scholarly journals Prognostic significance of FCGR2B expression for the response of DLBCL patients to rituximab or obinutuzumab treatment

2021 ◽  
Vol 5 (15) ◽  
pp. 2945-2957
Author(s):  
Malgorzata Nowicka ◽  
Laura K. Hilton ◽  
Margaret Ashton-Key ◽  
Chantal E. Hargreaves ◽  
Chern Lee ◽  
...  
Keyword(s):  
Messenger Rna ◽  
De Novo ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Free Survival ◽  
Inhibitory Molecule ◽  
Antibody Immunotherapy ◽  
Differential Responsiveness ◽  
Anti Cd20

Abstract Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.

The Influence of PET/Gallium (PET/Gal) Status and High-Dose Rituximab (HDR) in Patients with Aggressive, Large, B-Cell Lymphoma (LBCL) Receiving Autologous Stem Cell Transplants (ASCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3058-3058 ◽  
Author(s):  
Amin M. Alousi ◽  
Rima M. Saliba ◽  
Grace-Julia Okoroji ◽  
Chitra Hosing ◽  
Barry I. Samuels ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
De Novo ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Disease Status ◽  
High Dose ◽  
Free Survival ◽  
The Impact

Abstract Background: PET/Gal status has been reported to be an important predictor of outcome in patients with LBCL who receive an ASCT. Newer conditioning regimens which include high-dose rituximab (HDR) have been shown to improve results (Khouri, JCO, 2005). The impact of HDR on the outcome of patients based on PET/Gal status has not been determined. Methods: A retrospective review of patients with chemo-sensitive, LBCL who received an ASCT on a research protocol at MD Anderson between 1995 and 2005 was performed. Factors that were considered for outcome included: Age, IPI, # of prior chemotherapies, B2-microglobulin, disease status at transplant, HDR and PET/Gal status. In patients who received HDR, it was given with stem cell mobilization and then again on days +1 and +8 following transplant. Results: A total of 188 patients were identified. Median age was 49 years with 108 (57%) male patients. 147 patients (78%) had de novo LBCL and 41 (22%) had a LBCL of follicular origin (LBCL-F). 83 (39%) patients received HDR. At transplantation, 95 patients (50%) were in PR, 71 (38%) in CRU and 22 (12%) in CR. 142 (76%) patients were PET/Gal negative, 37 (20%) PET/Gal positive and 9 (4%) were unknown. Median follow-up was 47 months. On multivariate analysis, for patients with de novo LBCL, PET/Gal status and HDR were the only predictors for progression and progression free survival (PFS). Patients who were PET/Gal negative and those that received HDR had a hazard ratio (HR) of 0.3 (p<0.001) and 0.5 (p=0.02) for progression, respectively (see the table below for the cumulative incidence (CI) for progression and PFS at 54 months according to HDR and PET/Gal status for de novo LBCL undergoing ASCT). PET/Gal Status and HDR were also found to be predictive for patients with LBCL- F on univariate analysis, however due to the small numbers in this subset; multivariate analysis could not be performed. PFS at 54 months for patients with LBCL-F who were PET/Gal negative was 40% versus 17% in the PET/Gal positive group, (p=0.006). PFS for those LBCL-F patients who received HDR was 81% as compared to 23% for those who did not receive HDR, (p=0.007). Conclusions: The two most important predictors of outcome following ASCT are PET/Gal status and whether HDR was given with the transplant regimen. The addition of HDR to the transplant regimen decreases the risk for progression irrespective of PET/Gal status; however the improvement is more significant in patients with a negative PET/Gal scan. C.I. for progression and PFS at 54 months for de novo DLBCL PET/Gal Status HDR CI of Progression (%) Progression Free Survival Positive No 83 17 Positive Yes 54 45 Negative No 35 55 Negative Yes 22 75

Encouraging Activity of Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma: Results From a Phase II Study (BO20999),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3655-3655 ◽  
Author(s):  
Franck Morschhauser ◽  
Guillaume Cartron ◽  
Catherine Thieblemont ◽  
Philippe Solal-Celigny ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Response Duration ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Anti Cd20 ◽  
Large B Cell

