Clinical Implications of the New Molecular Knowledge for Treatment of Diffuse Large B-Cell Lymphoma

For more than 35 years, the standard induction therapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) consists of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Until recently, efforts to improve upon this regimen were empiric and without success, and consisted of adding additional cytotoxic drugs, intensifying doses and schedules of drugs, and consolidating initial responses with high dose therapy and autologous stem cell support. The addition of rituximab to standard CHOP therapy (RCHOP) more than a decade ago improved progression-free and overall survival, and now the majority of patients presenting with DLBCL are cured with induction therapy. Biological insights from gene expression profile (GEP) studies indicate substantial heterogeneity of DLBCL, which is largely responsible for treatment failure. We are now at the cusp of being able to utilize rational targeted therapies in biologically-defined subgroups of patients of DLBCL. In addition to cell-of-origin defined subgroups, GEP has defined stromal signatures and pathway-specific signatures in DLBCL which also predict outcome and potentially define a group of patients for a biologically-targeted therapy approach. At present, clinical development strategies include combining novel agents with standard RCHOP treatment and/or evaluating novel agents as maintenance or consolidation after RCHOP treatment. Two recent failures illustrate the challenges inherent in these approaches: RCHOP + bevacizumab (targeting angiogenesis) and R-CHOP followed by enzastaurin (targeting protein kinase C-b). Ongoing randomized trials are evaluating R-CHOP + bortezomib (proteasome inhibitor targeting NFkB), R-CHOP + ibrutinib (Bruton’s tyrosine kinase inhibitor targeting B-cell receptor signaling pathway), and R-CHOP + lenalidomide (immunomodulator with pleotropic effects) in specific GEP (or immunohistochemistry surrogates for GEP)-defined groups of patients. Finally, the majority of treatment failures in DLBCL appear to occur in patients with overexpression of c-MYC oncogene (often in combination with BCL-2 protein), which represents up to one third of patients when defined using immunohistochemistry. This unique subgroup occurs across cell-of-origin designations, and represents a substantial opportunity to improve outcome in DLBCL with the addition of novel therapeutics. This talk will review the considerable challenges in translating the exciting biology defined by GEP into the clinic for patients with DLBCL, provide an update on current and future trial designs, and conclude with a forward looking time to when GEP, or an accurate surrogate, is a component of the standard diagnostic algorithm to define optimal therapeutic approach to DLBCL.