A perspective on improving the R-CHOP regimen: from Mega-CHOP to ROBUST R-CHOP, the PHOENIX is yet to rise

The integration of rituximab (R) into cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) by Coiffier and colleagues was the first, and last, successful modification of this backbone regimen, which has endured now for almost 20 years. Countless attempts to redefine R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL) have migrated from a focus on dose-intense and dose-dense regimens, to the use of maintenance therapies, and most recently the addition of novel agents. To date, none have changed the basic formula. Although there are many reasons for the absence of success, the incredible molecular heterogeneity of DLBCL is likely to be a major complicating factor. It is clear that as the scientific field's understanding of the genetic heterogeneity of DLBCL deepens, a precision medicine approach should be accounted for and might be one of several paths that could lead to improved outcomes. The rapid identification of poor prognostic groups within the evolving diverse molecular landscape of DLBCL will create new opportunities to produce the next generation of studies with targeted agents against specific pathological drivers. It is conceivable that targeting these driver pathways will require more than one agent, and of course, splitting the pool of patients with DLBCL into smaller groups on the basis of molecular characteristics, will reduce the number of eligible patients for clinical trial investigation. The integration of immunological agents might afford new opportunities to develop treatments agnostic to the complex molecular diversity, while adding minimal toxicity to the regimen. With each of these iterations, the hope is to ultimately shift away from a one-size-fits-all chemotherapy mentality to one predicated on an individualised approach, whether that be through the use of a targeted small molecule or a biological drug. In this Viewpoint, we explore the history of the collective efforts to improve upon R-CHOP, and underscore those lessons that might help to reshape our future plans.