Clinical outcomes, patterns of relapse and molecular landscape of advanced stage High Grade B-cell Lymphoma

High-grade B cell lymphoma (HGBCL) is an aggressive clinical entity characterized by poor overall survival and high rates of CNS relapse. HGCBL traditionally includes cases harboring MYC rearrangement with concurrent BCL2 and/or BCL6 rearrangements (R). However, the prognostic implications of different combinations of rearrangements (MYC/BCL2, MYC/BCL6, or MYC/BCL2/BCL6) remain an open question with differing reports in the literature, and our knowledge of the clinical characteristics, response to treatment, and patterns of relapse remains incomplete. We identified clinical data from 124 cases of advanced-stage HGBCL treated at Memorial Sloan Kettering Cancer Center (69 MYC/BCL2-R, 34 MYC/BCL2/BCL6-R ('triple hit') and 21 MYC/BCL6-R). Thirty-six cases were subjected to targeted next-generation sequencing with MSK-IMPACT HEME. We confirm the poor prognosis of HGBCL, with low complete response rates (44%), poor overall survival (59.8% at 2 years) and high rates of CNS relapse (10.1%). Intensive regimens such as dose-adjusted R-EPOCH were associated with improved overall survival compared to R-CHOP based regimens. Unexpectedly, patients with MYC/BCL6-R disease had increased incidence of CNS relapse and rapid progression to death after relapse; we observed differing cell-of-origin in these cases compared to BCL2-R disease. In addition, counter to prior reports in DLBCL, HGBCL transformed from low-grade lymphoma was associated with improved survival in our cohort. Mutational profiling of HGBCL cases demonstrated enrichment for mutations associated with DLBCL, particularly GC-derived cases, as well as a high proportion of MYC mutations. Our results support the poor prognosis of HGBCL and the recent separation of MYC/BCL6 disease as a distinct clinical entity.