Abstract Abstract 3655 Obinutuzumab (GA101) is a type II glycoengineered, humanized anti-CD20 monoclonal antibody that has increased antibody-dependent cellular cytotoxicity and direct cell death activity but lower complement-dependent cytotoxicity compared with type I anti-CD20 antibodies such as rituximab and ofatumumab. GA101 is in clinical development for the treatment of lymphoma and chronic lymphocytic leukemia. The Phase I/II study BO20999 has evaluated the efficacy and safety of GA101 monotherapy in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (aNHL). Here, we report updated Phase II results including progression-free survival (PFS) and best overall response (BOR). Patients (n = 40) were randomized to receive GA101 (D1, D8 and D22, then 3-weekly for total of 9 infusions) at either a high dose (1,600 mg on D1 and D8, then 800 mg thereafter; 1,600/800 mg cohort; n = 19), or a flat low dose of 400 mg (400/400 mg cohort; n = 21). Baseline patient characteristics were similar for both cohorts (Table 1). The median observation time for all patients was 9.5 months (0.3–26.1 months). BOR rates are given in Table 2, with 8/25 diffuse large B-cell lymphoma (DLBCL) patients (32%) and 4/15 mantle cell lymphoma (MCL) patients (27%) responding to GA101. Among the patients with rituximab-refractory disease, a response was observed in 1/13 patients (7.7%) and 4/12 patients (33.3%) treated in the 400/400 mg and 1,600/800 mg cohorts, respectively. Of these, 4 patients (1,600/800 mg cohort) had a response duration > 6 months, with 2 patients having an ongoing response (response duration: 9.8, 16.5+, 19.5 and 20.0+ months). Median PFS for patients with DLBCL (Figure 1) was 1.9 months (range: 0.3–15.7 months) for the 400/400 mg cohort and 2.7 months (range: 0.2–22.3) months) for the 1,600/800 mg cohort (hazard ratio: 0.70; 95% CI: 0.30–1.66). For the DLBCL subgroup, response duration was 3.1, 3.1+, 5.8, 16.5+ and 19.5 months for the 5 responders in the 1,600/800 mg cohort, compared with 6.3, 8.6 and 9.8 months for the 3 responders in the 400/400 mg cohort. Individual response data indicated that 2 MCL patients had an ongoing response for ≥ 20 months (20.0 and 20.4 months). GA101 was well tolerated in both cohorts. Infusion-related reactions (IRRs; all grades) were the most common adverse event (AE), occurring in 81% of patients in the 400/400 mg cohort and 68% of patients in the 1600/800 mg cohort. Grade 3/4 AEs occurring in >5% of patients across both cohorts included IRRs (10%), tumor lysis syndrome (10%), cardiac failure (not treatment-related; 10%), anemia (14%) and thrombocytopenia (14%) in the 400/400 mg cohort and IRRs (5%) and anemia (5%) in the 1,600/800 mg cohort.Table 1.Baseline patient characteristicsCharacteristic400/400 mg (n = 21)1,600/800 mg (n = 19)All (n = 40)Median age, years (range)70 (43–80)72 (22–85)71 (22–85)Histology, nDLBCL101525MCL11415Median number of prior treatments, n (range)4 (1–17)3 (1–6)3 (1–17)Previous rituximab, n211940Rituximab refractory*, n131225Prior stem cell transplant, n268DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.*Rituximab refractory defined as patients who had a response of < 6 months or who failed to respond to a rituximab-containing regimen (rituximab monotherapy or in combination with chemotherapy) at any point during their treatment history.Table 2.Best overall response according to diagnosis and cohortDLBCLMCLResponse, n (%)400/400 mg (n = 10)1,600/800 mg (n = 15)400/400 mg (n = 11)1,600/800 mg (n = 4)Complete response (CR)0 (0.0)3 (20.0)2 (18.2)0 (0.0)CR unconfirmed1 (10.0)0 (0.0)0 (0.0)0 (0.0)Partial response2 (20.0)2 (13.3)0 (0.0)2 (50.0)Stable disease1 (10.0)1 (6.7)3 (27.3)0 (0.0)Progressive disease5 (50.0)9 (60.0)6 (54.5)2 (50.0)No response assessment1 (10.0)0 (0.0)0 (0.0)0 (0.0)DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.Figure 1.Progression-free survival for patients with diffuse large B-cell lymphomaFigure 1. Progression-free survival for patients with diffuse large B-cell lymphoma In conclusion, GA101 shows encouraging single-agent efficacy in these heavily pretreated patients with relapsed/refractory aNHL (DLBCL or MCL). A Phase III trial of rituximab plus CHOP vs GA101 plus CHOP in first-line DLBCL has recently started. Disclosures: Morschhauser: Roche: Honoraria; Celgene: Consultancy, Honoraria. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria; LFB: Honoraria. Milpied:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wenger:Roche: Employment. Wassner-Fritsch:Roche: Employment. Asikanius:Roche: Employment. Salles:Roche: Consultancy, Honoraria.

