scholarly journals 5-Hydroxymethylcytosine profiles of cfDNA are highly predictive of R-CHOP treatment response in diffuse large B cell lymphoma patients

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hang-Yu Chen ◽  
Wei-Long Zhang ◽  
Lei Zhang ◽  
Ping Yang ◽  
Fang Li ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Regression Model ◽  
B Cell ◽  
Treatment Response ◽  
Logistic Regression Model ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Invasive Approach ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background Although R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard chemotherapy regimen for diffuse large B cell lymphoma (DLBCL) patients, not all patients are responsive to the scheme, and there is no effective method to predict treatment response. Methods We utilized 5hmC-Seal to generate genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) from 86 DLBCL patients before they received R-CHOP chemotherapy. To investigate the correlation between 5hmC modifications and curative effectiveness, we separated patients into training (n = 56) and validation (n = 30) cohorts and developed a 5hmC-based logistic regression model from the training cohort to predict the treatment response in the validation cohort. Results In this study, we identified thirteen 5hmC markers associated with treatment response. The prediction performance of the logistic regression model, achieving 0.82 sensitivity and 0.75 specificity (AUC = 0.78), was superior to existing clinical indicators, such as LDH and stage. Conclusions Our findings suggest that the 5hmC modifications in cfDNA at the time before R-CHOP treatment are associated with treatment response and that 5hmC-Seal may potentially serve as a clinical-applicable, minimally invasive approach to predict R-CHOP treatment response for DLBCL patients.

FCGR3A and FCGR2A Polymorphisms Do Not Affect Response and Outcome of Patients with Diffuse Large B-Cell Lymphoma Treated with Rituximab and Chemotherapy. A Study Based on 554 Patients Included in GELA (Groupe d'Etude des Lymphomes de l'Adulte) Prospective Multicentric Study LNH2003

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 90-90
Author(s):  
Herve Ghesquieres ◽  
Fabrice Jardin ◽  
Sophie Pallardy ◽  
Aurélie Verney ◽  
Anne Laure Borrel ◽  
...  
Keyword(s):  
B Cell ◽  
Treatment Response ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Related Factors ◽  
Multicentric Study ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

