Double hit lymphoma: from biology to therapeutic implications

Abstract

So-called 'double-hit lymphomas' (DHL) or 'triple hit lymphomas' (THL) occur when MYC is concurrently rearranged with BCL2 and/or BCL6. These tumors are characterized by high proliferation rate and a very poor outcome following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin vincristine and prednisone) therapy, in most (though not all) studies that have looked at this. Though there is a paucity of published experience with other chemotherapy regimens, there is emerging evidence that more intensive approaches may improve outcome. Recently, there has been a lot of focus in the literature on 'double-expresser lymphomas' (DEL) with high MYC, BCL2 and/or BCL6 expression but typically without rearrangements of these genes. These DEL cases, have a poor outcome with R-CHOP and there is little consensus on how they should be approached. Expert commentary: This review will focus on the biology and treatment of DHL and DEL, discuss the outcome of these diseases with current standard as well as promising new approaches and conclude with a section on novel agents that are in development for these diseases.

The Expanding Role of the BCL6 Oncoprotein as a Cancer Therapeutic Target

“…It provides B-cells with simultaneous suppression of checkpoints through BCL6 along with the pro-growth and survival effects of MYC and BCL6. Not surprisingly the combination of MYC and/or BCL2 with BCL6 in DLBCL has been linked to unfavorable clinical outcomes (12). …”

Cytologic perspectives on neoteric B‐cell lymphoproliferative disorders

“…4,5 Concurrent derangements of BCL2 (an anti-apoptotic actor) and BCL6 (a transcription repressor) can be either the "second-hit" or "third-hit" in these disease states. 1 These lymphomas were described as epidemiologically infrequent with most patients being adults who presented with widespread and often extranodal disease.…”

Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes

“…However, a histopathological study of 492 mature aggressive B-cell neoplasms concluded that the proliferation fraction by Ki67 immunostaining is not useful to prescreen B-cell lymphomas as DHL or THL [89]. DEL overexpress Myc and BCL2/BCL6 but typically without rearrangements of these genes [24,87], though cut-off of double expression is not universally defined so far. THL is associated with rearrangement of Myc, BCL2 and also BCL6 [24].…”

“…DHLs are seen in approximately 5-10% of DLBCL patients and usually involve rearrangement of Myc oncogene with BCL2 (or sometimes BCL6) protein [24,86,87]. Using immunophenotypical data from larger studies on DHL, Aukema et al found that coexpression of CD10, BCL6, BCL2, and a high Ki67 proliferation index might be used to select potential DHLs in morphologically diagnosed DLBCL, though it may not be specific [88].…”