scholarly journals Loss of NR4A1 Accelerates the Development of Aggressive Lymphomas in Myc Induced Cancerogenesis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2444-2444
Author(s):  
Kerstin Wenzl ◽  
Katharina Troppan ◽  
Beata Pursche ◽  
Marco Bischof ◽  
Christine Beham-Schmid ◽  
...  
Keyword(s):  
B Cell ◽  
Median Survival ◽  
Conflicts Of Interest ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
Cancer Specific Survival ◽  
Oncogenic Potential ◽  
Aggressive Lymphomas ◽  
Significant Difference ◽  
The Impact

Abstract Introduction and Aim: We recently described a reduced NR4A1 and NR4A3 expression chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma compared to normal controls. Our survival analysis of aggressive lymphomas revealed that low NR4A1 expression was associated with poor cancer specific survival. Over-expression of NR4A1 in lymphoma cell lines led to a significantly higher proportion of lymphoma cells undergoing apoptosis and abrogated tumor growth in xenografts1. The aim of this study is to define the role of NR4A1 as a tumor suppressor in the development of lymphoid malignancies in vivo. Methods: To identify, whether the loss of NR4A1 has an impact in Myc driven lymphomagenesis we crossed EµMyc mice with NR4A1-/- mice and performed phenotypical analysis including measurement of tumor development, survival and immunophenotypic determination of the newly developed lymphomas by FACS analysis. To further investigate the impact of NR4A1 loss on the oncogenic potential of EµMyc lymphoma cells we isolated viable tumor cells (B220+ and 7AAD-) and cultured them for 72h with or without lipopolysaccharide (LPS) and determined the number of viable cells and their viability (B220 and 7AAD-staining by flow cytometry analysis) after 24h, 48h and 72h. Finally, expression levels of NR4A1, NR4A3 and Myc with or without NR4A1 loss were evaluated by using RT-qPCR. Results: EµMyc mice with NR4A1 loss (EµMyc NR4A1-/-, n=46) developed visible tumors significantly faster compared to EµMyc mice with NR4A1 (EµMyc NR4A1+/+, n=75) (median = 44 days for EµMyc NR4A1 -/- vs. 107 days for EµMyc NR4A1+/+; p<0.001). Additionally, EµMyc NR4A1-/- mice showed a significantly shorter life span (median survival = 77 days) compared to EµMyc NR4A1 +/+ mice (median survival = 156 days; p<0.001). By comparing the immunophenotype of the newly developed lymphoma between the two groups (EµMyc NR4A1+/+, n=17 and EµMyc NR4A1 /- , n=19), no significant difference was observed. Interestingly, EµMyc NR4A1-/- mice showed an increased frequency of strong CD93 expression (10 of 18, respectively, vs. 2 of 17 EµMyc NR4A1 +/+ mice, p=0.004). Since most of the EµMyc NR4A1-/- lymphoma were IgM negative (7 of 10) it might be speculated that NR4A1 loss leads to a more immature phenotype of the lymphoma. The number of viable B220+ lymphoma cells isolated from EµMyc NR4A1-/- mice was higher compared to B220+ lymphoma cells isolated from EµMyc NR4A1+/+ mice after 72h in culture with or without LPS (p=0.056; p=0,052). This was accompagnied by a higher in vitro proliferation rate as demonstrated by a higher percentage of BrdU positive cells of the EµMyc NR4A1-/- mice compared to B220+ EµMyc NR4A1+/+ cells with and without LPS stimulation (p= 0,064, p=0,038). Interestingly, we detected a 12 fold higher NR4A3 mRNA expression (p=0,038) in EµMyc NR4A1-/- tumors compared to EµMyc NR4A1+/+. Conclusion: Our data demonstrate that NR4A1 possesses tumor suppressive properties and that loss of NR4A1 accelerates Myc driven lymphomagenesis. Furthermore, this study indicates that deletion of NR4A1 confers a more aggressive behavior and increases the oncogenic potential of EµMyc driven lymphoma cells. 1. Deutsch AJ, Rinner B, Wenzl K, et al. NR4A1-mediated apoptosis suppresses lymphomagenesis and is associated with a favorable cancer specific survival in patients with aggressive B-cell lymphomas. Blood. 2014. Disclosures No relevant conflicts of interest to declare.

