Jean L. Koff

A Time to Kill: Targeting Apoptosis in Cancer

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.

Evaluating cell-of-origin subtype methods for predicting diffuse large B-Cell lymphoma survival: A meta-analysis of gene expression profiling and immunohistochemistry algorithms

BACKGROUND Patients with DLBCL exhibit widely divergent outcomes despite harboring histologically identical tumors. Currently, GEP and IHC algorithms assign patients to 1 of 2 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 using GEP and/or Hans, Choi, or Muris IHC algorithms. RESULTS Patients designated as GCB DLBCL using GEP fared significantly better in terms of overall survival than those with ABC DLBCL (hazard ratio, 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 patients disease and informing decisions regarding treatment options.

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

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 1,001 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.

Disease characteristics, patterns of care, and survival in very elderly patients with diffuse large B-cell lymphoma

Although the combination of 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 aged >80 years are less clear.

Comparison of the effectiveness of frontline chemoimmunotherapy regimens for follicular lymphoma used in the United States

Abstract To compare the effectiveness of frontline rituximab-chemotherapy regimens in clinical practice, we examined outcomes for patients with low-grade, stage III/IV follicular lymphoma receiving rituximab (R) with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), R with cyclophosphamide, vincristine and prednisone (R-CVP) or R with a fludarabine-based regimen (R-Flu) as frontline therapy. In total, 611 patients meeting these criteria were identified in the National LymphoCare Study: 47% receiving R-CHOP (n = 287), 31% receiving R-CVP (n = 187) and 22% receiving R-Flu (n = 137). Overall response rates were high (R-CVP 87%, R-CHOP 93%, R-Flu 94%; p = 0.017). Median follow-up was 7.4 years. R-CVP was associated with lower 5-year overall survival (R-CVP 76%, R-CHOP 86%, R-Flu 86%; p = 0.021) and progression-free survival (R-CVP 49%, R-CHOP 58%, R-Flu 64%; p = 0.029). There were no significant differences in survival in Cox models adjusted for baseline clinical factors, practice region/setting and post-treatment R maintenance/observation.

Intensive chemotherapy and consolidation with high dose therapy and autologous stem cell transplant in patients with mantle cell lymphoma

Abstract Mantle cell lymphoma (MCL) remains incurable with conventional chemotherapy without consensus on the optimal initial treatment. We examined our single center experience with frontline therapy for patients with MCL in consecutive cases diagnosed 1995-2011. Among 81 patients, median age was 59 (28% were ≥ 65 years of age), 95% had stage III/IV disease and 54% had a low risk MCL International Prognostic Index score. Thirty-five percent (n = 28) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 65% received R-HCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate/cytarabine; n = 53). Forty-one patients were consolidated with autologous stem cell transplant (ASCT). There were no significant differences in 2-year survival for R-CHOP versus R-HCVAD (p = 0.10) or for ASCT versus observation (p = 0.06). After controlling for clinical factors, R-HCVAD followed by ASCT was associated with superior progression-free survival (hazard ratio 0.26, 95% confidence interval 0.09–0.75).

Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype

Diffuse large B-cell lymphoma (DLBCL) has been categorized into two molecular subtypes that have prognostic significance, namely germinal center B-cell like (GCB) and activated B-cell like (ABC). Although ABC-DLBCL has been associated with NF-κB activation, the relationships between activation of specific NF-κB signals and DLBCL phenotype remain unclear. Application of novel gene expression classifiers identified two new DLBCL categories characterized by selective p100 (NF-κB2) and p105 (NF-κB1) signaling. Interestingly, our molecular studies showed that p105 signaling is predominantly associated with GCB subtype and histone mutations. Conversely, most tumors with p100 signaling displayed ABC phenotype and harbored ABC-associated mutations in genes such as MYD88 and PIM1. In vitro, MYD88 L265P mutation promoted p100 signaling through TAK1/IKKα and GSK3/Fbxw7a pathways, suggesting a novel role for this protein as an upstream regulator of p100. p100 signaling was engaged during activation of normal B cells, suggesting p100’s role in ABC phenotype development. Additionally, silencing p100 in ABC-DLBCL cells resulted in a GCB-like phenotype, with suppression of Blimp, IRF4 and XBP1 and upregulation of BCL6, whereas introduction of p52 or p100 into GC cells resulted in differentiation toward an ABC-like phenotype. Together, these findings identify specific roles for p100 and p105 signaling in defining DLBCL molecular subtypes and posit MYD88/p100 signaling as a regulator for B-cell activation.

New insights into the epidemiology of non-Hodgkin lymphoma and implications for therapy.

Non-Hodgkin lymphoma (NHL) comprises numerous biologically and clinically heterogeneous subtypes, with limited data examining the 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 the risk factors for NHL subtypes. We outline the heterogeneity and commonality among the 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.

To Each Its Own: Linking the Biology and Epidemiology of NHL Subtypes

Non-Hodgkin lymphoma (NHL) constitutes a diverse group of more than 40 subtypes, each characterized by distinct biologic and clinical features. Until recently, pinpointing genetic and epidemiologic risk factors for individual subtypes has been limited by the relative rarity of each. However, several large pooled case-control studies have provided sufficient statistical power for detecting etiologic differences and commonalities between subtypes and thus yield new insight into their unique epidemiologic backgrounds. Here, we review the subtype-specific medical, lifestyle, and biologic components identified in these studies, which suggest that a complex interplay between host genetics, autoimmune disorders, modifiable risk factors, and occupation contributes to lymphomagenesis.

A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin's lymphoma

Bortezomib‐containing combinations are active in non‐Hodgkin lymphoma (NHL) although peripheral neuropathy can limit their dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1·6 mg/m2) on days 1 and 8 of a 21‐day cycle for up to 8 cycles and R‐CHOP with a 1·5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan–Meier method. Among 29 eligible patients, NHL morphologies included follicular (n = 20), marginal zone (n = 5) and small lymphocytic lymphoma (n = 4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow‐up of 48·7 months, the 4‐year progression‐free and overall survivals were 83% and 93%. Twenty‐two patients experienced peripheral neuropathy of any grade, and two had grade 3 neuropathy. The combination of bortezomib with R‐CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL.