scholarly journals Obesity Is Associated with Increased Relapse Risk in Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1449-1449
Author(s):  
Kevin Tang ◽  
Jorge Mazzini ◽  
Martha P. Mims ◽  
Gustavo Rivero ◽  
Purnima Sravanti Teegavarapu
Keyword(s):  
Tumor Microenvironment ◽  
Regression Model ◽  
B Cell ◽  
Research Funding ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
Medical Center ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive Non-Hodgkin's lymphoma (NHL) characterized by clinical, biological and genetic heterogeneity. Despite the tremendous advancement in anticancer therapy against DLBCL, up to 40% of patients are refractory and/or relapse after first-line chemo-immunotherapy. Mechanisms responsible for chemo-immunotherapy failure are largely uncharacterized; however, it is believed the microenvironment contributes to tumor adaptation and survival. Several studies have shown that high body mass index (BMI) is associated with increased risk of developing DLBCL and obesity is an independent prognostic indicator of worse outcome when compared to non-obese patients. Weight gain alters the metabolic landscape of tumor microenvironment to inhibit T cell function and promote cellular growth. Obesity induced proinflammatory mediators can activate numerous signaling pathways including nuclear factor (NF)-KB that result in anti-apoptotic and increased proliferative efficiency in B-cells Here, we report the results of our retrospective study from two hospital systems in Houston, Texas evaluating the impact of BMI on progression-free-survival (PFS) in DLBCL patients receiving standard induction chemotherapy. Methods: After Institutional Review Boards (IRB) approval, patients (pts) were identified by electronic medical record database query. Inclusion criteria included: (a) age>18 years old, (b) DLBCL diagnosis confirmed by pathology review at Ben Taub Medical Center and Baylor St. Luke's Medical Center. BMI was calculated using patient's height and weight at diagnosis. For all comparison, we selected DLBCL pts with World Health Organization (WHO) predefined overweight, class I, II, III obesity to better capture effect of extreme BMI on DLBCL PFS. Cell-of-origin (COO) was determined by Hans classification. R-CHOP/R-EPOCH were classified as intense therapy whereas R-CVP/R-CEOP as non-intense therapy. Descriptive statistics was used to evaluate differential expression of clinical and laboratory variables. PFS among pts with BMI <35 and BMI >35 was estimated with Kaplan Meier Method. Cox regression model evaluated effect of independent variables on PFS for pts with DLBCL exhibiting obesity. SAS was used for all analysis. Results: 123 pts were identified. Demographic, clinical and laboratory data was balanced among DLBCL pts with and without BMI >35 (Table 1). Median BMI was 25.9 for pts with BMI<35 v 37.3 in pts with BMI >35. In the pts with BMI <35, 36.9% were classified as germinal center b-cell (GCB) subtype and 63.1% were classified as non-GCB subtype (p= NS). Within the BMI >35, 46.2% were GCB subtype and 53.9% were non-GCB subtype. 45.9% of pts had low International Prognostic Index (IPI) score in BMI<35 compared to 56.52% in BMI>35, whereas 54% had high IPI in BMI<35 compared to 43.48% in BMI>35. PFS was 2,864 days vs 763 days in patients with BMI <35 and >35, respectively (p=0.02). (Fig 1). To address effect of "type of therapy administered" (low v high intensity), COO, and age as confounders for our observation that PFS is inferior in DLBCL pts with BMI >35, Cox regression model was performed confirming the independent predictive role for BMI >35 only on DLBCL PFS. Conclusions: Our study demonstrates that obesity (BMI >35) results in increased relapse risk in DLBCL patients. In our population, risk of relapse was enhanced by higher BMI independent of age, therapy administered and COO. Obesity, by itself, especially BMI>35 (Class II and Class III) may represent a unique factor for adverse outcome in DLBCL. The mechanism for which extreme obesity leads to inferior PFS in DLBCL is unclear. It is possible that obesity induces "high risk" mutations acquisition and/or adversely modifies tumor microenvironment resulting in chemotherapy cytotoxic attenuation. Larger studies are needed to externally validate our observation. Figure 1 Figure 1. Disclosures Mims: Biogen: Current holder of individual stocks in a privately-held company; Incyte: Research Funding; IDEC: Current holder of individual stocks in a privately-held company; Celgene: Research Funding; Pfizer: Research Funding; AVEO: Research Funding.

scholarly journals Identification and Validation of a Prognostic Gene Signature for Diffuse Large B-Cell Lymphoma Based on Tumor Microenvironment-Related Genes

