS), and safety. Analysis used all enrolled patients. Results: 50 patients suffering from PCNSL, including 9 primary vitreoretinal lymphoma (PVRL) were included from July, 2017 to October, 2019. Median age was 72 years (range: 43 to 83), Median PS (ECOG) was 1 (range 0-1). The median number of cycles was 4 (range 1-35). At 84 days from start of treatment, 6 patients responded (4 CR+2PR). Overall, 3 patients whose response was not assessed were considered as failures, and the rates of ORR (CR+PR), stable disease (SD), progressive disease (PD) were 26% (13/50, 8 CR + 5 PR), 10% (5/50), 58% (29/50), respectively. ORR was 29% (12/41) and 11% (1/9) in primary cerebral lymphoma and PVRL respectively. After a median follow-up of 6.7 months (range 0.2-27.4), median PFS was 2.6 months, with 6-month PFS of 29.8% and 6-month OS of 60.4%. In responders, median duration of response was estimated at 10 months (95%CI, 2.7 to 12.5). Grade III and IV toxicities related to the drug were observed in 4 patients (8%) and one patient (2%) respectively. No related toxic death was reported. Conclusion: Pembrolizumab shows moderate activity in relapsed/ refractory PCNSL with acceptable toxicity, supporting further studies evaluating its use in combination therapies. Disclosures Hoang-Xuan: BTG: Consultancy, Research Funding. Houot:Bristol-Myers Squibb: Honoraria; MSD: Honoraria; Gilead: Honoraria; Kite: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Ahle:Roche: Honoraria; Novartis: Honoraria; Biogene: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria. Bories:Abbvie: Consultancy; Celgen: Consultancy; Gilead: Consultancy; BMS: Honoraria; Novartis: Honoraria. Houillier:BTG: Consultancy.

scholarly journals P.108 Diffuse large B-cell Lymphoma secondary to iatrogenic immunosuppression with unusual MRI findings and literature review

2016 ◽  
Vol 43 (S2) ◽  
pp. S45-S45 ◽  
Author(s):  
AH Naeem ◽  
MD Staudt ◽  
B Wang ◽  
D Lee ◽  
A Parrent
Keyword(s):  
Literature Review ◽  
B Cell ◽  
Cell Lymphoma ◽  
Immunosuppressive Agents ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Mri Findings ◽  
Axial Mass ◽  
Large B Cell

Background: Immunosuppressive therapy is a risk factor for lymphoproliferative disorders. We present a case of primary CNS B-cell lymphoma in the setting of iatrogenic immunosuppression from azathioprine usage. A literature review is provided. Methods: Case report Results: 64-year-old male presents with several weeks of cognitive decline, impaired speech, and headache with a history of ulcerative colitis (on azathioprine and 5-ASA) with no radiological evidence of systemic malignancy. MR showed left frontal extra-axial mass (4.0 x 2.4 x 4.0 cm) with heterogeneous enhancement of a solid component with local dural thickening. The enhancing mass had solid and cystic components. Radiological differential included dural metastasis, atypical meningioma or unusual intra-axial mass including GBM with some dural involvement. He underwent surgical resection, which showed a primary CNS lymphoma, diffuse large B-cell, CD 20 + and EBV +. Post-operatively his cognition improved. Azathioprine was stopped and 5-ASA was increased. He proceeded with MPVC (methotrexate, procarbazine, vincristine, and cytarabine) chemotherapy. Conclusions: Our case shows isolated extra-nodal CNS manifestation of lymphoma in the context of immunosuppressive medications with strikingly atypical MR findings leading to a pre-operative diagnostic dilemma. Treatment is challenging and needs to be individually tailored due to a need for stopping immunosuppressive agents in conjunction with CNS lymphoma treatment.

Cell-of-Origin in Diffuse Large B-Cell Lymphoma: Are the Assays Ready for the Clinic?