Cell of Origin Determination in Diffuse Large B-Cell Lymphoma: Performance of Immunohistochemical (IHC) Algorithms and Ability to Predict Outcome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 950-950 ◽  
Author(s):  
Brian T. Hill ◽  
Angela M.B. Collie ◽  
Tomas Radivoyevitch ◽  
Eric D. Hsi ◽  
John Sweetenham
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
De Novo ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Free Survival

Abstract Abstract 950 INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) can be categorized by its cell of origin (CoO) as either being derived from a germinal center B-cell (GCB) or activated B-cell (ABC). Primary mediastinal DLBCL represents a third, distinct entity. This classification was initially defined by gene expression profiling (GEP), which remains the gold standard for such determination. Determination of CoO will likely become the basis for patient selection for clinical trials of targeted therapies. Several algorithms and methods have been developed that use immunohistochemistry (IHC) to differentiate GCB-DLBCL from non-GCB DLBCL. These include the Hans algorithm (utilizes staining for CD10, Bcl-6 and Mum1), the Choi algorithm (utilizes additional staining for GCET1 and FoxP1) as well as the Tally method (does not use Bcl-6 and utilizes LMO2 as a tie-breaker stain for otherwise equivocal cases). Recently, it has been recognized that IHC approaches to assign CoO may not be reproducible even at highly experienced laboratories. We sought to determine the performance of these IHC assays in our laboratory as a necessary step in developing trials based on CoO stratification. METHODS: We reviewed 108 adult (age ≥18) cases of de novo DLBCL, the majority of which were treated with chemoimmunotherapy (R-CHOP or R-CVP) at the Cleveland Clinic from 2000–2010. Diagnostic biopsies were available for all cases. IHC staining was performed on tissue microarrays (TMAs), and published algorithms (Hans, Choi and Tally) were applied to categorize cases as GCB or non-GCB. In addition, gene expression profiling was completed in a subset of these cases, for which frozen tissue was available. A linear predictor score for gene expression profiling (GEP) was used to assign cases in 31 of 33 cases with 2 technical failures at the array stage (overall success rate 84.8%). Clinical details including age, sex, International Prognostic Index (IPI) stage at diagnosis, treatment, progression free survival (PFS) and overall survival (OS) were captured for 69 of the 108 patients. Actuarial survival analysis was performed according to the Kaplan and Meier method, and the curves compared by the log-rank test. RESULTS: For the 69 patients with adequate clinical follow-up, the median age was 64 years old (range 18–88). There were 49% males and 51% females. The distribution of patients with stage I, II, III, and IV disease at the time of diagnosis was 20%, 14%, 20%, and 32% (14% had unknown stage). The 5-year overall survival of patients was 88%. Results of the Hans algorithm, Choi algorithm and Tally method were interpretable in 98 (90.7%), 95 (87.9%) and 88 (81.5%) of 108 cases, respectively. Inability to assign subtypes was due to suboptimal staining of the TMA (tissue loss or poor staining of an individual core). Using GEP to assign CoO, 42% of cases were classified as GCB, 42% as ABC and 14% were unclassifiable. The sensitivities of the Hans, Choi and Tally approaches to identify the CoO predicted by GEP were 0.83, 0.83, and 0.58 for correctly identifying GCB cases, respectively, and were 0.70, 0.70 and 0.80 for identifying non-GCB cases, respectively. The positive predictive values of the Hans, Choi and Tally approaches were 0.83, 0.83, and 1.0 for GCB and 0.78, 0.78, and 0.89 for non-GCB. As shown in the figure, 5-year overall survival was significantly superior for GCB relative to ABC cases using GEP (100% vs. 58.9%, P < 0.001) and for GCB vs. non-GCB cases for the algorithms of Hans (100% vs. 82.3%, P = 0.0197) and Choi (95.6% vs. 78.0%, P = 0.0482). The Tally method was not predictive of outcome, possibly due to insufficient power (5-year OS 94.4% for GCB vs. 80.7% for non-GCB, P = 0.1725). Similar findings were observed for progression-free survival. CONCLUSIONS: The Hans and Choi algorithms are reasonable methods for identifying PFS and OS differences based on CoO for de novo DLBCL treated with chemoimmunotherapy. The positive predictive value is universally high for all algorithms tested, but the sensitivity of IHC for identifying CoO was fair, particularly for the Tally method. IHC represents a valid biomarker to identify non-GCB cases. Clinical trials of DLBCL that stratify patients by IHC are feasible provided the performance characteristics of the algorithms are taken into consideration during study design. Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance of Cell of Origin Subclassification in Diffuse Large B Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5081-5081
Author(s):  
Muath Dawod ◽  
Juan Gomez-Gelvez ◽  
Ahmad Mattour ◽  
Kedar V. Inamdar ◽  
Nalini Janakiraman
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
Statistical Significance ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Free Survival ◽  
Large B Cell Lymphoma