2021 ◽  
Vol 11 ◽  
Author(s):  
Tao Pan ◽  
Yizi He ◽  
Huan Chen ◽  
Junfei Pei ◽  
Yajun Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
Large B Cell Lymphoma ◽  
Prognostic Prediction ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumor entity, which makes prognostic prediction challenging. The tumor microenvironment (TME) has a crucial role in fostering and restraining tumor development. Consequently, we performed a systematic investigation of the TME and genetic factors associated with DLBCL to identify prognostic biomarkers for DLBCL. Data for a total of 1,084 DLBCL patients from the Gene Expression Omnibus database were included in this study, and patients were divided into a training group, an internal validation group, and two external validation groups. We calculated the abundance of immune–stromal components of DLBCL and found that they were related to tumor prognosis and progression. Then, differentially expressed genes were obtained based on immune and stromal scores, and prognostic TME‐related genes were further identified using a protein–protein interaction network and univariate Cox regression analysis. These genes were analyzed by the least absolute shrinkage and selection operator Cox regression model to establish a seven-gene signature, comprising TIMP2, QKI, LCP2, LAMP2, ITGAM, CSF3R, and AAK1. The signature was shown to have critical prognostic value in the training and validation sets and was also confirmed to be an independent prognostic factor. Subgroup analysis also indicated the robust prognostic ability of the signature. A nomogram integrating the seven-gene signature and components of the International Prognostic Index was shown to have value for prognostic prediction. Gene set enrichment analysis between risk groups demonstrated that immune-related pathways were enriched in the low-risk group. In conclusion, a novel and reliable TME relevant gene signature was proposed and shown to be capable of predicting the survival of DLBCL patients at high risk of poor survival.

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.

scholarly journals Proteomic analysis in diffuse large B-cell lymphoma identifies dysregulated tumor microenvironment proteins in non-GCB/ABC subtype patients

2021 ◽  
pp. 1-14
Author(s):  
Susanne Bram Ednersson ◽  
Mimmie Stern ◽  
Henrik Fagman ◽  
Herman Nilsson-Ehle ◽  
Sverker Hasselblom ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Proteomic Analysis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 454-454 ◽  
Author(s):  
Yucai Wang ◽  
Umar Farooq ◽  
Brian K. Link ◽  
Mehrdad Hefazi ◽  
Cristine Allmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

scholarly journals Inflammatory Cells in Diffuse Large B Cell Lymphoma

2020 ◽  
Vol 9 (8) ◽  
pp. 2418
Author(s):  
Roberto Tamma ◽  
Girolamo Ranieri ◽  
Giuseppe Ingravallo ◽  
Tiziana Annese ◽  
Angela Oranger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Tumor Antigens ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B cell lymphoma (DLBCL), known as the most common non-Hodgkin lymphoma (NHL) subtype, is characterized by high clinical and biological heterogeneity. The tumor microenvironment (TME), in which the tumor cells reside, is crucial in the regulation of tumor initiation, progression, and metastasis, but it also has profound effects on therapeutic efficacy. The role of immune cells during DLBCL development is complex and involves reciprocal interactions between tumor cells, adaptive and innate immune cells, their soluble mediators and structural components present in the tumor microenvironment. Different immune cells are recruited into the tumor microenvironment and exert distinct effects on tumor progression and therapeutic outcomes. In this review, we focused on the role of macrophages, Neutrophils, T cells, natural killer cells and dendritic cells in the DLBCL microenvironment and their implication as target for DLBCL treatment. These new therapies, carried out by the induction of adaptive immunity through vaccination or passive of immunologic effectors delivery, enhance the ability of the immune system to react against the tumor antigens inducing the destruction of tumor cells.

scholarly journals Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma

Haematologica ◽  
2020 ◽  
pp. haematol.2019.243626 ◽  
Author(s):  
Matias Autio ◽  
Suvi-Katri Leivonen ◽  
Oscar Brück ◽  
Satu Mustjoki ◽  
Judit Mészáros Jørgensen ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Immune Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Regulation of p27 by S-Phase Kinase- Associated Protein 2 Is Associated with Aggressiveness in Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3760-3760
Author(s):  
Ritsuko Seki ◽  
Koichi Ohshima ◽  
Tomoaki Fujisaki ◽  
Naokuni Uike ◽  
Fumio Kawano ◽  
...  
Keyword(s):  
B Cell ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
S Phase ◽  
Prognostic Impact ◽  
Treatment Groups ◽  
Skp2 Expression ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. In this study, we investigated the significance of Skp2 and p27 expression in diffuse large B cell lymphoma (DLBCL) treated with CHOP or CHOP-R. All patients (671) were diagnosed as having DLBCL at the twenty different hospitals and were treated with either CHOP (425) or CHOP-R (246) from 1996 to 2005. All specimens were histopathologically recomfirmed by one pathologist with expertise before entering into this study. Their clinical characteristics, including either the IPI or R-IPI factors, were evenly matched in both treatment groups. The median follow-up of living patients was 3.7 and 2.1 y for CHOP vs CHOP-R, respectively. Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. There were 257 patients with high Skp2 expression (cutoff value >40% positive cells) (257/671,39.0%). High Skp2 expression was found in all IPI groups. Expression of p27 (P<.001) was associated with better overall survival (OS), whereas expression of Skp2 was associated with worse OS in CHOP treatment groups (P<.001). We also examined the prognostic impact of Skp2 according to various expression degree of Skp2, Skp2 expression remained a significant predictor of survival (<40%,40–79%,≥80%, P<.001). The multivariant analysis revealed that both the IPI score and the expression of Skp2 and p27 were independent predictors of OS and PFS in both treatment groups (P<.001). The patients with high Skp2 expression in combination with low p27 expression were related to worst survival in CHOP group (Fig1A). Interestingly, even in CHOP-R group, both high Skp2 expression and low p27 expression were the strong biomarker of worse prognosis (Fig 1B). DLBCL patients with high Skp2 expression did not benefit from the addition of R to CHOP. Conclusion: Addition of rituximab did not provide a beneficial outcome to DLBCL with high Skp2 and low p27 expression. Therapeutic strategies other than CHOP-R will be needed for DLBCL patients exhibiting a high Skp2 and low p27 expression at the time of diagnosis. Figure Figure

