Double Hit Diffuse Large B-cell Lymphomas
Double Hit Diffuse Large B-cell Lymphomas
Although diffuse large B-cell lymphoma (DLBCL) is curable with standard chemoimmunotherapy, over 30% of patients with advanced stage disease experience refractory disease or progression. Recent studies suggest that rearrangement of the myc oncogene occurs in approximately 10% of patients with DLBCL, and confers a very poor prognosis, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as "double hit DLBCL". Using immunohistochemistry, up to 30% of patients have evidence of increased expression of myc, which occurs in both activated B-cell and germinal center type DLBCL. When bcl-2 is also positive by immunohistochemistry, prognosis is also poor. There are no randomized studies guiding treatment for patients with double hit DLBCL, but new datasets are emerging suggesting a possible role for dose-adjusted EPOCH infusional chemotherapy with rituximab. This review will conclude with a survey of novel agents which may be rationally incorporated into chemotherapy platforms for this high risk subset of DLBCL.
Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoma in the United States, and over the past two decades, significant improvements in overall survival for a substantial subset of patients have resulted from the incorporation of rituximab into the CHOP chemotherapy regimen. For example, data from a population-wide database indicated that the 2-year progression-free survival of newly diagnosed DLBCL improved from 51% to 69% after R-CHOP became standard therapy. Clinical prognostic scoring systems may be utilized to determine prognosis of patients newly diagnosed with DLBCL, and these remain robust in the rituximab era. The international prognostic index (IPI: age >60, elevated LDH, performance status >1, stage >2 and extranodal sites >1) predicts a 59% overall survival for highest risk group at 3 years in a modern dataset. Efforts at refining this prognostic index include the NCCN IPI, which incorporates specific sites of disease involvement. Compared with the IPI, the NCCN-IPI better discriminated low- and high-risk subgroups (5-year overall survival: 96% vs. 33%) in two large retrospective datasets.
However, these clinical prognostic features are clearly surrogates for differential biology within DLBCL. Gene expression studies have indicated that DLBCL is a heterogeneous disease entity, as cell-of-origin studies reveal at least three distinct subtypes: primary mediastinal, activated B-cell, and germinal center B-cell types. These subtypes also predict for outcomes at diagnosis even when adjusted for clinical features, with inferior outcomes observed with activated B-cell type disease. Alternative strategies of organizing gene expression data emphasize this heterogeneity of DLBCL, with subsets characterized by signatures of host response, oxidative phosphorylation, and B-cell receptor pathway elements.
Rearrangement of the myc oncogene, resulting in constitutive overexpression, is necessary for the diagnosis of Burkitt lymphoma. The incidence of myc rearrangement, measured with FISH, in patients with DLBCL is variable between series, but appears to be in the range of of 6–16%. Given the relative frequency of these diseases, there are more patients diagnosed with myc-positive DLBCL than with Burkitt lymphoma each year in the United States. Over the past three years, the impact of this abnormality on outcome in DLBCL has become clear, and indeed it may be the most powerful biological predictor of negative outcome for DLBCL in the rituximab era. This review will detail the prognostic power of myc positivity measured by both FISH and immunohistochemistry, correlate this information with gene expression information and the importance of associated bcl-2 rearrangements, and summarize data regarding optimal therapeutic strategies for patients with this abnormality.
Abstract and Introduction
Abstract
Although diffuse large B-cell lymphoma (DLBCL) is curable with standard chemoimmunotherapy, over 30% of patients with advanced stage disease experience refractory disease or progression. Recent studies suggest that rearrangement of the myc oncogene occurs in approximately 10% of patients with DLBCL, and confers a very poor prognosis, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as "double hit DLBCL". Using immunohistochemistry, up to 30% of patients have evidence of increased expression of myc, which occurs in both activated B-cell and germinal center type DLBCL. When bcl-2 is also positive by immunohistochemistry, prognosis is also poor. There are no randomized studies guiding treatment for patients with double hit DLBCL, but new datasets are emerging suggesting a possible role for dose-adjusted EPOCH infusional chemotherapy with rituximab. This review will conclude with a survey of novel agents which may be rationally incorporated into chemotherapy platforms for this high risk subset of DLBCL.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoma in the United States, and over the past two decades, significant improvements in overall survival for a substantial subset of patients have resulted from the incorporation of rituximab into the CHOP chemotherapy regimen. For example, data from a population-wide database indicated that the 2-year progression-free survival of newly diagnosed DLBCL improved from 51% to 69% after R-CHOP became standard therapy. Clinical prognostic scoring systems may be utilized to determine prognosis of patients newly diagnosed with DLBCL, and these remain robust in the rituximab era. The international prognostic index (IPI: age >60, elevated LDH, performance status >1, stage >2 and extranodal sites >1) predicts a 59% overall survival for highest risk group at 3 years in a modern dataset. Efforts at refining this prognostic index include the NCCN IPI, which incorporates specific sites of disease involvement. Compared with the IPI, the NCCN-IPI better discriminated low- and high-risk subgroups (5-year overall survival: 96% vs. 33%) in two large retrospective datasets.
However, these clinical prognostic features are clearly surrogates for differential biology within DLBCL. Gene expression studies have indicated that DLBCL is a heterogeneous disease entity, as cell-of-origin studies reveal at least three distinct subtypes: primary mediastinal, activated B-cell, and germinal center B-cell types. These subtypes also predict for outcomes at diagnosis even when adjusted for clinical features, with inferior outcomes observed with activated B-cell type disease. Alternative strategies of organizing gene expression data emphasize this heterogeneity of DLBCL, with subsets characterized by signatures of host response, oxidative phosphorylation, and B-cell receptor pathway elements.
Rearrangement of the myc oncogene, resulting in constitutive overexpression, is necessary for the diagnosis of Burkitt lymphoma. The incidence of myc rearrangement, measured with FISH, in patients with DLBCL is variable between series, but appears to be in the range of of 6–16%. Given the relative frequency of these diseases, there are more patients diagnosed with myc-positive DLBCL than with Burkitt lymphoma each year in the United States. Over the past three years, the impact of this abnormality on outcome in DLBCL has become clear, and indeed it may be the most powerful biological predictor of negative outcome for DLBCL in the rituximab era. This review will detail the prognostic power of myc positivity measured by both FISH and immunohistochemistry, correlate this information with gene expression information and the importance of associated bcl-2 rearrangements, and summarize data regarding optimal therapeutic strategies for patients with this abnormality.