Abstract Abstract 5081 Background: Diffuse large B cell lymphoma (DLBCL) is a heterogeneous disease that has been divided into three different prognostic subgroups: Germinal Center B cell-like (GC), Activated B cell-like (ABC) and type 3 according to gene expression profile using cDNA. Immunohistochemistry (IHC) has been used as surrogate to identify these cell-of-origin subgroups. Data about the prognostic value of IHC has been conflicting. Patients and methods: In this retrospective study, we reviewed the charts of 252 patients diagnosed with DLBCL at Henry Ford Hospital from 1999 to 2012. We excluded patients with HIV, transformed lymphomas and unavailable samples. Data was collected on a total of 157 patients. The following data was gathered: age, sex, race, IPI score, disease stage, hemoglobin, white blood and platelet counts, best response achieved and dates of treatment start, relapse, death or last follow up. Tissue microarray slides with the following IHC stains (CD10, MUM1, Bcl6) were prepared and reviewed when needed. Using Hans Algorithm, samples were divided into two major groups (GC-like and non-GC-like). 3-year progression free and overall survivals were compared between all subgroups using a log-rank test. Continuous variables were reported as median and range, and compared using Wilcoxon rank-sum tests. Categorical variables were reported as median and range, and compared using Chi-square tests. Statistical significance was set at p<0. 05. Results: Eighty patients (51%) were classified as GC-like, and 77 patients (49%) as non-GC-like. GC-like subgroup had a significantly longer 3-year progression free survival (90% vs 74%, P=0. 024), as compared with the non-GC-like subgroup. There was a trend toward longer overall survival but it didn't reach statistical significance (74% vs 67%, P=0. 161). For all patients, IPI stands as a strong prognostic index with 3-year overall survival of (85% and 46%, P=<. 001) in patients with low IPI (0 to 2) and high IPI (3 to 5) respectively. Interestingly, in patients with low IPI, cell of origin stands as a prognostic factor with 3-year progression free survival of (96% and 81%, P=0. 032) in GC-like and non-GC-like groups respectively. While in patients with high IPI, there was no significant difference in progression free survival in cell-of-origin subgroups. Conclusion: Cell of origin subclassification as determined by IHC surrogate markers predict for better progression free survival in GC-like subgroup but not for overall survival. While this prognostic value was maintained in patients with low IPI, there was no prognostic significance in patients with high IPI. IPI is still a valuable prognostic tool in patients with DLBCL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Multi-Institutional Outcomes Analysis of Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with Ibrutinib

