Navigating between Scylla and Charybdis: A roadmap to do better than Pola-RCHP in DLBCL

In treating diffuse large B-cell lymphoma (DLBCL), oncologists have traditionally relied on the chemotherapy backbone of R-CHOP as standard of care. The two dangers that the hematologist must navigate between are the aggressive disease (Charybdis that in absence of therapy destroys systematically all the ships) and the toxicity of the therapies (Scylla with its six monstrous heads that devour six crew members at a time), and hematologists have to navigate very carefully between both. Therefore, three different strategies were employed with the goal of improving cure rates: de-escalating regimens, escalating regimens, and replacement strategies. With a replacement strategy, a breakthrough in treatment was identified with polatuzumab vedotin (anti-CD79B antibody/drug conjugate) plus R-CHP. However, this regimen still did not achieve the elusive universal cure rate. Fortunately, advances in genomic and molecular technologies have allowed for an improved understanding of the heterogenous molecular nature of the disease to help develop and guide more targeted, precise, and individualized therapies. Additionally, new pharmaceutical technologies have led to the development of novel cellular therapies, such as CAR T-cell therapy, that could be more effective, while maintaining an acceptable safety profile. Thus, we aim to highlight the challenges of DLBCL therapy as the need to address therapeutic regimens eventually no longer tethered to a chemotherapy backbone. In the intersection of artificial intelligence and multi-omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics), we propose the need to analyze multidimensional biologic data to launch a decisive attack against DLBCL in a targeted and individualized fashion.