Comparison Between CD20-Negative and CD20-Positive Diffuse Large B Cell Lymphoma; Characteristics and Clinical Outcome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4891-4891
Author(s):  
Jungmin Jo ◽  
Changhoon Yoo ◽  
Yongchel Ahn ◽  
Seong Joon Park ◽  
Shin Kim ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Risk Group ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Significant Difference ◽  
Large B Cell

Abstract Abstract 4891 Background CD20 is a non-glycosylated phosphoprotein expressed on the surface of all mature B-cells. CD20 is expressed on all stages of B cell development except the first and last. However, complete lack of CD20 expression occurred in a few cases without previous rituximab (R-) treatment. The immunohistochemostry (IHC) studies which we used were not perfect for confirmation of expression. However, we intended to investigate characteristics and clinical outcome of CD20-negative diffuse large B-cell lymphoma (DLBCL), not detected with usual method, and to compare with CD20-positive. Methods The records of Non-Hodgkin's Lymphoma patient registry were reviewed in Asan Medical Center. Between September 2003 and February 2009, a total of 407 patients were diagnosed DLBCL and 16 patients (3.9%) out of 407 confirmed CD20-negative DLBCL by IHC. The rest of patients (n=391) were CD20-positive and unconfirmed cases were excluded. Retrospective analysis of complete response (CR), disease-free survival (DFS), and overall survival (OS) was performed. Results The median age was 60.5 years old (range 31–81) in CD20-negative patients. Ten patients were males. The Ann Arbor stage was I in 3 patients, II in 3 patients, and III or IV in 10. Six patients were low risk group, 7 patients in intermediate, and 3 in high risk group according to international prognostic index (IPI). Most of patients (62.5%) received cyclophosphamide, doxorubicin, vincristin, and prednisone (CHOP) chemotherapy in CD20-negative and 295 patients (75.4%) with R-CHOP in CD20-positive DLBCL. The Baseline characteristics was not different in both groups except Hans classifier (p=0.02). With a median follow-up time of 32.3 months (range 0.5–83.4), the CR rate was 73.5%, the 3-year OS was 69.5%, and 3-year DFS 74.2% in all patients. CD20-positive and CD20 negative groups had a CR rate of 73.7%, 68.8% (p=0.146), respectively, a 3-year OS of 70.7%, 40.0% (p=0.003), a 3-year DFS of 75.4%, 44.6% (p< 0.001), respectively. The 3-year OS and DFS also had significant difference with adjusted IPI (p<0.001, respectively). Conclusions CD20-negaive DLBLC was not infrequently with usual IHC method (around 4%). The survival outcome was poor compared with CD20-positive DLBLC because of high relapse rate. It was caused without rituximab treatment in CD20-negative. Development of novel target agents like rituximab should be explored to improve outcome and maintain the CR status of CD20-negative DLBCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prediction and Optimization of the Therapeutic Effect of mTOR Inhibitors in Aggressive B-Cell Lymphomas

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4441-4441
Author(s):  
Chengfeng Bi ◽  
Xiaoyan Zhang ◽  
Zhang Xuan ◽  
Wing C Chan ◽  
Timothy McKeithan ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Mtor Inhibitors ◽  
B Cell Lymphoma ◽  
Mechanism Study ◽  
B Cell Lymphomas ◽  
Lymphoma Cells ◽  
Induced Apoptosis ◽  
Aggressive B Cell Lymphoma

Abstract Mechanistic target of rapamycin complex 1 (mTORC1) is a central integrator of nutrient and growth factor inputs that controls cell growth in all eukaryotes. Rapamycin and its analogs (rapalogs) have been approved for the treatment of relapsed mantle cell lymphoma. A large proportion of aggressive B-cell lymphoma patients, however, respond poorly to rapalogs. The second generation of mTOR inhibitors function as ATP-competitive inhibitors (TORi), directly targeting the mTOR catalytic site. TORis have been proven to be more effective than rapalogs in cancer treatment. However, the mechanism underlying the cytotoxic effect of TORis in aggressive B-cell lymphomas remains unclear. In this study, we demonstrated that TORi-induced apoptosis is predominantly dependent on loss of mTORC1-mediated 4EBP phosphorylation. Knocking out Rictor, a key component of mTORC2, or inhibiting p70S6K has little effect on TORi-induced apoptosis. In contrast, increasing the EIF4E:4EBP ratio by either overexpressing EIF4E or knocking out 4EBP1/2 protected lymphoma cells from TORi-induced cytotoxicity. Furthermore, down-regulation of MCL1 and BCL-XL expression plays an important role in TORi-induced apoptosis whereas BCL-2, in cells with high expression, confers resistance to TORi treatment. Based on the mechanism study, we demonstrated that BH3 profiling, primarily NOXA and HRK stimulation, can effectively predict the cytotoxicity of the TORi in lymphoma cells. Also, in combination with pro-apoptotic drugs, especially BCL-2 inhibitors, the TORi exerted powerful anti-tumor effects both in vitro and in vivo. Taken together, this study provides mechanistic insight in TORi treatment in aggressive B-cell lymphoma and identified a mean to predict and improve its effectiveness clinically. Disclosures No relevant conflicts of interest to declare.

