Long-term clinical outcomes from the smart start trial: rituximab, lenalidomide and ibrutinib in patients with newly diagnosed large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) represents the most common non-Hodgkin lymphoma, in which ~60–85% of patients achieve a complete response (CR) with standard frontline chemoimmunotherapy approaches [ 1 , 2 , 3 ]. Despite these promising response rates, ~40% of patients can develop relapsed or refractory disease, and significant research efforts have been devoted to improving the durability and response with frontline therapies through the incorporation of novel agents [ 1 , 2 ]. Due to its biologic heterogeneity, DLBCL is subclassified by cell of origin (COO) into germinal center B-cell (GCB) and activated B-cell-like (ABC), the latter being considered in the “non-GCB” DLBCL group and heralding inferior outcomes with 2-year progression-free survival (PFS) as low as 40% [ 4 , 5 ]. However, non-GCB DLBCL harbors multiple targetable vulnerabilities, including chronic activation of B-cell transcription factors for differentiation (i.e. nuclear factor kB, IRF4) [ 6 , 7 , 8 ]. Harnessing these biological vulnerabilities, the Smart Start trial (NCT02636322) served as a proof-of-concept that a frontline non-cytotoxic RLI combination regimen utilizing rituximab with the immunomodulatory agent, lenalidomide, and Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, results in excellent efficacy outcomes with a favorable safety profile [ 9 ]. After an initial lead-in phase with RLI targeted therapy for 2 cycles, 86% achieved an overall response rate (ORR), following which 95% of patients achieved a CR after receiving RLI-chemotherapy from cycles 3 to 8 [ 9 ]. Furthermore, with a median follow-up of 31 months, a 2-year PFS and overall survival (OS) of 91% and 97% were observed, respectively [ 9 ]. Herein, we now report the seven-year updated analysis of the safety and efficacy outcomes from the Smart Start trial.