Patients diagnosed with the non-germinal center B-cell (non-GCB) subtype of diffuse large B-cell lymphoma (DLBCL) have inferior outcomes with standard immunochemotherapy. The Bruton’s tyrosine kinase inhibitor ibrutinib and the immunomodulator lenalidomide both have shown promising clinical activity in non-GCB DLBCL as single agents, and the combination has demonstrated synergistic action in preclinical models. In a prior study, the combination of rituximab, lenalidomide, and ibrutinib (RLI) in relapsed non-GCB DLBCL showed an overall response rate (ORR) of 55%.1 At the ASCO 2019 Annual Meeting, researchers reported the final results of rituximab, lenalidomide, and ibrutinib combination treatment given prior to chemotherapy in newly diagnosed non-GCB DLBCL patients.
In this single-arm, open-label, phase 2 study, adult patients with newly diagnosed non-GCB DLBCL who had adequate organ function and performance status were eligible. The primary objectives were to determine the ORR at the end of 2 cycles of RLI alone, and to determine the complete response rate (CRR) after 2 cycles of RLI followed by 6 cycles of chemotherapy plus RLI. All patients were treated with a 375-mg/m2 dose of rituximab administered intravenously on day 1, oral ibrutinib 560 mg daily, and 25 mg of oral lenalidomide given on days 1 through 10 of 21-day cycles for 2 cycles, followed by 6 additional cycles of rituximab, lenalidomide, and ibrutinib plus chemotherapy.
A total of 60 patients were enrolled, with 58 patients evaluable for disease response. The median age was 64 years, and 50% were male. A majority of the evaluable patients had high-risk disease characteristics, 65% had advanced-stage disease, and 77% had a Ki-67 of ≥80%. In terms of safety, the most commonly reported adverse events included nausea, peripheral sensory neuropathy, and diarrhea. One patient experienced fatal central nervous system aspergillosis; this was attributed to high-dose corticosteroids plus rituximab, lenalidomide, and ibrutinib, leading researchers to prohibit concomitant use of corticosteroids during the rituximab, lenalidomide, and ibrutinib-only cycles.
The ORR for 2 cycles of rituximab, lenalidomide, and ibrutinib was 86%, and the CRR was 36%. Median time to progression and median overall survival were not reached. One patient refused to proceed with the preplanned chemotherapy after achieving a CR with 2 cycles of rituximab, lenalidomide, and ibrutinib, and remained relapse-free at the data cutoff.
In sum, the Smart Start trial demonstrated that the combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is effective in patients with newly diagnosed non-GCB DLBCL. Additional studies are evaluating an adjusted regimen with more cycles of rituximab, lenalidomide, and ibrutinib with less chemotherapy consolidation.
Abstract 7508; Westin J, et al.
- Ramchandren R, Johnson P, Ghosh N, et al. The iR2 regimen (ibrutinib, lenalidomide, and rituximab) is active with a manageable safety profile in patients with relapsed/refractory non-germinal center-like diffuse large B-cell lymphoma. Blood. 2018;132:402.