Diffuse Large B-Cell Lymphoma/High-Grade B-Cell Lymphoma With MYC and BCL6 Rearrangements: A Study of 60 Cases

Classification of cases of diffuse large B-cell lymphoma (DLBCL)/high-grade B-cell lymphoma (HGBL) with MYC and BCL6 rearrangements, referred to here as BCL6 double-hit lymphoma (DHL), is controversial. We assessed 60 cases of BCL6-DHL and compared this cohort to 224 cases of DHL with MYC and BCL2 rearrangements (BCL2-DHL) and 217 cases of DLBCL not otherwise specified. Compared with the DLBCL cohort, patients with BCL6-DHL had more aggressive clinical features such as frequent extranodal involvement, high-stage disease, a high International Prognostic Index score, and an elevated serum lactate dehydrogenase level (P < .01 for all). Compared with the BCL2-DHL cohort, patients with BCL6-DHL had similarly aggressive clinical features but a lower frequency of germinal center B-cell (GCB) immunophenotype and MYC and BCL2 double expression. Patients with BCL6-DHL showed overall survival (OS) intermediate between patients with DLBCL and BCL2-DHL. Following induction with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, patients with BCL6-DHL demonstrated poor OS similar to patients with BCL2-DHL and worse OS than that of patients with DLBCL (P = .024). However, among patients who received rituximab, etoposide phosphate, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH), there was no significant difference in OS among the 3 groups (P = .146). Gene expression profiling showed that 60% of BCL6-DHL cases had a double-hit (DH)-like signature compared with 10% of DLBCL-GCB and 93% of BCL2-DHL cases. The DH-like signature in BCL6-DHL cases was associated with a GCB immunophenotype. Based on these data, we suggest that BCL6-DHL cases are clinically more aggressive than DLBCL and patients may benefit from a more aggressive therapy than R-CHOP. The data also suggest that BCL6-DHL, as currently defined, is heterogeneous and that neoplasms with a GCB immunophenotype are more likely to have a DH-like signature and behave more aggressively. Last, we suggest that BCL6-DHL cases deserve to be recognized separately in a lymphoma classification to facilitate further understanding of these neoplasms and for optimal patient management.