Why R-CHOP + X is not enough: lessons learned and next steps in the mission to improve frontline therapy for diffuse large B-cell lymphoma

Two-thirds of newly diagnosed cases of diffuse large B-cell lymphoma (DLBCL) are cured with R-CHOP, an immunochemotherapy regimen that has been the standard of care for almost two decades. Ongoing molecular characterization of DLBCL has revealed a heterogeneous disease comprised of multiple subtypes based on putative cell of origin or somatic mutations with unique oncogenic signaling pathways. The door has been opened to the use of novel agents that target the specific molecular vulnerabilities of DLBCL, but despite this, multiple randomized studies have not identified a suitable drug ‘X’ to combine with R-CHOP. This report will review recent attempts to add individual novel agents to R-CHOP in the mission to improve frontline treatment for DLBCL and discuss promising ongoing studies. It will offer potential strategies to explore when designing future clinical trials, including exploiting synergy between multiple novel agents.