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1115-1115 ◽  
Author(s):  
Allison Marie Winter ◽  
Daniel J. Landsburg ◽  
Francisco J. Hernandez-Ilizaliturri ◽  
Nishitha Reddy ◽  
Stephen Smith ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
De Novo ◽  
Molecular Subtype ◽  
Single Agent ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Free Survival ◽  
Large B Cell Lymphoma

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with distinct survival differences according to molecular subtype with superior outcomes in patients with the germinal center B cell-like (GC) subtype as compared to those with the activated B cell-like (ABC) subtype. Efficacy data for single-agent ibrutinib in patients with relapsed/refractory (r/r) DLBCL are limited to a single clinical trial of 80 patients. In that study, higher response rates were observed for r/r ABC-DLBCL compared to GC-DLBCL (37% vs. 5%), when assigned by gene expression profiling (GEP). The response rate of those with unknown/unclassifiable DLBCL was 22%. Despite biologic rationale for selective cytotoxicity of ibrutinib for ABC-DLBCL, it is not clear that such preferential activity will be observed when subtyping based on immunohistochemical (IHC) staining is used, as the correlation with subtype determined by GEP and IHC is imperfect. Furthermore, GEP is time consuming and expensive so IHC is used in clinical practice to differentiate GC from non-GC, the latter of which includes both ABC and unclassifiable DLBCL. We retrospectively analyzed outcomes of patients with r/r DLBCL treated with ibrutinib at a number of large academic medical centers. Methods: We reviewed medical records of all patients with DLBCL treated with ibrutinib at five U.S. tertiary-care cancer centers from 2013 to 2016. We included patients with de novo DLBCL as well as those transformed from indolent lymphoma if the ibrutinib was given for the DLBCL histology. Patients were excluded if they received ibrutinib for ≤ 14 days. Molecular subtype (GC vs non-GC) was determined by local pathology findings and/or the investigator's application of the Hans algorithm. Categorical variables were compared between groups using the Chi-square test. Outcomes were calculated from the date of initiation of ibrutinib. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Thirty five patients met inclusion criteria (27 de novo and 8 transformed DLBCL). The median age at diagnosis was 61 years (range 38-88) with 66% men.By Hans IHC criteria, there were 21 cases of non-GC, 9 GC and 5 were unknown.The median number of treatments prior to ibrutinib was 3 (range 1-8). 30% of patients had undergone prior autologous stem cell transplant. Characteristics including age, gender, transformed versus de novo, relapsed versus refractory, number of prior therapies, and prior use of transplant did not significantly differ between subgroups. The overall response rate (ORR) to ibrutinib was 29% with 4 patients achieving a complete response (CR) and 6 achieving a partial response (PR). When evaluated by subtype assigned by IHC, GC-DLBCL patients had an ORR of 44% and non-GC-DLBCL patients had an ORR of 19%. There was no significant difference in the rates of CR, PR, stable disease, or progressive disease between the subtypes (p=0.185) or between de novo ortransformed disease (P = 0.114). The median progression-free survival (PFS) was comparable for patients with the GC, non-GC, and unknown subtype (3.9, 2.2, and 4.1 months, respectively, P = 0.382, Figure). The median overall survival (OS) was longer for patients with the GC subtype (10.5 months) compared to 5.5 months for patients with the non-GC subtype, and 9.7 months for those with unknown subtype but this difference was not statistically significant (P=0.564). Figure: Progression Free Survival of r/r DLBCL Patients Treated with Ibrutinib, based on Hans Algorithm Subtype Conclusions: Responserates to single agent ibrutinib in the GC and non-GC subtypes of r/r DLBCL do not appear different when using Hans algorithm to assign subtypes. PFS and OS were modest in both groups and not statistically different. In conclusion, until GEP or other molecular technologies such as Nanostring are in more widespread use for routine subtyping of DLBCL, caution is advised when selecting patients for subtype-specific therapy, as clinical outcomes for patients receiving ibrutinib may not differ by cell of origin as determined by IHC. Figure Figure. Disclosures Reddy: celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees; INFINITY: Membership on an entity's Board of Directors or advisory committees. Shadman:Pharmacyclics: Honoraria, Research Funding. Smith:Spectrum: Honoraria; Celgene: Honoraria; Abbvie: Research Funding; Genentech: Honoraria.

