Atezolizumab combined with immunogenic salvage chemoimmunotherapy in patients with transformed diffuse large B-cell lymphoma

Abstract

Patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) transformed from indolent B-cell lymphomas, including Richter transformation, have a poor prognosis. PD-1/PD-L1 antibodies produce modest objective and complete response rates in B-cell non-Hodgkin lymphoma as monotherapy but may synergize with immunogenic chemotherapies such as gemcitabine and oxaliplatin (GemOx). Thus, we evaluated the safety and efficacy of atezolizumab plus rituximab and GemOx (R-GemOx+Atezo) in R/R transformed DLBCL, including Richter transformation. We conducted a phase I trial including patients with transformed DLBCL after ≥1 prior therapy. Patients received up to four cycles of R-GemOx+Atezo. Patients in complete remission could then proceed to R-Atezo maintenance until progression. A safety lead-in with evaluation of dose-limiting toxicity was performed to confirm the recommended phase II dose; subsequently the treatment was administered to two expansion cohorts: one with transformed follicular lymphoma (FL) and the other with non-FL transformed DLBCL, including Richter transformation. Twenty-seven patients were enrolled. One of the six patients in the safety lead-in had a dose-limiting toxicity attributed to atezolizumab, a grade 4 Stevens-Johnson syndrome. The most common grade ≥3 events were neutropenia (18.5%), lymphopenia (18.5%), and thrombocytopenia (14.8%). The overall and complete response rates were 59% and 33%, respectively. The overall and complete response rates in transformed FL were 79% and 43%, respectively, and 38% and 23% in transformed non-FL, respectively. The median progression-free survival and overall survival of the total population were 4.2 and 7.7 months, respectively. R-GemOx+Atezo was well tolerated and demonstrated promising preliminary efficacy in patients with relapsed/refractory transformed DLBCL.

Figure 1.

Clinical trial profile of this single-arm trial of rituximab, gemcitabine, oxaliplatin, and atezolizumab. (A) Study schema. (B) CONSORT diagram. EOT: end of treatment; DLT: dose-limiting toxicity; PET/CT: positron emission tomography/ computed tomography; PB: peripheral blood; BX: biopsy; C8D1: cycle 8, day 1.

Figure 2.

Duration of response in patients treated with rituximab, gemcitabine, oxaliplatin, and atezolizumab. (A) Duration of response in all treated patients. (B) Duration of response in patients achieving complete or partial response. (C) Swimmer plot of patients enrolled. 95% CI: 95% confidence interval; NR: not reached; CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; NA: not available; Tx: treatment; R-Atezo: rituximab and atezolizumab.

Figure 3.

Survival outcomes in patients treated with rituximab, gemcitabine, oxaliplatin, and atezolizumab. (A) Progression-free and overall survival for all treated patients. (B) Progression-free survival for patients with follicular lymphoma or non-follicular lymphoma. (C) Overall survival for patients with follicular lymphoma or non-follicular lymphoma. 95% CI: 95% confidence interval; NR: not reached.