Richter syndrome, the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), occurs in about 2% to 10% of patients with CLL.1 These patients typically have a poor prognosis. Venetoclax, a Bcl-2 inhibitor, has shown clinical activity in DLBCL and in DLBCL-type Richter syndrome. Atezolizumab is a humanized immunoglobulin monoclonal antibody that prevents interaction with the PD-1 receptor. Preliminary data of atezolizumab alone or in combination with the CD-20 monoclonal antibody obinutuzumab demonstrated safety and efficacy in heavily pretreated patients with DLBCL.
In this phase 2 trial, the combination of venetoclax, atezolizumab, and obinutuzumab was evaluated in Richter syndrome. Adult patients with Eastern Cooperative Oncology Group performance status 0 to 2 with a diagnosis of DLBCL Richter syndrome from CLL/small lymphocytic lymphoma were eligible to participate. Patients with pretreated Richter syndrome, prior therapy with venetoclax or atezolizumab, central nervous system involvement, and/or a history of autoimmune disease were excluded from the study.
Of the 28 patients enrolled in the study, 9 will be included in the safety run-in phase. In the expansion phase, treatment will include obinutuzumab dosed at 1000 mg for cycles 1 through 8, atezolizumab dosed at 1200 mg for cycles 1 through 18, and venetoclax dosed at 20 mg in Cycle 1, escalating to 50 mg on days 1 through 8, 100 mg on days 8 through 15, and 200 mg on days 15 through 21 of Cycle 2, then 400 mg for cycles 3 through 18.
The primary end point of the study is safety and tolerability for the run-in phase and efficacy for the expansion phase. Efficacy end points will include overall response, complete remission, response duration, progression-free survival, and overall survival. Researchers will also evaluate rates of minimal residual disease negativity. Researchers hypothesize that this combination regimen may provide improved outcomes in a difficult-to-treat patient population.
Abstract TPS7575; Montillo M, et al.
- Parikh SA, Kay NE, Shanafelt TD. How we treat Richter syndrome. Blood. 2014;123:1647-1657.