Expression of the c-Met Oncogene Correlates with Favorable Progression Free Survival In Classical Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3880-3880
Author(s):  
Chuanhui Xu ◽  
Anke Van Den Berg ◽  
Wouter Plattel ◽  
Nele Ruther ◽  
Huang Xin ◽  
...  
Keyword(s):  
Cell Growth ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Signaling Pathway ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Free Survival

Abstract Abstract 3880 Background The HGF/c-Met signaling pathway regulates a variety of biological processes, including proliferation, survival and migration. Aberrant c-Met activation has been implicated in the pathogenesis of many human cancers. Furthermore, c-Met is of prognostic significance in several types of cancer such as diffuse large B cell lymphoma, bladder cancer, breast cancer, colorectal cancer and ovarian cancer. Expression of c-Met in Hodgkin lymphoma (HL) patients, as well as increased levels of HGF in the urine of HL patients has been reported, but no prognostic studies or functional data have been reported. Methods We studied the prognostic significance of c-Met expression by immunohistochemistry on paraffin sections of classical HL (cHL) patients from two independent patient cohorts. Functional studies were performed on HL cell line L428 that showed high c-Met levels, constitutive phosphorylated c-Met and no HGF expression. The effect of stimulation by HGF and inhibition by c-Met kinase inhibitor SU11274 was investigated by Western blot, cell proliferation and cell cycle progression analysis. Results Expression of c-Met was detected in Hodgkin Reed-Sternberg (HRS) cells in 52% (79/152) of primary cHL tissue samples and expression of its ligand, hepatocyte growth factor (HGF), was detected in HRS cells in 8% (10/120) of the cHL patients. Co-expression of HGF and c-Met in HRS cells was observed in only 3% (4/120) of cHL patients. A variable percentage of infiltrating cells stained positive for HGF, supporting a predominant paracrine activation route. In contrast to its adverse prognostic impact in other cancers, high c-Met expression significantly correlated with favorable 5 year progression free survival in both patient cohorts. To explain these unexpected findings we studied the c-Met/HGF signaling pathway in the L428 cHL cell line. The levels of phosphorylated c-Met, Akt, and Erk1/2 were upregulated upon HGF stimulation and this induction could be blocked by inhibiting c-Met activation with SU11274. Activation with HGF did not effect cell growth, while SU11274 alone suppressed cell growth. SU11274, as well as inhibitors of PI3K, MEK1/2 and Erk1/2 (downstream targets of the HGF/c-Met signaling pathway) induced G2/M cycle arrest. Conclusion Expression of c-Met in tumor cells was observed in 52% of cHL patients. In contrast to its prognostic value in other cancers, expression of c-Met in HRS cells of cHL patients correlated with favorable prognosis in two independent cohorts. Although triggering of c-Met in L428 cells with HGF induced activation of its downstream factors, no effect was observed on proliferation. Remarkably, the c-Met inhibitor did suppress cell growth of L428 cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Prognostic Significance of Combined Pretreatment Fibrinogen and Neutrophil-Lymphocyte Ratio in Various Cancers: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Rongqiang Liu ◽  
Shiyang Zheng ◽  
Qing Yuan ◽  
Peiwen Zhu ◽  
Biao Li ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Meta Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Progression Free Survival ◽  
Regression Analyses ◽  
Free Survival ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Meta Regression

