Optimal Management of Double-Hit Lymphoma.

Abstract

Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured by using standard immunochemotherapy, a sizeable proportion of patients cannot. Therefore, it is critical to be able to identify these patients up-front by looking at various clinical and biologic characteristics. DLBCL is a heterogeneous disease with clinical, morphologic, and genetically distinct subtypes, and it is important to understand how these various factors impact treatment outcome as a prerequisite for the development of effective and specific treatment strategies for clinically and molecularly defined subtypes.Whereas the role of clinical characteristics, such as those comprising the International Prognostic Index score, in predicting outcome has been understood for some time, many recent studies demonstrate a prognostic role for individual tumor biomarkers. Biomarkers are thus becoming more andmore of an important consideration in first-line optimal therapy selection. Most DLBCL cases can be divided into one of two molecular subtypes—a germinal center B-cell subtype or an activated B-cell (ABC) subtype—on the basis of mechanisms of oncogenic activation.Outcomes for patients with the ABC subtype are significantly inferior after standard therapy than are outcomes for those with the germinal center B-cell subtype; therefore, there is a need todevelop novel strategies for theABC subtype. It has beenhelpful that anumberof recently developed agents have shown selective activity within the ABC subtype, and randomized clinical trials to test someof these agents in the up-front setting are in progress. Role of MYC and BCL2 Whereas discovering the cell of origin has been helpful in the development of therapeutic agents, there has been much interest and focus in the literature on the roles ofMYC and BCL2 in DLBCL. Several retrospective studies have investigated these roles, and it has been shown that after standard CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or R-CHOP(rituximabplusCHOP) therapy, cases that harbor a MYC rearrangement, which is usually detected by fluorescent in situ hybridization, or both aMYC and a BCL2 rearrangement (double-hit lymphomas [DHLs]) have inferior outcomes. In patients with DHL, BCL2 is typically the translocation partner withMYC but it can sometimes be BCL6, or there can be three rearrangements with BCL2 and BCL6 (triple-hit lymphoma). In addition, by using immunohistochemistry to assess expression ofMYCandBCL2 inDLBCL,various groups have demonstrated that approximately 20% to 25% of newly diagnosed patients with DLBCL have high levels of MYC and BCL2 protein expression, without translocations in the majority of cases. These cases have been called double-expresser lymphomas, and patients do not respond well to treatment with standard R-CHOP therapy. An important question, therefore, is how should these patients be managed?