The high-grade B-cell lymphomas: Double hit and more

Both the 2022 WHO HAEM5 and the International Consensus Classification of lymphoma have refined the way we now approach high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements moving the previous generation of classification a step forward. The unifying biology of MYC/BCL2 tumours has been clearer and their inferior prognosis confirmed compared to those with morphological similarities but lacking the classifying cytogenetic abnormalities. FISH testing has largely become population based and we have learnt much from this. We can readily define molecular categories and apply these widely to clinical practice. Uncertainty has however been shed upon the place of double MYC/BCL6 translocations in defining a common disease group. We have enhanced knowledge of outcomes and the role of therapy intensification to overcome chemotherapy resistance. For those patients failed by initial induction chemotherapy, immunotherapy approaches, including CAR-T therapies, are improving outcomes. Novel inhibitors, targeting dysregulated oncogenic proteins are being explored at pace. The rare, but difficult, diagnostic classification HGBL (NOS) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double and triple hit lymphoma are numbered as this review synergises the current data on biology, prognosis, and therapies in HGBL.