Toxicity and tolerability of DA-EPOCH-R for aggressive lymphomas in the elderly: A retrospective cohort study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20030-e20030
Author(s):  
Shanley Banaag ◽  
Manish Singla ◽  
Mary Kwok ◽  
Dechang Chen
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
Dose Level ◽  
Cell Lymphoma ◽  
Age Groups ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Aggressive Lymphomas ◽  
Significant Difference ◽  
Large B Cell

e20030 Background: There remain concerns regarding appropriate patient selection for dose-adjusted EPOCH-R in the treatment of lymphoma, particularly diffuse large B-cell lymphoma, where efficacy is comparable to R-CHOP but significantly more toxic. As the average age at diagnosis of DLBCL is between 60-70 years old, ability of elderly patients to complete and tolerate therapy is critical in treatment decision. Our aim was to investigate the differences in tolerability and toxicity of DA-EPOCH-R among different age groups. Methods: We conducted a retrospective review of patients treated with DA-EPOCH-R at Walter Reed National Military Medical Center. The institutional pharmacy database was queried to identify adult patients diagnosed with lymphoma and treated with DA-EPOCH-R from July 2005 through March 2018. Chart reviews were performed and information on dose reductions, delays, and adverse treatment effects were recorded and stratified between patients aged < 45 years, 45-59, 60-74 and ≥75 years. Results: 70 patients were identified for review. Average age was 55.8 +/- 15.5 years; 49% of patients were ≥ 60 years, including 9 patients who were ≥ 75 years. Diagnoses included diffuse large B-cell lymphoma (n = 46), transformed lymphoma (n = 12), primary mediastinal B-cell lymphoma (n = 4), Burkitt lymphoma (n = 3), T-cell lymphoma (n = 3), and high-grade B-cell lymphoma, NOS (n = 2). There was no significant difference in the median number of cycles completed between the age groups ( p= 0.2540). However, there was a significant difference in the maximum dose level achieved ( p= 0.0003). The median dose level achieved was 3.4 for patients age < 45 (range 1-5), 2.5 for patients age 45-59 (range 1-5), 1.88 for patients age 60-74 (range 1-4), and 0.88 for patients age ≥75 (range -2 to 2). Patients greater than 60 years were more likely to have any dose delay ( p= 0.001), more total dose delays (p = 0.004), and to experience gastrointestinal (GI) toxicities ( p= 0.014). There were no significant differences seen in peripheral neuropathies ( p= 0.425) nor hospitalizations ( p= 0.242). One patient passed away due to toxicity. Conclusions: This study demonstrates the use of DA-EPOCH-R in a real-world setting for the treatment of aggressive lymphomas. Our data suggest that elderly patients can complete all planned courses of DA-EPOCH-R but do not reach the dose intensity achieved by younger patients. In addition, elderly patients are more likely to require dose delays and experience GI toxicities without significant differences in hospitalizations or peripheral neuropathy.

Combination of Rituximab with Initial Chemotherapy Improves Outcome of Primary Mediastinal B-Cell Lymphoma: A Retrospective Analysis of a Single Institution Cohort

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1283-1283 ◽  
Author(s):  
Abraham Avigdor ◽  
Tsvi Sirotkin ◽  
Noga Shemtov ◽  
Miriam Berkowicz ◽  
Yaron Davidovitz ◽  
...  
Keyword(s):  
B Cell ◽  
Retrospective Analysis ◽  
Predictive Value ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Historical Comparison ◽  
Pet Ct ◽  
Significant Difference ◽  
The Impact