2015 ◽  
pp. e458-e466 ◽  
Author(s):  
David W. Scott
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Practical Implementation ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma worldwide and consists of a heterogeneous group of cancers classified together on the basis of shared morphology, immunophenotype, and aggressive clinical behavior. It is now recognized that this malignancy comprises at least two distinct molecular subtypes identified by gene expression profiling: the activated B-cell-like (ABC) and the germinal center B-cell-like (GCB) groups—the cell-of-origin (COO) classification. These two groups have different genetic mutation landscapes, pathobiology, and outcomes following treatment. Evidence is accumulating that novel agents have selective activity in one or the other COO group, making COO a predictive biomarker. Thus, there is now a pressing need for accurate and robust methods to assign COO, to support clinical trials, and ultimately guide treatment decisions for patients. The “gold standard” methods for COO are based on gene expression profiling (GEP) of RNA from fresh frozen tissue using microarray technology, which is an impractical solution when formalin-fixed paraffin-embedded tissue (FFPET) biopsies are the standard diagnostic material. This review outlines the history of the COO classification before examining the practical implementation of COO assays applicable to FFPET biopsies. The immunohistochemistry (IHC)-based algorithms and gene expression–based assays suitable for the highly degraded RNA from FFPET are discussed. Finally, the technical and practical challenges that still need to be addressed are outlined before robust gene expression–based assays are used in the routine management of patients with DLBCL.

No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3615-3615
Author(s):  
Gonzalo Gutiérrez-García ◽  
Luis Colomo ◽  
Neus Villamor ◽  
Leonor Arenillas ◽  
Antonio Martínez ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Primary Cns Lymphoma ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous category of lymphoid tumors that comprises different clinical forms not fully recognized in the WHO classification. In this regard, extranodal (EN) DLBCLs have particular clinicobiological features and outcome, sometimes related to the specific site where the lymphoma arises. Nowadays, rituximab plus chemotherapy (CT) is the gold-standard in the treatment of DLBCL. However, the superiority of rituximab-CT (R-CT) over CT alone has not been addressed for all the clinical subsets of the disease and, in fact, the clinical role of the new therapies might be different for primary nodal or EN DLBCLs. The aim of this study was to assess the impact of rituximab in patients suffering from nodal or EN DLBCL. Two-hundred and thirty non-immunocompromised patients (112M/118F; median age, 61 years) diagnosed with CD20+DLBCL in a single institution between 1997 and 2006 (five years before and after establishing R-CT as the standard treatment in DLBCL) and treated with adriamycin-containing regimens were the subject of the present study. The series included 148 primary nodal and 82 EN DLBCL. Patients with primary CNS lymphoma were excluded and lymphomas arising at Waldeyer ring were considered as nodal DLBCL. The main EN sites were GI (n=26), bone (n=13), soft tissue (n=13), lung/pleura (n=9), liver (n=9), and other (n=12). Main clinico-biological and evolutive variables were analyzed. One hundred nineteen patients received only CT and 111 R-CT. Eighty-seven cases with available information were assigned to germinal center B-cell-like (GCB) (41%) or non-GCB (59%) groups according to the Hans method (Blood2004;103:275–82) based on CD10, BCL6 and MUM1 expression. Main initial features, including the primary nodal or EN origin, international prognostic index (IPI), and GCB/non-GCB categories were similar for CT and R-CT groups. No correlation was observed between the GCB/non-GCB groups and the primary site of the tumor, although nodal lymphomas more frequently expressed MUM1 than EN (69% vs. 31%, respectively; p=0.01). CR rate and 5-year overall survival (OS) according to the treatment arm (CT vs. R-CT) is detailed for the whole series and for the nodal and EN groups in the table and OS curves depicted in the figure. In the whole series, variables predicting poor OS in the multivariate analysis were high-risk IPI (RR 2.5; p<0.001), primary nodal involvement (RR 1.6; p=0.04) and no R-CT treatment (RR 1.9; p=0.002). In the nodal group, IPI and no R-CT maintained the prognostic value, whereas in the primary EN only IPI predicted OS. Moreover, no difference in OS was observed according to the nodal or EN origin in those patients receiving R-CT. Biological subtypes GCB vs. non-GCB did not add predictive information neither in the whole series nor in the nodal or EN groups. In conclusion, patients with primary EN DLBCL seem to have little benefit from the use of R-CT. Nevertheless, this intriguing observation should be confirmed in further prospective studies. Complete response CR (%) 5-years OS (%) CT R-CT CT R-CT *p<0.002 R-CT vs. CT All cases (n=230) 59 79* 46 70* Primary nodal (n=148) 54 78* 34 71* Primary extranodal (n=82) 68 78 70 69 Figure Figure

