Smart Start: Rituximab, Lenalidomide, and Ibrutinib in Patients With Newly Diagnosed Large B-Cell Lymphoma

Abstract

PURPOSE Chemoimmunotherapy for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades. Both preclinical models and clinical data suggest the combination of lenalidomide and ibrutinib may have synergy in DLBCL, particularly in the non–germinal center B-cell-like subset. METHODS We enrolled 60 patients with newly diagnosed non–germinal center B-cell-like DLBCL in this investigator-initiated, single-arm phase II trial of rituximab, lenalidomide, and ibrutinib (RLI) with the sequential addition of chemotherapy (ClinicalTrials.gov identifier: NCT02636322 ). Patients were treated with rituximab 375 mg/m2 intravenous once on day 1, lenalidomide 25 mg once per day on days 1-10, and ibrutinib 560 mg once daily continuously of each 21-day cycle (RLI). After two cycles, standard chemotherapy was added to RLI for six additional cycles. The primary end points were overall response rate (ORR) after two cycles of RLI alone and complete response rate after completion of RLI with chemotherapy. In evaluable samples, circulating tumor DNA and DLBCL90 assays were performed. RESULTS The median age was 63.5 years (range: 29-83 years) with 28% age 70 years or older. The revised international prognostic index identified 42% as high risk, and 62% were double expressor of MYC and BCL2 protein. The ORR after two cycles of RLI was 86.2%, and the complete response rate at the end of RLI-chemotherapy was 94.5%. With a median follow-up of 31 months, the progression-free survival and overall survival were at 91.3% and 96.6% at 2 years, respectively. CONCLUSION Smart Start is the first study, to our knowledge, to treat newly diagnosed DLBCL with a targeted therapy combination before chemotherapy. RLI produced a high ORR, and RLI with chemotherapy resulted in durable responses. This establishes the potential for developing biologically driven and noncytotoxic first-line therapies for DLBCL.

A phase 1/2 study of lenalidomide and obinutuzumab with CHOP for newly diagnosed DLBCL

“…Promising combination regimens include tafasitamab and L with R-CHOP 41 , 42 and ibrutinib and L with R-CHOP. 43 …”

Diffuse Large B-Cell Lymphoma (DLBCL): Early Patient Management and Emerging Treatment Options

“… 2022 [ 111 ] NCT02636322 SMART Start II R + ibrutinib + lenalidomide ≥ 18 y., non-GCB,PS ≤ 2 60 ORR 86 A highly effective chemo-free regimen. 2019 [ 112 ] NCT01855750 PHOENIX III Ibrutinib + R-CHOP vs R-CHOP ≥ 18 y., non-GCB, stage II–IV, R–IPI ≥ 1, PS ≤ 2 419 / 419 EFS at 3 y. 70 / 67 Ibrutinib + CHOP does not improve EFS.…”

“…111 Lenalidomide plus ibrutinib and rituximab, a chemotherapy-free regimen, was tested in the pilot SMART Start study. 112 Patients with non-GCB DLBCL who entered this trial were treated with 2 cycles of chemotherapy-free regimen followed by CHOP or EPOCH with 1-year PFS of 93%. This regimen was shown to be safe and effective, and opened up a new discussion about potential implementation of chemo-free regimens in daily practice.…”

Management of Diffuse Large B-Cell Lymphoma: Are We Getting Smarter?

“…Investigators from the MD Anderson Cancer Center have attempted to bridge this personalization gap with a trial using novel agents selected on the basis of cell-of-origin determination (Smart Start). 6 These investigators conducted a phase II study with a window design element, selecting patients with non-GCB DLBCL (meaning enriched for ABC) and initiating treatment with two cycles of rituximab, lenalidomide, and ibrutinib (RLI). Conventional chemotherapy was not added until cycle 3 (Fig 1).…”

“…In the article that accompanies this editorial, 6 a novel strategy to the frontline management of diffuse large B-cell lymphoma is investigated. Although there are no immediately practice-changing findings, the strategy used can serve as a template for incorporating novel agents into frontline management.…”