Relapsed Diffuse Large B-Cell Lymphoma: Clinical Utility of Cell of Origin

Although cases of diffuse large B-cell lymphoma (DLBCL) may look identical under the microscope, DLBCL is a clinically and biologically heterogeneous group of lymphomas. Multiple clinical features such as age 60 years or older, stage III/IV, high lactic dehydrogenase, two or more extranodal sites of disease, and an Eastern Cooperative Oncology Group performance status of 2 or more, all features included in the International Prognostic Index, have been associated with a poorer outcome. However, even within the International Prognostic Index categories, a wide range of outcomes has been noted. In recent years, several different oncogenic pathways have been recognized as playing a role in the various subtypes of DLBCL. Gene expression profiling (GEP) studies have now revealed a major division on the basis of the cell of origin of DLBCL into germinal center B-cell-like (GCB) disease, activated B-cell-like (ABC) disease, and primary mediastinal B-cell disease. When the gold standard GEP is applied to patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, the 3-year overall survival of patients with GCB is 74% and of patients with ABC is 40%. In addition, the tumor microenvironment seems to play a major role in the pathogenesis of DLBCL and may represent another target for therapy. A favorable subtype, stromal-1 signature, reflects extracellular matrix deposition and infiltration of the lymphoma by macrophages that transmit trophic signals or suppress an antilymphoma response. Stromal-2 signature, which is less favorable, is associated with a high blood vessel density. Because performing GEP has required frozen tissue, it has not been practical in many cases of lymphoma. Therefore, alternative methods such as immunohistochemistry (IHC) and polymerase chain reaction have been developed. The most commonly used criteria include stains of bcl-10, bcl-6, and MUM1, the Hans criteria. Using these criteria, patients with the GCB subset of DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone had a 3-year overall survival of 85% compared with 69% for the ABC subtype. Other algorithms have been produced using different criteria. However, little information is available on the cell of origin and outcome at the time of relapse or on specific therapies that might improve the outcome in the subtypes. As described in the article by Thieblemont et al that accompanies this editorial, patients with DLBCL were randomly assigned in the Bio-CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study to receive either rituximab, ifosfamide, carboplatin, etoposide (R-ICE) or to receive rituximab, dexamethasone, cytarabine, cisplatin (R-DHAP) as salvage chemotherapy. When treatment interaction was tested, the GCB-like DLBCL, on the basis of the Hans algorithm, was significantly associated with a better progression-free survival in the R-DHAP arm but not on the R-ICE arm. Is this a reproducible finding and is it clinically meaningful? In prior studies of patients with relapsed DLBCL, the subtype of ABC is over-represented because of the higher likelihood of relapse. In one previous study, no difference by cell of origin at the time of salvage chemotherapy could be distinguished; however, the patients in that study received the R-ICE regimen. The finding of improvement with specific salvage regimens by subtype will need to be confirmed in a prospective trial. One concern with the use of IHC classifiers is the accuracy of the technique. In the Bio-CORAL study, the percentage of patients with the GCB phenotype was 49% on the basis of the Hans algorithm, 72% on the basis of the Muris algorithm, and 27% on the basis of the Nyman algorithm. A small subset of 39 patients in the study by Thieblemont et al had the gold standard GEP performed, which showed that 51% of the patients had GCB. There was a 75% concordance between the GEP results and the Hans algorithm in the study. This is similar to the 80% concordance that has previously been reported for the Hans technique. More recently, newer techniques have had improved concordance, such as the Choi algorithm and the so-called Tally algorithm that combines many of the other algorithms. However, a concern of any of the IHC techniques is that some of the antibodies are difficult to use (eg, bcl-6), may not be reproducible in inexperienced laboratories, and are not commercially available (eg, germinal center B-cell expressed transcript-1 [GCET1], forkhead box protein-1 [FOXP1]) or Clinical Laboratory Improvement Amendmentapproved. Althoughonly39caseswereconfirmedbyGEP in the Thieblemont study, the study did confirm the benefit of the R-DHAP regimen for patients with GCB-like DLBCL. As we understand more about the tumor and stromal biology of lymphoma, we may be able to use this information to develop newer molecularly targeted treatment strategies. Genetic lesions found in GCB-like DBLCL include t(14;18) translocation, deletion of the tumor suppressor phosphatase and tensin homolog, amplification of the microRNA cluster mi-17-92, bcl-6 expression, and p53 mutations. On the basis of this information, agents that affect apoptosis, bcl-6, or p53 modulators may be more effective in patients with GCB-like DLBCL. One hypothesis set forward with respect to the results in the Bio-CORAL study is that the cytarabine-containing regimen of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 31 NOVEMBER 1 2011