scholarly journals Mutated MYD88 Regulates HCK Pro-Survival Signaling through JunB in MYD88 Mutated B-Lymphoma Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3778-3778
Author(s):  
Xia Liu ◽  
Jiaji G Chen ◽  
Manit Munshi ◽  
Lian Xu ◽  
Amanda Kofides ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
B Cell ◽  
Tyrosine Kinases ◽  
Research Funding ◽  
Primary Cns Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
Lymphoma Cells ◽  
Cell Commitment ◽  
Myd88 Signaling

Hematopoietic cell kinase (HCK) is a member of the SRC family tyrosine kinases (SFKs) that is down-regulated in later stages of B-cell ontogeny. In MYD88 mutated B-cell lymphomas, HCK is aberrantly over-expressed and is activated and triggers multiple growth and survival pathways including BTK, PI3Kδ/AKT and ERK1/2 which are essential to tumor cell survival. Ibrutinib, a pleiotropic inhibitor of BTK, that produces remarkable responses in MYD88 mutated WM, ABC-DLBCL, and Primary CNS Lymphoma was found also potently inhibits HCK. Mutations that abolish ibrutinib-HCK binding greatly diminish anti-tumor activity in MYD88 mutated lymphoma cells, highlighting the importance of HCK as an essential target in MYD88 driven diseases. To clarify the transcriptional regulation of HCK in MYD88 mutated malignancies, we performed promoter binding TF profiling, PROMO weighted transcription factor (TF) consensus binding analysis, and chromatin immuno-precipitation (ChIP) studies. We identified PAX5, and mutated MYD88 downstream signaling mediators, STAT3, AP-1 and NF-kB as important drivers of HCK transcription. Knockdown of PAX5, a crucial regulatory factor required for B-cell commitment and identity, abrogated HCK transcription in MYD88 mutated lymphoma cells. Deletion of STAT3, AP-1 or NF-kB binding sites greatly reduced corresponding TFs binding and HCK promoter activity, indicating the importance of MYD88 directed signaling in the regulation of HCK transcription. Among AP-1 complex components, JunB but not c-Jun showed greatest relevance to TLR/MYD88 signaling and regulation of HCK transcription. Since STAT3 and NF-kB are known downstream mediators of mutated MYD88 signaling, we focused on the function of JunB. JunB phosphorylation increased following MYD88 pathway activation through TLR4 (with LPS-EB) or TLR9 (with ODN-2006), as well as lentiviral mediated expression of mutated MYD88 (L265P) but not wild type MYD88 (MYD88-WT) at Thr102 and Thr104 in either MYD88 mutated BCWM.1 cells or MYD88-WT Ramos cells. Conversely, c-Jun phosphorylation was not impacted by either intervention. Knockdown of MYD88 in BCWM.1 WM cells also reduced the phosphorylation of JunB, while c-Jun phosphorylation showed modest increase. Moreover, knockdown of JunB reduced HCK protein levels in MYD88 mutated WM and ABC-DLBCL cells. These data demonstrate that JunB is an important mediator of mutated MYD88 signaling among AP1 complex members and is directly involved in the regulation of HCK expression in MYD88 mutated B-cell lymphoma. The findings provide new insights into the transcriptional regulation of HCK by MYD88 driven TFs, and opportunities for further advancing targeted therapeutics in MYD88 driven B-cell malignancies. Disclosures Hunter: Janssen: Consultancy. Castillo:TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Research Funding. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

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