Abstract Primary mediastinal B-cell lymphoma (PMBCL) is a relatively rare clinico-pathologic subtype of diffuse large B-cell lymohoma. The optimal management, the prognostic factors and the role of PET/CT scan in this entity remain a matter of debate. While several retrospective studies suggested that dose-dense regimens are more effective than standard CHOP, the impact of adding rituximab (R) on the outcome of patients (pts) with PMBCL has not been fully evaluated. In this retrospective analysis we reviewed the clinical and radiological records of 81 consecutive pts with PMBCL treated in Sheba Medical Center between August 1985 and October 2006. Chemotherapy in the pre-rituximab era (−R cohort) included VACOPB (n=47) or 6 courses of standard CHOP (n=5). Since October 2002, 6 cycles of R were added concurrent with the treatment in another 29 pts (+R cohort): R-VACOPB (n=21) and R-CHOP (n=8). Radiotherapy was not administered following initial chemotherapy to any of the pts. Median age at diagnosis was 31 years (yrs) (range 17–61). Stage I/II and bulky mediastinum (≥ 10 cm in diameter) were present in 88% and 33%, respectively, and extranodal involvement was evident in 44% of all pts. After a median follow-up of 85 months (range 9–240), the overall (OS) and progression-free (PFS) survival at 5 yrs for the entire cohort were 89% and 66%, respectively, with a plateau 1–2 yrs following treatment. PFS at 5 years was significantly better with +R (81%) than with -R cohort (58%, P=0.03). Five-year PFS in pts treated with R-VACOPB, R-CHOP, VACOP-B and CHOP were 84%, 74%, 62%, 20%, respectively (P=0.025). Yet, there was no significant difference in OS between +R and -R cohorts (96% vs. 88% at 5 yrs, p=0.29). Direct survival comparisons demonstrated that 5-yr OS and PFS were significantly better in VACOPB than in CHOP (P=0.04 and 0.05, respectively) and that R-VACOPB was significantly superior to VACOPB in terms of PFS (p=0.05). In contrast, there was no difference in 5-yr PFS between R-VACOPB and R-CHOP (p=0.44). Univariate analysis revealed that aaIPI was not predictive of OS (p=0.51). Age above 31 yrs (p=0.02) and pericardial effusion (p=0.04) were the only predictors of reduced OS. Furthermore, beginning in 2003, 16 consecutive pts in the +R cohort, who were scanned by PET/CT-FDG before starting and after completion of therapy, were also evaluated in the middle (mid-PET) of treatment. The estimated 3-year PFS rate for mid-PET negative pts (n=8) and for mid-PET positive pts (n=8) was 86% and 75%, respectively (P=0.48). In terms of treatment failure, the negative predictive value of mid-PET was 100%, while the positive predictive value was only 25%. In conclusion, our population-based historical comparison demonstrates that the addition of R to anthracycline-based therapy significantly improved PFS in pts with PMBCL. We observed superior PFS with VACOPB compared with CHOP, but this superiority was abrogated by the introduction of R as part of initial therapy. These findings merit further study in randomized prospective studies.

Cross-Species Investigations Reveal Role, Mechanism and Predictive Power of Paracrine, Secondary Senescence in B-Cell Lymphoma Therapy

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3715-3715
Author(s):  
Jan R. Dörr ◽  
Maja Milanovic ◽  
Yong Yu ◽  
Julia Kase ◽  
Dido Lenze ◽  
...  
Keyword(s):  
B Cell ◽  
Predictive Power ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Brdu Incorporation ◽  
Lymphoma Cells ◽  
Long Term Outcome

Abstract Abstract 3715 Apoptosis and cellular senescence operate as anti-tumor safeguard mechanisms. Unlike apoptotic cells, senescent cells remain viable, and, hence, may crosstalk to other cells in their vicinity over extended periods of time. In fact, cells that entered oncogene-induced senescence or anticancer therapy-induced senescence (TIS) present with a senescence-associated secretory phenotype (SASP), a massive production of secretable factors, which reportedly reinforces senescence through an intracellular mechanism. Utilizing the Eμ-myc transgenic mouse lymphoma model, we provide evidence for an outcome-relevant paracrine, DNA damage-independent secondary senescence program (SecS) in vitro and in vivo. Apoptosis-blocked (bcl2-infected) lymphoma cells from different genetic backgrounds were treated with the DNA-damaging anticancer agent adriamycin in vitro or the alkylating agent cyclophosphamide upon lymphoma formation in mice in vivo. TIS and SecS was detected based on senescence-associated b-galactosidase activity (SA-b-gal), Ki67 staining and BrdU incorporation. The secretome of senescent cells was analyzed by proteomics, gene expression and protein arrays. Overall and progression free survival in mice and patients was assessed by Kaplan-Meier analysis. Transcriptome and secretome analyses followed by functional studies found extracellular matrix proteins, especially small leucine-rich proteoglycans (SLRP), but not NF-kB-dependent cytokines and chemokines, to induce SecS in proliferating lymphoma cells in a paracrine fashion, and linked a “high secretor” status to stronger SecS induction. Dissecting senescence-mediating pathways in recipient cells by biochemical, genetic and pharmacological means unveiled an essential role for the LDL receptor-related protein 1 (LRP1), a receptor for SLRP and other SASP components, through the cell-cycle inhibitor p21CIP1 in SecS. Accordingly, mice harboring TIS-capable but genetically SecS-defective lymphomas (e.g. lacking LRP1 or p21CIP1 expression) experienced inferior long-term outcome to therapy. Not only the recipient cell-based LRP1 status but also the genetically and biologically distinct donor cell-based secretor gene signature stratified outcome in mice. Strikingly, humanized versions of both classifiers were predictive in a large cohort of diffuse large B-cell lymphoma (DLBCL) patients, where they identified – although composed of different gene sets – largely overlapping patient subgroups with superior prognosis, again suggesting SecS as the critical underlying treatment effector principle. Our study highlights the predictive power of senescence for treatment outcome in DLBCL, and provides functional examples (which will be discussed at the meeting) for SASP-related non-genotoxic pro-senescent therapies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals High Level MYC Amplification in Aggressive B-Cell Lymphomas: Is It a Marker of Aggressive Disease?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1693-1693
Author(s):  
Priyanka Pophali ◽  
Lisa M Marinelli ◽  
Rhett P. Ketterling ◽  
Reid Gregory Meyer ◽  
Ellen D. McPhail ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
B Cell Lymphoma ◽  
Reference Laboratory ◽  
Fish Analysis ◽  
Low Grade ◽  
Aggressive Disease ◽  
Significant Difference ◽  
Definition Of ◽  
High Level

