SUMMARY Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole exome sequencing and transcriptome sequencing in a cohort of 1001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

The process of apoptosis is essential for maintaining the physiologic balance between cell death and cell growth. This complex process is executed by two major pathways that participate in activating an executioner mechanism leading to chromatin disintegration and nuclear fragmentation. Dysregulation of these pathways often contributes to cancer development and resistance to cancer therapy. Here, we review the most recent discoveries in apoptosis regulation and possible mechanisms for resensitizing tumor cells to therapy.

Background Although rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered standard therapy for diffuse large B-cell lymphoma (DLBCL), patterns of use and the impact of R-CHOP on survival in patients >80 years are less clear. Methods We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to characterize presentation, treatment, and survival patterns in DLBCL patients diagnosed from 2002–2009. Chi-squared tests compared characteristics and initial treatments of DLBCL patients >80 years and ≤80 years. Multivariable logistic regression models examined factors associated with treatment selection in patients >80 years; standard and propensity score-adjusted multivariable Cox proportional hazards models examined relationships between treatment regimen, treatment duration, and survival. Results Among 4,635 patients with DLBCL, 1,156 (25%) were >80 years. Patients >80 were less likely to receive R-CHOP and more likely to be observed or receive rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP); both p<0.0001. Marital status, stage, disease site, performance status, radiation therapy, and growth factor support were associated with initial R-CHOP in patients >80. In propensity score-matched multivariable Cox proportional hazards models examining relationships between treatment regimen and survival, R-CHOP was the only regimen associated with improved OS (hazard ratio (HR) = 0.45, 95% confidence interval (CI) = 0.33–0.62) and LRS (HR=0.58, 95% CI 0.38–0.88). Conclusions Although DLBCL patients >80 years were less likely to receive R-CHOP, this regimen conferred the longest survival and should be considered for this population. Further studies are needed to characterize the impact of DLBCL treatment on quality of life in this age group.

Non-Hodgkin lymphoma (NHL) comprises numerous biologically and clinically heterogeneous subtypes, with limited data examining risk factors for these distinct disease entities. Many limitations exist when studying lymphoma epidemiology, therefore until recently little was known regarding the etiology of NHL subtypes. This review highlights the results of recent pooled analyses examining risk factors for NHL subtypes. We outline heterogeneity and commonality among risk factors for NHL subtypes, with proposed subtype-specific as well as shared etiologic mechanisms. In addition, we describe how the study of lymphoma epidemiology may translate into prevention or therapeutic targeting as we continue to explore the complexities of lifestyle and genetic factors that impact lymphomagenesis.

Background Patients with diffuse large B-cell lymphoma (DLBCL) exhibit widely divergent outcomes despite harboring histologically identical tumors. Currently, gene expression profiling (GEP) and immunohistochemistry algorithms (IHC) assign patients to one of two main subtypes: germinal center B-cell-like (GCB), or activated B-cell-like (ABC), the latter of which historically carries a less favorable prognosis. However, it remains controversial as to whether these prognostic groupings remain valid in the era of rituximab therapy. Materials and Methods A systematic literature review identified 24 articles from which meta-analyses were conducted, comparing survival outcomes for patients assigned to either GCB or ABC/non-GCB subtype by GEP and/or Hans, Choi or Muris IHC algorithms. Results Patients designated as GCB DLBCL by GEP fared significantly better in terms of overall survival than those with ABC DLBCL (HR = 1.85, P < .0001). In contrast, the Hans and Choi algorithms failed to identify significant differences in overall survival (P = .07 and P = .76 respectively) between GCB and non-GCB groups. Conclusions Our study illustrates a lack of evidence supporting the use of the Hans and Choi algorithms for stratifying patients into distinct prognostic groups. Rather, GEP remains the preferred method for predicting the course of a patient’s disease and informing decisions regarding treatment options.