A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma

Abstract

The phase II CAVALLI (NCT02055820) study assessed efficacy and safety of venetoclax, a selective, B-cell lymphoma-2 (Bcl-2) inhibitor, with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in first-line (1L) diffuse large B-cell lymphoma (DLBCL), including patients demonstrating Bcl-2 protein overexpression by immunohistochemistry (Bcl-2 IHC-positive). Eligible patients ≥18 years with previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2-5. Venetoclax 800 mg (days 4-10, cycle 1 and days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and CHOP (6-8 cycles); 21-day cycles. Primary endpoints: safety, tolerability, and complete response (CR) at end of treatment (EOT). Secondary endpoints: progression-free survival (PFS) and overall survival. Comparative analyses used covariate-adjusted R-CHOP controls from the GOYA/BO21005 study, an appropriate contemporary benchmark for safety and efficacy. Safety and efficacy analyses included 206 patients. CR rate at EOT was 69% in the overall population and was maintained across Bcl-2 IHC-positive subgroups. With median follow-up of 32.2 months, trends were observed for improved investigator-assessed PFS for venetoclax plus R-CHOP in the overall population (Hazard ratio [HR] = 0.61, 95% confidence interval [CI], 0.43-0.87) and Bcl-2 IHC-positive subgroups (HR = 0.55, 95% CI, 0.34-0.89), versus R-CHOP. Despite a higher incidence of grade 3/4 hematologic adverse events (86%), related mortality was not increased (2%). Chemotherapy dose intensity was similar in CAVALLI versus GOYA. The addition of venetoclax to R-CHOP in 1L DLBCL demonstrates increased but manageable myelosuppression and the potential of improved efficacy particularly in high-risk, Bcl-2 IHC-positive patient subgroups.

Apoptotic Blocks in Primary Non-Hodgkin B Cell Lymphomas Identified by BH3 Profiling

“…Given that venetoclax is being tested in combination with other chemotherapies, such as rituximab, cyclophosphamide, doxorubicin, and vincristine (components of RCHOP) in DLBCL [ 31 ] and bendamustine-rituximab in FL [ 32 ], we determined whether exposure to frontline chemotherapy drugs could bring cells closer to the apoptotic threshold and synergize with venetoclax to initiate apoptosis. Since the supply of primary lymphoma cells is limited, and their growth and viability are poor ex vivo over long periods of culture, we performed BH3 profiling on HGBL-DH cell lines after exposure to different chemotherapies in vitro.…”

“…RCHOP and venetoclax should be effective in high-grade lymphomas that express BCL2 protein, are not class B, and co-depend on BCL2 and MCL1 (53% of our diagnostic DLBCL samples). This combination appeared to translate into a clinical benefit in patients with BCL2+ DLBCL in the phase II CAVALLI study [ 31 ]. Thus, BH3 profiling could be used to predict patients’ responses to venetoclax and select drugs that could be synergistic.…”

One Patient Diagnosed With Primary Refractory Diffuse Large B Cell Lymphoma Successfully Salvaged With BCL2 Inhibitor Followed by anti-CD19 CAR-T Suffered From a Secondary Onset of Severely CRS

“…Double expressor lymphoma is high expression of BCL2 and MYC protein by immunohistochemistry, cutoff of which is 50% and 40% respectively. There are several studies reporting the outcomes of BCL2 inhibitor combined chemotherapy as rst or salvage therapy for refractory or relapse DLBCL [14][15][16]. One prospective phase II study found trend was observed for improved investigator-assessed PFS for venetoclax plus R-CHOP as a front-line therapy in the BCL2 IHC-positive subgroups (HR = 0.55, 95% CI, 0.34-0.89), compared with R-CHOP [16].…”

“…There are several studies reporting the outcomes of BCL2 inhibitor combined chemotherapy as rst or salvage therapy for refractory or relapse DLBCL [14][15][16]. One prospective phase II study found trend was observed for improved investigator-assessed PFS for venetoclax plus R-CHOP as a front-line therapy in the BCL2 IHC-positive subgroups (HR = 0.55, 95% CI, 0.34-0.89), compared with R-CHOP [16]. However, ORR of BCL2 inhibitor monotherapy for relapsed/refractory DLBCL is only 15%-18% without details of BCL2 protein expression [6,7].…”

Circulating RNA biomarkers in diffuse large B-cell lymphoma: a systematic review

“…These classifications may complement conventional prognostic scores, such as the international prognostic index (IPI), in identifying high-risk subsets of patients [16]. The importance of understanding the heterogeneity in DLBCL was illustrated by several studies that identified subgroups of high-risk patients that could benefit from associating targeted therapy to standard treatment, emphasizing the significance of a personalized medicine approach [17][18][19].…”