Abstract MYC amplification (amp) is a marker of poor prognosis in many non-hematologic malignancies. While MYC translocations in B cell lymphoma (BCL) have been extensively studied, little is known about the significance of MYC amp. Recent studies describe increased MYC copy numbers (3-10 copies/cell) to be associated with more aggressive BCL. The WHO 2017 does not include MYC amp in the definition of high-grade BCL (HGBCL) with MYC and BCL2 and/or BCL6 rearrangement ("double-hit lymphoma", DHL). However, it also states that high-level MYC amp occurring together with a MYC rearrangement, and concurrent with BCL2 rearrangement likely has a similar clinical impact as classic DHL. Although increased MYC copy number is commonly identified by routine fluorescence in situ hybridization (FISH) testing in BCL, the experience of our large cytogenetics reference laboratory suggests that high-level MYC amp, defined as uncountable MYC signals, is far less common. Therefore, we sought to characterize the clinical, pathologic and cytogenetic features of patients with BCL showing high-level MYC amp. The Mayo Clinic cytogenetic database was retrospectively reviewed for all cases of BCL with high-level MYC amp seen by FISH from January 2010 - February 2018. All FISH studies reported as MYC amp were re-reviewed by a cytogeneticist to verify the level of amp and the MYC probes involved. Pathology was reviewed by two independent hematopathologists. Clinical information was collected through chart review. Survival analysis was performed using Kaplan-Meier curves and the Wilcoxon rank-sum test. FISH analysis for MYC aberrations identified 44/9715 (0.45%) cases with high-level MYC amp. Of cases with available H&E, the most common morphology was diffuse large BCL (DLBCL) (82%; 28/34), followed by HGBCL (15%; 5/34) and plasmablastic BCL (3%; 1/34). Hans cell of origin (COO) algorithm immunohistochemistry (IHC) identified 21/25 (84%) germinal center B-cell-like (GCB), and 4/25 (16%) non-GCB cases. 21/27 (78%) cases were BCL2+ by IHC. MYC+ by IHC was ≥40% in 21/28 (75%) and <40% in 7/28 (25%) cases. 9/17 (53%) were "double expressers" (DEL) by IHC. MYC amp probe signals appeared in a cloud-like distribution (CLD) in 31 (70%) or in a single homogenous staining region (HSR) in 13 (30%) [Figure 1A]. Among 38 cases with amp in a MYC break-apart probe, 21 (55%) had amp of 5' alone, 15 (40%) of intact and 2 (5%) of the 3' probe alone. 7/44 (16%) had MYC translocations (5 IGH; 2 non-IGH). BCL2 rearrangement was seen in 15/39 (38%) cases, and BCL6 rearrangement in 3/36 (8%). Only 2/44 (4%) cases met the current WHO 2017 definition of DHL. Clinical data was available for 20 cases. Median age at diagnosis was 64.5 (range 25-88) years with M:F of 1.5:1. Only 1/14 (7%) had bone marrow while 16/18 (88.8%) had other extranodal sites of involvement (8 gastrointestinal). The clinical presentation was heterogeneous: 13 de novo, 3 post-transplant, 3 transformed from low grade and 1 mediastinal BCL. 9/14 had an elevated LDH, median 387 (225 - 2063) U/L. R-CHOP was the most common first line therapy in 12/17 (70%). At median follow-up of 18.2 (range 0.4 - 88.9) months, 9 patients had died, 3 were in relapse and 8 remained in first complete remission. Lymphoma relapse/progression was the most common cause of death in 7/9 (78%). The median overall survival (OS) was 29.3 months [Figure 1B]. There was no statistically significant difference in OS by morphologic classification (DLBCL vs HGBCL, p=0.6), double expresser (Yes/No, p=0.19), COO (GCB vs non-GCB, p=0.08), MYC amp pattern (HSR vs CLD, p=0.48), MYC amp probe (3' vs 5' vs intact, p=0.31), MYC rearrangement (Yes/No, p=0.1), or MYC amp with concurrent BCL2/BCL6 rearrangement (Yes/No ,p=0.2). To our knowledge, this is the first study to characterize the clinical, pathologic and cytogenetic features of BCL with strictly-defined high level MYC amp identified by FISH. The 5' signal alone, or the intact MYC probe are most frequently amplified, and two distinct patterns of amp can be seen. Predominant extra nodal involvement is an important clinical observation. These cases are usually DLBCL, GCB type, and infrequently have concurrent MYC/BCL2/BCL6 rearrangement. Our study suggests that BCL with high-level MYC amp may have an aggressive disease course regardless of MYC, BCL2 and BCL6 gene rearrangement status. A larger series is necessary to further understand the clinical significance of high-level MYC amp in BCL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