Abstract Abstract 90 Background: rituximab had dramatically improved the prognosis of patients with Diffuse Large B-cell Lymphoma (DLBCL) in combination with chemotherapy. Many biological and clinical studies suggested considerable inter-individual variability in term of anti-CD20 monoclonal antibody (mAb) activity with tumor and host-related influencing factors. Among host-related factors, the presence of functional polymorphisms in FcG receptors genes as FCGR3A-158V/F influences the affinity for IgG1 and consequently the antibody dependant cellular cytotoxicity (ADCC) with therapeutic mAbs such as rituximab. The clinical consequence reported to date consists in a better response rate to rituximab monotherapy for FCGR3A-158V homozygous patients treated for follicular lymphoma compared FCGR3A-158F carriers. In DLBCL and in the context of combination with chemotherapy, the role of FCGR3A and FCGR2A SNPs on treatment response and patient's outcome is not clear with few prospective studies. The aim of this study is to determine the impact of FCGR3A and FCGR2A SNPs on response and outcome of newly diagnosed DLBCL patients included in the prospective trials of the GELA (LNH2003 program). Patients and Methods: 1564 patients from France, Switzerland and Belgium were included in the 5 prospective multicentric trials of the LNH2003 program of the GELA designed for DLBCL patients who were stratified in different subgroups based on age and International Prognostic Index (IPI) score. A sample of peripheral blood lymphocytes was collected before treatment from 760 patients who signed a specific consent form for this genetic study. After pathologic review and exclusion of patients not receiving rituximab (48 patients), 554 DLBCL patients were available for this study. SNPs were genotyped using a TaqMan® based assay. Results: The median age of the 554 patients was 61 years (range, 18–93 years), 57% of them were male and 50% of patients presented at diagnosis a 2–3 age-adjusted IPI score. Chemotherapy regimen consisted in a combination of rituximab with CHOP-21 (110 patients, 20%), CHOP-14 (181 patients, 33%), low dose CHOP for patients older than 80 years (60 patients, 11%), or ACVBP regimen (203 patients, 36%). At the end of treatment, complete response (CR) or unconfirmed CR was observed in 75% of patients. After a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) was 70.2% and 75.7%, respectively. The distribution of the VV, VF and FF FCGR3A alleles was 14.8%, 46.4%, 38.8%, and 27.8%, 48.6%, 23.6% for HH, HR and RR FCGR2A alleles, respectively, and were therefore consistent with Hardy-Weinberg equilibrium. Initial clinical characteristics of patients (age, sex, Performance Status, stage, B-symptoms, number of extra-nodal sites, LDH level, IPI) were not different according to the two FCGR SNPs. CR/CRu after induction therapy was observed in 61%, 66%, 61% for VV, VF and FF carriers (P = .46) and 60%, 64%, 64% for HH, HR and RR carriers (P =.70), respectively. No difference of response after consolidation treatment was observed between each genotype of FCGR3A and FCGR2A SNPs. The 3-year PFS was 65.3%, 71.4%, 70.5% for FCGR3A VV, VF and FF carriers (P = .43) and 69.2%, 67.6%, 76.6% for FCGR2A HH, HR, RR carriers (P =.09), respectively. The 3-year OS was also not different between the three genotypes of each FCGR SNPs. Conclusions: To our knowledge, this is the largest prospective multicentric study that investigates the role of FCGR2A and FCGR3A SNPs on treatment response and outcome in a large series representing the whole spectrum of DLBCL patients. Based on these results, modification of rituximab schedule according to the FCGR3A and FCGR2A genotypes does not appear worth investigating. Others host-related factors influencing the efficiency of immunotherapy need to be investigate. Disclosures: No relevant conflicts of interest to declare.

