Double-hit lymphoma has been recognized as a distinct diagnosis for a decade, but its definition is still evolving. A gene rearrangement is called a 'hit,' and the diagnosis previously covered MYC rearrangements alongside BCL2 and/or BCL6. The 2024 WHO classification narrowed the category to MYC and BCL2 rearrangements only, with MYC/BCL6 double hits now classified as genetic subtypes of DLBCL not otherwise specified or high-grade B-cell lymphoma NOS. The reason is that MYC/BCL2 double-hit lymphomas form a homogeneous group, while MYC/BCL6 cases are heterogeneous.
The disease traditionally carries a poor prognosis, with inferior progression-free and overall survival compared with non-double-hit DLBCL when treated with R-CHOP. Clinically, it can be difficult to distinguish from other large B-cell lymphomas. Jason Westin, MD, of MD Anderson, says the only definitive way to know is pathology testing, and that patients and doctors are 'flying blind' if fluorescence in situ hybridization (FISH) has not been done. He calls FISH a 'bedrock' test that should be part of the initial workup.
For the rare patient with localized, low-risk disease, treatment may resemble standard DLBCL care. Most patients, however, have advanced-stage, high-risk disease and need intensive chemoimmunotherapy, most commonly R-EPOCH. A single-arm phase II study reported a 4-year event-free survival rate of 73%, higher than historical controls. Westin estimates that about half of patients will eventually need therapy for relapsed or refractory disease. In that setting, further chemotherapy is unlikely to help, and CAR T-cell therapy is the preferred option; a multicenter analysis found no difference in progression-free survival between double-hit and non-double-hit patients treated with CD19-directed CAR T cells.
Randomized trials specifically for double-hit lymphoma are difficult because the disease is uncommon, and phase III trials in large B-cell lymphoma are often underpowered for these patients. Westin and colleagues are running ZUMA-23, a phase III trial testing the CAR T-cell therapy axi-cel versus standard care as first-line treatment in high-risk large B-cell lymphoma, defined by an International Prognostic Index of 4/5. Many double-hit patients present with that score, so the trial may help clarify the best frontline approach.