Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL

In diffuse large B cell lymphoma (DLBCL), tumors belonging to the ABC but not GCB gene expression subgroup rely upon chronic active B cell receptor signaling for viability, a dependency that is targetable by ibrutinib. A phase III trial (“Phoenix;” ClinicalTrials.gov: NCT01855750) showed a survival benefit of ibrutinib addition to R-CHOP chemotherapy in younger patients with non-GCB DLBCL, but the molecular basis for this benefit was unclear. Analysis of biopsies from Phoenix trial patients revealed three previously characterized genetic subtypes of DLBCL: MCD, BN2, and N1. The 3-year event-free survival of younger patients (age ≤60 years) treated with ibrutinib plus R-CHOP was 100% in the MCD and N1 subtypes while the survival of patients with these subtypes treated with R-CHOP alone was significantly inferior (42.9% and 50%, respectively). This work provides a mechanistic understanding of the benefit of ibrutinib addition to chemotherapy, supporting its use in younger patients with non-GCB DLBCL. [Display omitted] •BTK inhibitor ibrutinib plus R-CHOP is effective in younger patients with ABC DLBCL•Genetic subtypes of DLBCL differ in genotype, phenotype, and oncogenic mechanisms•MCD and N1 subtypes acquire mutations that promote chronic active BCR signaling•Patients with the MCD and N1 subtypes have 100% survival with ibrutinib plus R-CHOP Wilson et al. show that patients with two genetic subtypes of DLBCL—MCD and N1—have 100% survival when treated with the BTK inhibitor ibrutinib plus R-CHOP chemotherapy but ≤50% survival when treated with R-CHOP alone. Both subtypes acquire mutations fostering B cell receptor signaling and BTK dependence, accounting for the therapeutic response.