The Under-Treatment of Elderly Medicare Diffuse Large B-Cell Lymphoma Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 237-237
Author(s):  
Sacha Satram-Hoang ◽  
Sandra Skettino ◽  
Khang Hoang ◽  
Sridhar R Guduru ◽  
Ashok Gunuganti ◽  
...  
Keyword(s):  
Logistic Regression ◽  
B Cell ◽  
Real World ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Patient Characteristics ◽  
Risk Of Death ◽  
Large B Cell Lymphoma ◽  
Recommended Therapy ◽  
Large B Cell

Abstract Abstract 237 Introduction: Prior real-world data show that a large proportion of the elderly population with diffuse large b-cell lymphoma (DLBCL) are not receiving the recommended therapy for their disease. Over half of the patients diagnosed with DLBCL are over the age of 60 and clinical trials show that patients over the age of 60 respond well to current guideline-based therapy. We set out to examine the patient characteristics associated with receiving recommended therapy and the survival outcomes in an older population in routine clinical practice. Methods: We conducted a retrospective cohort analysis of 9866 DLBCL patients in the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Patients were diagnosed between January 1, 2000 to December 31, 2007, were >66 years, and continuously enrolled in Medicare Part A and B with no HMO coverage in the year prior to diagnosis. Chi-square test for categorical variables and ANOVA or t-test for continuous variables were used to assess differences in patient and disease characteristics by treatment status. Logistic regression modeling assessed the patient characteristics predictive of not receiving treatment. Kaplan-Meier curves and Cox proportional hazards regression assessed survival by treatment type. Date of last follow-up was December 31, 2009. Results: There were 7832 (80%) patients who received treatment and 2034 (20%) who did not receive treatment during the study time period. Untreated patients were older at diagnosis with mean age of 81 compared to 76 years in treated patients (p<.0001). As age increased, the treatment rate significantly decreased especially among patients >80 years (Table 1). Untreated patients were also more likely non-white (15% vs. 12%; p<.01), diagnosed with stage IV disease (33% vs. 29%; p<.0001), had higher comorbidity burden, and lived in areas of lower socioeconomic status than treated patients (p<.0001). In the adjusted logistic regression model, increasing age, non-white race, higher comorbidity score, and lower income were predictive of not receiving treatment. The multivariate survival analysis, adjusting for age, sex, race, stage, histology, comorbidity, income, and year of diagnosis, demonstrated a 3-fold higher risk of death in the untreated patients (HR=2.98; 95%CI=2.81–3.16) compared to treated patients. Conclusions: This real-world analysis of elderly DLBCL patients confirmed that 20% of them are not receiving treatment, and the rate of under-treatment is even more pronounced among those >80 years. As a consequence, untreated patients had a 3-fold higher risk of death compared to those who received treatment. Disclosures: Satram-Hoang: Genentech, Inc.: Consultancy. Skettino:Genentech, Inc.: Employment, Roche Stock Other. Reyes:Genentech, Inc.: Employment, Roche Stock Other.