P52 Activation in Monomorphic B-Cell Post-Transplant Lymphoproliferative Disorders without BAFF-R Expression.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2932-2932
Author(s):  
Alexis Proust ◽  
Patricia Rince ◽  
Rita Creidy ◽  
Thierry Lazure ◽  
Monique Fabre ◽  
...  
Keyword(s):  
B Cell ◽  
Conflicts Of Interest ◽  
In Situ Hybridisation ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Solid Organ ◽  
Growth And Survival ◽  
Post Transplant ◽  
Significant Difference ◽  
Activation Profile

Abstract Abstract 2932 Poster Board II-908 Post-transplant lymphoproliferative disorders (PTLD) are one of the worse prognostic complications after solid organ or bone marrow stem cells transplantation. Most of them are associated to EBV known to activate NF-kB pathway especially by constitutive p65 expression. BAFF cytokine, a B cell-activating factor belonging to the tumour necrosis factor (TNF) family, have been described to modulate cell growth and survival in non Hodgkin lymphomas. However, little is known on the association between EBV, BAFF/BAFF-R signalling and canonical and non canonical NF-kB pathways expression in PTLD. Thus, we intend to study the role of EBV, NF-κB and BAFF/BAFF-R expression in PTLD.Our study has been investigated in two different contexts of diffuse large B-cell lymphoma (DLBCL). 20 cases of DLCBL resulting from immunocompetent patients (DLBCL/IC) and 13 from post-transplant recipients (DLBCL/PTLD) were compared. Indeed, all cases were characterized by histology and immunohistochemistry (IHC) was used to detect B-cell markers and to identify their germinal center (GC) or non GC (NGC) origin. EBV was detected by in situ Hybridisation (ISH) using EBER probe. Latent proteins LMP1 and EBNA2 as well as replicative protein ZEBRA were also detected by IHC. In addition, p50 and p52 proteins expression was carried out to study NF-kB pathway activation. We showed in DLBCL/IC, regardless of the ontogenic profile GC/NGC, that BAFF-R is expressed in 40% of cases, while in DLBCL/PTLD NGC pattern, BAFF-R is expressed in only one case out of 13 (7,7%) (p<0,05). Moreover, there was no significant difference in p50 expression between the categories of DLBCL studied. In contrast, we have shown a significant expression of p52 in DLBCL/PTLD (8 out of 13 cases) compared to DLBCL/IC (4 out of 20 cases) (p<0.005). In DLBCL/PTLD, there was no expression of BAFF-R ; this pattern could be related to the presence of EBV and LMP1 since p52 expression is mostly observed in EBV+ DLBCL/PTLD (5 out of 7 p52+ cases). In conclusion, the activation profile of DLBCL/PTLD is mostly not associated with BAFF/BAFF-R expression while NF-kB2 pathway is activated. Disclosures: No relevant conflicts of interest to declare.

Is There a Benefit of Adding Rituximab to CHOP in the Overall Survival of Patients with B-Cell Non-Hodgkin′s Lymphoma in a Developing Country ?

