Diffuse Large B-Cell Lymphoma

Abstract

Large B-cell lymphomas, with an estimated 150,000 new cases annually worldwide, represent almost 30% of all cases of non-Hodgkin’s lymphoma. Patients typically present with progressive lymphadenopathy, extranodal disease, or both and require therapy. Despite the advanced stage at presentation in the majority of patients, more than 60% can be cured with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy (Fig. 1A). Patients with treatment failure after R-CHOP often have a poor outcome — in particular, those with disease that is refractory to frontline or subsequent therapies — although some patients can have a durable remission and be cured after secondary therapies. Over the past two decades, improved insights into large B-cell lymphomas, in terms of epidemiology, prognostic factors, and biologic heterogeneity, have led to a refinement of disease classification and the development of new therapeutic approaches.

Figure 1 (facing page).. Outcomes of Diffuse Large B-Cell Lymphoma (DLBCL), Risk Factors, and Biologic Features.

Panel A shows Kaplan–Meier survival estimates for all patients with newly diagnosed DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in British Columbia, Canada (2001–2019). Time to progression (TTP) is measured from the date of diagnosis to the date of disease progression or death from lymphoma, with deaths from unrelated causes censored. This curve highlights that the risk of DLBCL progression is highest within the first 2 years, followed by a lower risk of progression for up to 10 years. Progression-free survival (PFS) is measured from the date of diagnosis to the date of progression or death from any cause. Given that the median age of patients with DLBCL is in the mid-60s, the difference between the TTP and PFS curves reflects the competing risk of death from unrelated causes. The marginal difference between the PFS and overall survival (OS) curves reflects the limited number of patients cured with secondary therapies, although new therapies may improve overall survival. Panel B shows reported risk factors for the development of DLBCL. Panel C shows the heterogeneous biologic features that reflect insights gained over the past 20 years. Gene expression profiling originally delineated two molecular subtypes, germinal center B-cell–like and activated B-cell–like, which are believed to arise from different stages of B-cell lymphoid differentiation (cell of origin), with gene expression resembling their normal B-cell counterparts. Distinct functional profiles and genetic aberrations have been identified within the two subtypes, but heterogeneity within these subtypes has also been recognized. On the basis of the results of in-depth genomic analyses, new taxonomies for DLBCL have been proposed, designated as the LymphGen classification and DLBCL clusters. These taxonomies further refine DLBCL genomic classification and may better delineate distinct biologic entities. The postulated associations between cell-of-origin molecular subtypes and these new genomic entities are denoted by solid arrows, indicating robust associations; dashed arrows indicate weaker associations or uncertain associations. Genetic hallmarks based on recurring genomic aberrations and resultant deregulated genetic pathways have been identified within entities, which are associated with varied prognoses. DLBCL with a MYC rearrangement and a concurrent rearrangement in BCL2, BCL6, or both (double-hit [DH] or triple-hit [TH] lymphoma) is currently classified as a high-grade B-cell lymphoma (HGBCL-DH/TH). HGBCL-DH/TH cases, together with cases with an EZB subtype with a MYC DH gene signature (EZB-MYC+),^, largely cluster with the EZB subtype and harbor biologic features associated with a poor clinical outcome. BCR denotes B-cell receptor, CNS central nervous system, EBV Epstein–Barr virus, HHV8 human herpesvirus 8, HIV human immunodeficiency virus, HL Hodgkin’s lymphoma, miR-17–92 microRNA cluster 17–92, NF-κB nuclear factor κB, PI3K phosphatidylinositol 3-kinase, SLE systemic lupus erythematosus, and TNF/LTA, tumor necrosis factor/lymphotoxin alpha.

Figure 2 (facing page).. Algorithm for the Management of Large B-Cell Lymphomas.

Diagnostic confirmation is based on careful pathological review of biopsy material (preferably from an excisional biopsy). Clinical and pathological features should be used to categorize patients according to the World Health Organization (WHO) classification for lymphoid cancers in order to identify patients with large B-cell lymphomas who may require alternative therapies. Routine staging investigations should be performed to distinguish patients with limited-stage disease (typically defined as Ann Arbor stage I or II, with nonbulky mass <7.5 to 10 cm, without systemic symptoms and with disease that can be encompassed by a radiation field) from those with advanced-stage disease. Evaluation of patients with a high risk of CNS involvement should include magnetic resonance imaging (MRI) of the brain and cytologic evaluation of cerebrospinal fluid, with flow cytometry to rule out occult CNS involvement. Patients with limited-stage disease may be treated with an abbreviated course of immunochemotherapy, with or without radiation therapy. Standard therapy for patients with advanced-stage disease is six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy, regardless of the immunohistochemical (IHC) profile (e.g., double-expressor lymphoma [DEL]) or molecular subtype. Outcomes in patients with high-risk DLBCL remain unsatisfactory with R-CHOP, and clinical trials should strongly be considered. Although CNS-penetrating systemic therapy, such as high-dose methotrexate with R-CHOP, can be considered for patients at high risk for CNS recurrence, the value of this approach remains unproven. Response should be assessed with ¹⁸F-fluorodeoxyglucose positron-emission tomography and computed tomography (¹⁸F-FDG PET-CT), according to the Lugano classification criteria, with interpretation according to the Deauville five-point scale.^,, Patients with evidence of relapsed or refractory disease should undergo repeat biopsy and staging to optimize further therapy. Patients who are eligible for autologous stem-cell transplantation (ASCT eligible) should receive platinum-based salvage therapy, with those who have a response proceeding to ASCT. Patients who do not have a response to salvage therapy or who have a relapse after ASCT, as well as those who are not candidates for ASCT because of age and coexisting medical conditions, are considered to be ASCT ineligible. There are numerous treatment alternatives for these patients, and selection of therapy should be individualized on the basis of disease and clinical characteristics of the patient. Based on regulatory approvals, some options may be indicated only for third-line therapy and beyond (e.g., CAR T-cell therapy at present) and therefore thoughtful sequencing of available therapies is instrumental. Clinical trials incorporating new agents should strongly be considered at all phases of therapy. CBC denotes complete blood count, COO cell of origin, Cr creatinine, DA-EPOCH-R dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab, FISH fluorescence in situ hybridization, H&E hematoxylin and eosin, HBV hepatitis B virus, HCV hepatitis C virus, LDH lactate dehydrogenase, LFTs liver-function tests, NOS not otherwise specified, and XRT radiation therapy.