Programmed Death-1 Ligand Is Uniformly Expressed On Primary Mediastinal Diffuse Large B-Cell Lymphoma Cells with No Influence On Patient Survival.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2671-2671
Author(s):  
Vit Prochazka ◽  
Tomas Papajik ◽  
Patrik Flodr ◽  
Pavla Latalova ◽  
Zuzana Prouzova ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Treatment Response ◽  
Tumor Cells ◽  
Clinical Characteristics ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Hla Dr ◽  
Large B Cell

Abstract Abstract 2671 Introduction: Primary mediastinal diffuse large B-cell lymphoma (PMBCL) is an uncommon disease with an aggressive clinical course and potential curability. Growing evidence suggests that host antitumor immunity suppression may play a role in resistant cases. The most studied candidate molecules are ligands PD-L1 (CD 274) and PD-L2 (CD 273) expressed by lymphoma cells, which effectively suppress host T cells. The PD ligand genes are located on chromosome 9p24.1 close to Janus kinase 2 (JAK2) gene. The clinical impact of PD-L1/PD-L2 protein expression has not been described in PMBCL. Methods: Tumor samples of 27 previously untreated patients were analyzed. Clinical characteristics were as follows: median age at diagnosis 35 years (20–74), female-to-male ratio 1.7:1, most patients (70%) had limited mediastinal disease and a mean tumor diameter of 10.7 cm. The IPI and aaIPI scores were low in 67% and 37%, intermediate-low in 26% and 41% and intermediate-high in 7% and 22%, respectively. No patients were assigned to a high risk group. All patients were treated with anthracycline-based chemotherapy 15% with CHOP and 85% with third-generation intensive regimen. Therapy was intensified in 70% of the cases with high-dose therapy and autologous stem cell transplantation. Most of the patients (70%) received rituximab and 15% were also treated with IF radiotherapy. Formalin-fixed and paraffin-embedded tissues were processed in routine tissue sections (approx. 5 micrometers) and placed on plus slides. After antigen retrieval with the use of the enzymatic or microwave oven processes, indirect immunohistochemistry with commercially available primary antibodies in optimized dilution was performed: CD20 clone L27, CD23 clone 1B12, CD30 clone Ber-H2, CD10 clone G27-P, Bcl-2 clone 100, Bcl-6 clone PGB6p, MUM1/IRF4 clone MUM1p, CD274 polyclonal, CD273 polyclonal, and HLADR clone TAL.1B5. For visualization, a secondary antibody with the standard avidin-biotin (ABC) method was applied. Results were expressed as a percentage of positive tumor cells and H-score (product of percentage of positive cells and staining intensity). Cytogenetic analysis with a locus-specific FISH probe (9p24) and arrayCGH was carried out in 15 (56%) of the patients. Results: Final treatment response was assessed in 26 (96%) patients (1 patient did not passed restaging procedures yet), CR was achieved in 22 (85%), PR in three and one patient progressed. After a median follow-up of 73 months (6.1 yrs), 22/26 (84%) patients are alive in the 1st CR, and only three patients died. Five-year PFS was 82.6% (95% CI 0.67–0.98) and five-year overall survival was 90.9% (95% CI 0.79–1.00). All samples expressed PD-L2 in (a median of) 80% of tumor cells with a median H-score of 90. PD-L2 protein expression was very low - six cases were negative and in positive cases, median expression was only 5% (H-score 5). HLA-DR expression was detected in all cases with a median positivity of 70% (H-score 140). Cytogenetic analysis detected amplification of 9p24.1 in 8/15 (53%) of the cases. When analyzing clinical characteristics, only correlation of high HLA-DR expression with limited clinical stage (p=0.04) and low IPI (p<0.01) was found. There was no correlation between treatment response quality and HLA-DR or PD-L2 expression, but high PD-L1 expression (above the median) correlated with non-CR status after treatment (p=0.07). Due to a low number of relapses, there was no relationship between protein expression and survival. No difference was found between cases with or without JAK-2 copy gain in terms of PD-1L expression (71% vs. 73%, p=0.92) or PD-L1 H-score (80 vs. 73, p=0.55); expression of PD-2L was higher (4% vs. 9%, p=0.19) in cases with JAK-2 amplification. Conclusion: Frontline intensive therapy is very effective in PMBCL patients. This is why no clear prognostic impact of protein expression of PD ligands or HLA expression was observed. There was constant high PD-L1 protein expression in PMBCL, low PD-2L expression and a high proportion of cases with JAK-2 gene amplification. Preliminary data show relationship between tumor immunogenicity (HLA-DR expression) and lymphoma aggressiveness. High PD-1L protein expression may probably influence treatment response quality. Further analyses are needed to clarify correlation between 9p24.1 amplification and PD-L protein expression. Supported by grants: MZ ÈR IGA NT 11103, LF-2012-007 and MSM 6198959205. Disclosures: Prochazka: Roche: Travel grants Other.

