So-called double-hit diffuse large B cell lymphomas (DLBCLs) with both MYC and BCL2 rearrangements are known to hold an unfavourable prognosis. Now, two studies reveal new subsets of tumours with overlapping high-risk phenotypes.

In one of the studies, David Scott and colleagues defined a 104-gene expression signature (DHITsig) that distinguished double-hit DLBCLs from other germinal centre B cell-like (GCB)-DLBCLs, which are typically associated with a favourable prognosis. However, only 52% of patients with DHITsig-positive disease were found to have MYC and BCL2 rearrangements. Importantly, in retrospective analyses of patients treated with R-CHOP immunochemotherapy, positivity for the DHITsig was associated with inferior outcomes, irrespective of MYC/BCL2 status. Using a different gene expression signature previously observed in Burkitt lymphoma (a disease related to, but generally more aggressive than, DLBCL), another group of investigators led by David Westhead similarly identified a subset of poor prognosis ‘molecular high grade’ (MHG) DLBCLs, ~50% of which were defined cytogenetically as double-hit DLBCLs. These findings essentially double the number of patients with high-risk, double-hit phenotype GCB-DLBCL, such that they account for ~15% of all patients with DLBCL.

“In clinical practice, double-hit DLBCLs are increasingly treated differently to other GCB-DLBCLs, most often using more intensive chemotherapy, and we suggest that this practice might usefully be extended to the whole MHG group,” says Westhead. By contrast, “after identifying and removing patients with DHITsig-positive tumours, the GCB-DLBCL population now has an outstanding prognosis (5-year disease-specific survival of ~90%), obviating the need for treatment escalation in this group,” adds Scott.

These findings essentially double the number of patients with high-risk, double-hit phenotype…

Regarding the way forwards, “the first step will be to retrospectively apply this new classification system to completed clinical trials in order to determine whether existing treatment regimens will be useful,” states Scott. Additionally, “we are starting to design prospective trials in the high-risk group, initially with more intensive chemotherapy, but ultimately with agents targeting the particularities of the biology,” Westhead concludes. Importantly, Scott and Westhead are comparing their findings with the aim of forming a consensus definition for prospective clinical use.