Purpose. The prognostic value of a new scoring system, termed F-NLR, that combines pretreatment fibrinogen level with neutrophil-lymphocyte ratio has been evaluated in various cancers. However, the results are controversial. The purpose of this study was to comprehensively analyze the prognostic value of F-NLR score in patients with cancers. Methods. An integrated search of relevant studies was conducted by screening the PubMed and Embase databases. Pooled hazard ratios, with 95% confidence intervals (CIs), for overall survival (OS) and disease-free survival (DFS)/progression-free survival (PFS) were calculated to estimate the prognostic significance of F-NLR score in patients with various tumors. A random effects model was used for comprehensive analysis, and subgroup and meta-regression analyses were used to explore sources of heterogeneity. Results. Thirteen articles reporting data from of 4747 patients were included in the study. Pooled analysis revealed that high F-NLR score was significantly associated with poor OS ( HR = 1.77 ; 95% CI, 1.51–2.08) and poor DFS/PFS ( HR = 1.63 ; 95% CI, 1.30–2.05). Subgroup and meta-regression analyses did not alter the prognostic role of F-NLR score in OS and DFS/PFS. Conclusions. Increased F-NLR score is significantly associated with poor prognosis in patients with cancers and can serve as an effective prognostic indicator.

scholarly journals MBCL-04. 5 – AZACYTIDINE IN TREATMENT OF CHILDREN WITH DE NOVO AND RELAPSED METASTATIC MEDULLOBLASTOMA: RESULTS OF INTERCENTER PILOT STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii387-iii387
Author(s):  
Andrey Levashov ◽  
Dmitry Khochenkov ◽  
Anna Stroganova ◽  
Marina Ryzhova ◽  
Sergey Gorelyshev ◽  
...  
Keyword(s):  
Gene Amplification ◽  
De Novo ◽  
Prognostic Significance ◽  
N Gene ◽  
Free Survival ◽  
Tumor Bed ◽  
Craniospinal Radiation ◽  
Therapeutic Program ◽  
Grade 3

Abstract The aim of this study was to estimate treatment toxicity and event-free survival (EFS) according to therapeutic program, MYC/MYC-N gene amplification and MGMT/DNMT (1, 3a, 3b) proteins expression in tumor cells. From 2016 to 2018 twenty four patients were included in trial. Children underwent adjuvant therapy: craniospinal radiation (CSI) or local radiation therapy (RT) to the relapsed site up to 23.4Gy with 5-azacytidine, 2 cycles methotrexate/5-azacytidine/cisplatin/etoposide, 3 cycles 5-azacytidine/temozolomide - for relapsed group (arm A, n = 5); for patients with de novo medulloblastoma: arm B, n = 11 – vincristine/cyclophosphamide/cisplatin/etoposide (OPEC) - based induction, CSI 36Gy + local RT to the tumor bed up to 54Gy with 5-azacytidine, 1 cycle OPEC and 2 cycles thiophosphamide/carboplatin with auto stem cell transplantation (auto-SCT); arm C, n = 8 – cyclophosphamide/cisplatin - based induction, CSI 23.4 Gy followed by 2 cycles 5-azacytidine/thiophosphamide/carboplatin with auto-SCT, local RT with 5-azacytidine. The combination of 5-azacytidine with local RT or temozolomide was safety and tolerability. Arm C was discontinued due to severe gastrointestinal grade 3/4 toxicity, hemorrhagic syndrome after combination of 5-azacytidine with thiophosphamide/carboplatin. EFS was 0% in arm A, 53.0 ± 15.5%, 50.0 ± 17.7% in arms B and C, a median follow-up 8.8 ± 1.1 months (arm A), 18.8 ± 2.5 months (arm B), 25.0 ± 4.4 months (arm C). Addition of 5-azacytidine to RT or chemotherapy did not improve EFS of patients with MYC/MYC-N gene amplification positive tumor. There was not determined any prognostic significance of MGMT/DNMT (1, 3a, 3b) proteins expression in this cohort.

Sign in / Sign up

Export Citation Format

Share Document