Central Nervous System Relapse in Patients with Diffuse Large B-Cell Lymphoma: Analysis of Incidence and Prognostic Factors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1666-1666
Author(s):  
Masahiro Uni ◽  
Yuki Kagoya ◽  
Yasuhito Nannya ◽  
Fumihiko Nakamura ◽  
Mineo Kurokawa
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Initial Diagnosis ◽  
High Dose ◽  
Cns Involvement ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Large B Cell

Abstract The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone) has significantly improved the outcome of diffuse large B-cell lymphoma (DLBCL). However, its secondary involvement in the central nervous system (CNS) is still a fatal event, and optimal therapeutic strategies have remained to be established. Combined immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine is currently in use for patients with CNS relapse, though treatment outcome has not been evaluated enough. In the present study, we aimed to analyze the incidence and prognosis of CNS relapse of aggressive B-cell lymphoma in comparison with those of systemic relapse in the era of rituximab-containing regimens. We also estimated the risk factors and prognostic factors for CNS relapse. We retrospectively analyzed 278 consecutive adult patients (≥16 years old) who were diagnosed as DLBCL or primary mediastinal large B-cell lymphoma (PMLBL) at The University of Tokyo Hospital, Tokyo, Japan, from August 2003 through August 2013. We excluded patients who had CNS or intraocular involvement at diagnosis since those patients had received high-dose methotrexate-based therapy instead of R-CHOP. Four to six courses of intrathecal administration of methotrexate were performed in patients with adrenal gland, testis or breast involvement as prophylaxis for CNS relapse. The median follow-up period was 42 months, and the median age was 66 years (range, 23-91). Overall, 67 patients (24.1%) had relapse at any site, of which 24 patients (35.8%) had CNS involvement. The median interval between initial diagnosis and the occurrence of secondary CNS involvement was 212 days, and 15 of the 24 patients (62.5%) had CNS relapse within 1 year from the initial diagnosis. Multivariate analysis revealed that multiple or diffuse extranodal involvement at initial diagnosis (hazard ratio [HR] 3.74, 95% confidence interval [CI] 1.28-10.91; P<0.01) was associated with the development of CNS relapse against non-CNS relapse. Chromosomal abnormality was investigated in 112 patients, of which 38 had abnormal karyotypes as identified by G-banding analysis for lymph nodes. Patients with CNS relapse more frequently harbored chromosomal abnormalities compared with those without relapse in univariate analysis (P=0.01). We also analyzed the survival of patients with primary CNS lymphoma (PCNSL) as a control. Only two (7%) of 27 patients with PCNSL died during the follow-up period. Five-year OS from initial diagnosis was 92.3% (95% CI: 82.5-100.0%), and was significantly better than that for patients with CNS relapse (33.9%, 95% CI: 17.3-66.3%, P<0.01). Among 24 patients with CNS relapse, eight (33%) had systemic lesions other than CNS when diagnosed as CNS relapse, and four (17%) patients newly developed systemic lesions while treated for CNS relapse. Patients without concurrent systemic lesions attained a rather good prognosis by chemo-radiotherapy, while those harboring concurrent systemic lesions had dismal outcome (one-year OS after the diagnosis of relapse: 74.0% versus 12.4%, P<0.01, Figure 1, systemic relapse was treated as a time-dependent covariate). These results indicate that controlling systemic lesions as well as CNS ones is essential for treating patients with secondary CNS involvement of DLBCL. CNS lesions would be well controlled with R-MPV implementation as salvage therapy, nevertheless we should be careful for concurrent systemic lesions which might require different therapeutic strategies. Disclosures Nannya: Chugai Pharmaceutical　CO., LTD: Speakers Bureau; Pfizer: Research Funding. Kurokawa:Chugai Pharmaceutical　CO., LTD: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding.

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