Abstract

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous diagnostic category that is comprised of two prominent molecular subtypes, termed activated B cell-like (ABC) and germinal center B cell-like (GCB). These DLBCL subtypes are now viewed as molecularly distinct diseases since they arise from distinct stages of normal B cell development, require distinct recurrent genetic abnormalities to become malignant, have distinct cure rates with current chemotherapy regimens, and respond differentially to targeting agents. We defined a 'chronic active' form of B cell receptor (BCR) signalling that activates NF-kB in ABC DLBCLs. Such ABC DLBCLs are killed by knockdown of BCR signalling components, such as the kinase BTK or components of the BCR itself. Over one fifth of ABC DLBCLs have mutations affecting the CD79B or CD79A subunits of the BCR that augment BCR signalling. To attack chronic active BCR signalling therapeutically, we initiated clinical trials in relapsed/refractory DLBCL of ibrutinib, an irreversible and highly selective inhibitor of BTK. Ibrutinib monotherapy induced a high rate of complete and partial responses in ABC DLBCL, while GCB DLBCL tumours rarely responded. Given its excellent safety profile and selective mechanism of action, we are hopeful that ibrutinib can be combined with both chemotherapy and other signalling modulators to achieve cures for these patients. Several rational combinations of targeted agents for the therapy of ABC DLBCL will be presented.