Double-hit lymphomas: current paradigms and novel treatment approaches

Double-hit lymphomas (DHLs) are a heterogeneous group of mature B-cell lymphomas that harbor concurrent rearrangements of MYC and BCL2 or, occasionally, BCL6. Several studies have now shown that they are associated with a very aggressive clinical course and poor outcome after standard R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy, with few patients surviving beyond 2 years. Due to their rarity, there is a paucity of data evaluating patient outcomes with alternative strategies to R-CHOP and no consensus on how they should be optimally managed. Recent studies have demonstrated that a significant proportion of diffuse large B-cell lymphoma (DLBCL) cases have high protein expression of MYC and BCL2 as detected by IHC. These so-called "double-expressor" DLBCLs are also associated with a poor outcome after R-CHOP, even when MYC and BCL2 rearrangements are absent. There is much interest in developing new strategies for DHL and better characterizing the underlying biology that drives their poor prognosis. Alternative chemotherapy platforms to R-CHOP, such as DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab), are under investigation for MYC-rearranged DLBCL, including DHL, and several novel small-molecule inhibitors of MYC and BCL2 are in development.