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4892-4892
Author(s):  
Guillermo J. Ruiz-Delgado ◽  
David Gomez Almaguer ◽  
Luz C. Tarin-Arzaga ◽  
Olga Cantú-Rodríguez ◽  
Carlos Alarcon-Urdaneta ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Developing Country ◽  
Conflicts Of Interest ◽  
Positive Impact ◽  
B Cell Lymphoma ◽  
Fold Increase ◽  
Developed Countries ◽  
Number Of Cycles ◽  
The Impact

Abstract Abstract 4892 Rituximab ( R ) has changed the prognosis of patients with non-Hodgkin′s lymphoma (NHL) in developed countries, but its role has not been analyzed in underprivileged circumstances. One hundred and two patients with NHL treated in a developing country were analyzed: 28 patients with follicular lymphoma (FL) and 74 diffuse large B cell lymphoma (DLCL). Patients were treated upfront with either CHOP or R-CHOP; the decision to employ R depending solely on the ability of patients to defray it. In DLCL, 42 were given CHOP and 32 R-CHOP, whereas in FL 19 were given CHOP and 9 R-CHOP. The impact of the addition of R was found to be more clear in FL than in DLCL. In patients with DLCL, the overall survival (OS) was 87% at 80 months for those treated with R-CHOP and 84% at 145 months for those treated with CHOP (p NS). In patients with FL, the OS was 89% at 88 months for those treated with R-CHOP and 71% at 92 months for those treated with CHOP (p =.05). In a multivariate analysis, other variables were identified to be associated with the OS were IPI and number of cycles in DLCL. It is concluded that rituximab produced a mild positive impact in the OS of patients with FL, but not in those with DLCL. Since the addition of rituximab results in a 36 fold increase in treatment costs, these observations may be important to decide therapeutic approaches in NHL patients living in underprivileged circumstances. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacy of Yttrium-90 Iburitumomab Tiuxetan for Early Relapsed/Refractory Indolent B-Cell Lymphoma: A Single Institute Retrospective Analysis in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5333-5333
Author(s):  
Keiichi Nakata ◽  
Shigeo Fuji ◽  
Ryo Nakata ◽  
Kazuhito Tsutsumi ◽  
Shuhei Kida ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Significant Prognostic Factor ◽  
Hematopoietic Stem ◽  
The Impact ◽  
Yttrium 90

Abstract Introduction: Indolent B-cell lymphoma is a type of non-Hodgkin's lymphoma that grows slowly and is not a curative disease. Yttrium-90 (90Y) iburitumomab tiuxetan is used in patients with relapsed/refractory indolent B-cell lymphoma, data is still limited in the rituximab era. In addition, previous studies did not assess the impact of early progression of disease within 2 years (POD24) which was reported to be associated with a poor prognosis in follicular lymphoma (Casulo et al, J Clin Oncol 2015) on the efficacy of 90Y iburitumomab tiuxetan. Thus, here we assessed the efficacy of 90Y iburitumomab tiuxetan in relapsed/refractory indolent B-cell lymphoma, and analyzed the impact of POD24 in this setting. Methods: We retrospectively analyzed the clinical outcomes of 51 patients with a relapsed/refractory indolent B-cell lymphoma who received 90Y iburitumomab tiuxetan at our institute from February 2009 to January 2018. POD24 was defined as progression within 24 months from the beginning of induction chemotherapy. Survival outcomes including overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Results: The median age was 64 years (range 37-88 years) at the time of receiving 90Y iburitumomab tiuxetan, and 29 (56.9%) were male. Disease subtypes were as follows: follicular lymphoma (n=44, 86.3%), mantle cell (n=4, 7.8%), marginal zone (n=2, 3.9%), and MALT lymphoma (n=1, 2.0%). The median number of previous regimens was 2 (range 1-9) and included rituximab-based therapy in all patients. Disease status at the time of receiving 90Y iburitumomab tiuxetan were as follows: complete remission (CR n=3, 5.9%), partial remission (PR n=13, 25.5%), stable disease (SD n=3, 5.9%), progression disease (PD n=32, 62.7%). The median follow-up time was 3.7 years (range 0.3-8.8 years) and overall response rate (ORR) was 94.1% (CR 56.9%, PR 37.3%). The ORR in patients with POD 24 was 95.0% (CR 60.0%, PR 35.0%), compared to 93.5% (CR 54.8%, PR 38.7%) with non-POD24. The 3-year OS and PFS rates for all patients receiving 90Y iburitumomab tiuxetan were 83.6% and 41.0%, respectively. POD24 was a significant prognostic factor for PFS in univariate analysis (1.2 years in patients with POD24 vs. 3.3 years in patients with non-POD24, (P=0.02) (Figure1). In multivariate analysis, POD24 was an independent prognostic marker of PFS (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.22-0.87, P=0.02). Conclusion: 90Y iburitumomab tiuxetan was highly effective in patients with relapsed/refractory indolent B-cell lymphoma patients. However, in patients with POD24, duration of response was short. Thus, another treatment strategy including hematopoietic stem cell transplantation should be considered. Disclosures No relevant conflicts of interest to declare.