Genetic Variations In Immune Regulatory Genes and The Risk For Diffuse Large B-Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4286-4286
Author(s):  
Jeong-Eun Kang ◽  
In-Suk Kim ◽  
Nam-Hee Kim ◽  
Min Kyoung Kim
Keyword(s):  
Logistic Regression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Variations ◽  
Permutation Testing ◽  
Large B Cell Lymphoma ◽  
Increased Risk ◽  
Il10 Gene ◽  
Large B Cell

Abstract Introduction There is growing evidence linking genetic variations of immune regulation genes to non-Hodgkin lymphoma (NHL) etiology. In a large consortial study, it has been recently reported that an increased risk for NHL, especially the major lymphoma subtype diffuse large B-cell lymphoma (DLBCL), with genetic variations in immune regulatory genes that mediate inflammation and autoimmunity. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 57 genetic variations of 7 candidate genes, and their relation to risk for DLBCL in Koreans. Methods The case-control series consisted of 192 de novo DLBCL treated at five hospitals throughout Korea from August 2001 through August 2009 and 192 individuals from the population with age and gender matched healthy volunteers. The DNA samples were genotyped using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (Sequenom, Inc., San Diego, CA). We genotyped 11 haplotype-tagging SNPs (htSNPs) of spleen tyrosine kinase (STK), 9 htSNPs of Fc fragment of IgG, low affinity IIa, receptor (FCGR2A), 3 htSNPs of Fc fragment of IgG, low affinity IIIa, receptor (FCGR3A), 15 htSNPs of interferon regulatory factor 4 (IRF4), 9 htSNPs of interleukin 7 receptor (IL7R), 7 htSNPs of interleukin 10 (IL10), and 3 htSNPs of tumor necrosis factor (TNF) genes. We used logistic regression to evaluate the association between genotypes and haplotypes with DLBCL. For DLBCL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the co-dominant model for each SNP. The haplotypes were reconstructed according to the genotyping data and the linkage disequilibrium status of these SNPs. Results We did not find significant associations between the htSNPs of FCGR2A, FCGR3A, IRF4, IL7R, and TNF genes and the risk of DLBCL. However, the minor allele heterozygotes of the rs3021094 htSNP of IL10 gene (P-trend = 0.028) and the rs2991216 htSNP of the SYK gene (P-trend = 0.035) showed an increased risk of DLBCL. On 10-million permutation testing, the haplotype including rs3021094 variant allele of IL10 gene was significantly associated with an increased risk of DLBCL (P = 0.001), however, the haplotype including rs2991216 variant allele of STK gene was statistically insignificant (P = 0.055). Conclusions This study presents several novel aspects of the genetic susceptibility to develop DLBCL. Although this study did not show statistically significant association between STK htSNPs and risk for DLBCL on 10-millinon permutation testing, we demonstrated that genetic variants and haplotypes of IL10 gene showed the significantly increased risk for DLBCL. Larger studies that focus on the role of the STK and IL10 genes will support to confirm causal variants to develop diffuse large B-cell lymphoma. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Systematic Review of the Potential of MicroRNAs in Diffuse Large B Cell Lymphoma

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 144 ◽  
Author(s):  
Ane Larrabeiti-Etxebarria ◽  
Maria Lopez-Santillan ◽  
Borja Santos-Zorrozua ◽  
Elixabet Lopez-Lopez ◽  
Africa Garcia-Orad
Keyword(s):  
Systematic Review ◽  
B Cell ◽  
Treatment Response ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Extracellular Vesicle ◽  
Human Patient ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of invasive non-Hodgkin’s lymphoma (NHL). DLBCL presents with variable backgrounds, which results in heterogeneous outcomes among patients. Although new tools have been developed for the classification and management of patients, 40% of them still have primary refractory disease or relapse. In addition, multiple factors regarding the pathogenesis of this disease remain unclear and identification of novel biomarkers is needed. In this context, recent investigations point to microRNAs as useful biomarkers in cancer. The aim of this systematic review was to provide new insight into the role of miRNAs in the diagnosis, classification, treatment response and prognosis of DLBCL patients. We used the following terms in PubMed” ((‘Non-coding RNA’) OR (‘microRNA’ OR ‘miRNA’ OR ‘miR’) OR (‘exosome’) OR (‘extracellular vesicle’) OR (‘secretome’)) AND (‘Diffuse large B cell lymphoma’ OR ‘DLBCL’)” to search for studies evaluating miRNAs as a diagnosis, subtype, treatment response or prognosis biomarkers in primary DLBCL in human patient populations. As a result, the analysis was restricted to the role of miRNAs in tumor tissue and we did not consider circulating miRNAs. A total of thirty-six studies met the inclusion criteria. Among them, twenty-one were classified in the diagnosis category, twenty in classification, five in treatment response and nineteen in prognosis. In this review, we have identified miR-155-5p and miR-21-5p as miRNAs of potential utility for diagnosis, while miR-155-5p and miR-221-3p could be useful for classification. Further studies are needed to exploit the potential of this field.

scholarly journals Diffuse Large B-Cell Lymphoma with Overexpression of Cyclin E Substantiates Poor Standard Treatment Response and Inferior Outcome

2006 ◽  
Vol 12 (7) ◽  
pp. 2125-2132 ◽  
Author(s):  
Alexandar Tzankov ◽  
Andreas Gschwendtner ◽  
Florian Augustin ◽  
Michael Fiegl ◽  
Ellen C. Obermann ◽  
...  
Keyword(s):  
B Cell ◽  
Treatment Response ◽  
Standard Treatment ◽  
Cell Lymphoma ◽  
Cyclin E ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell
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