scholarly journals Development of Humanized Diffuse Large B-Cell Lymphoma Mouse Models

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4501-4501
Author(s):  
Syed Mehdi ◽  
Ying-Zhi Xu ◽  
Leonard Shultz ◽  
Samantha L. Kendrick ◽  
Donghoon Yoon
Keyword(s):  
Transgenic Mice ◽  
Tumor Cells ◽  
Median Survival ◽  
Conflicts Of Interest ◽  
Xenograft Model ◽  
B Cell Lymphoma ◽  
Patient Specific ◽  
Significant Difference ◽  
Organ Specific

Abstract Introduction DLBCL is a commonly diagnosed, aggressive non-Hodgkin's lymphoma with ~40% of patients experiencing refractory or relapsed disease. Development of alternative therapies that target molecular features defining these unresponsive tumors is an active area of research to significantly advance the field and improve these patient's clinical management. However, few DLBCL animal models exist to test the efficacy of newly developed treatments, and are restricted to transgenic or xenograft mice that often fail to recapitulate the heterogeneous sub-classifications of this complex disease. While transgenic mice allow for spontaneous tumor formation, these models rely on inducing expression of specific oncogenes that drive a select group of DLBCL. The xenograft model offers several advantages, such as reproducing late-stage disease and shortening the model development time, but consist of implanting the tumor cells in a localized region or subcutaneously into immune-deficient mice. Despite some benefits of the transplant approach, these models are limited by their engraftment reproducibility and interactions with host micro-environments. Here, we explored the utility of humanizing Nod-Scid-IL2Rg null (NSG) mouse strains with factors associated with enhancing myeloid and lymphoma cell growth to establish a pipeline for rapid, reliable generation of in vivo DLBCL models. Methods We transduced the well-established human DLBCL cells, U2932, with the luciferase (Luc)-EGFP gene. The Luc-expressing (U2932-Luc) tumor cells were sorted for GFP positivity (GFP +) and expanded. The U2932-Luc cells (1 x 10 6/100µl PBS) were injected IV via tail vein into 8~12-week-old mice of various humanized NSG strains (representing equal numbers of each sex). NSG mice were humanized by transgenic expression of human cytokines (either human IL6 alone or IL6 plus SCF, GM-CSF, and IL-3) with the CMV promoter. Each experiment included of U2932-Luc cell transplanted group and control groups. We assessed U2932-Luc cell engraftment and growth by weekly in vivo imaging (IVIS 200 Imager, Perkin Elmer). To evaluate the organ specific engraftment/progression, we confirmed engraftment by bioluminescence imaging at the 2 nd week, then euthanized one mouse per week. At 15 minutes before euthansia, luciferin was injected via intraperitoneal injection. Following euthanasia, the organs were excised and underwent ex vivo IVIS imaging. The spleen, lungs, and liver were then fixed with 10% formalin and embedded in paraffin. Sections were stained with hematoxylin and eosin, and an anti-CD20 antibody to evaluate the tumor morphology using a Zeiss AXIO Imager M2 microscope (Zeiss, Nashville, TN). All other mice were monitored for survival and the median survival between the IL6 and IL6/SGM3 mice were compared using the Log-rank test. Results Similar to previously reported DLBCL humanized strain (MISTRG) (Hashwah, 2019), we used the IL6/SGM3 expressing strain. However, our studies also included the IL6 only humanized strain. We found that both the IL6 and IL6/SGM3 strains were highly permissive to DLBCL growth. The IL-6 strain exhibited a heightened growth of U2932 cells relative to the IL-6/SGM3 mice. As shown in Figure 1, the IL6 mice survived longer than IL6/SGM3 mice. Significant difference between the median survival of IL6 and IL6/SGM3 mice i.e. 48 days vs 42 days was observed (p &lt; 0.0482). The organ specific evaluation demonstrated that U2932-Luc cells were initially engrafted and grew in the lung, liver, and spleen. Subsequently, U2932 cells were found in the skeleton, ovary, and brain. Of note, we detected significantly enlargements of the kidney, spleen, and ovary at the terminal stage. Conclusions Our humanized mouse model approach of using U2932 human DLBCL cells transduced with the Luc gene in the NSG-IL6 and NSG-IL6/SGM3 mice reproduced the clinical features of an aggressive DLBCL that paralleled the original patient. This model will provide a new tool to enable expansion of patient samples while overcoming the current limitations of DLBCL xenografts and transgenic mice. The ability to maintain growth of patient-derived samples within clinically relevant locations has great potential to more accurately test patient-specific, personalized treatment strategies. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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