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

• Published in: Blood 2021-02, Vol.137 (5), p.600-609
• Main Authors: Morschhauser, Franck, Feugier, Pierre, Flinn, Ian W., Gasiorowski, Robin, Greil, Richard, Illés, Árpád, Johnson, Nathalie A., Larouche, Jean-François, Lugtenburg, Pieternella J., Patti, Caterina, Salles, Gilles A., Trněný, Marek, de Vos, Sven, Mir, Farheen, Samineni, Divya, Kim, Su Y., Jiang, Yanwen, Punnoose, Elizabeth, Sinha, Arijit, Clark, Emma, Spielewoy, Nathalie, Humphrey, Kathryn, Bazeos, Alexandra, Zelenetz, Andrew D.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Clinical Trials and Observations; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Fatigue - chemically induced; Female; Gastrointestinal Diseases - chemically induced; Genes, bcl-2; Granulocyte Colony-Stimulating Factor - therapeutic use; Hematologic Diseases - chemically induced; Humans; Infections - etiology; Kaplan-Meier Estimate; Life Sciences; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Male; Middle Aged; Neoplasm Proteins - antagonists & inhibitors; Prednisone - administration & dosage; Prednisone - adverse effects; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Rituximab - administration & dosage; Rituximab - adverse effects; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Vincristine - administration & dosage; Vincristine - adverse effects; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2020006578

The phase 2 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+). Eligible patients were ≥18 years of age and had previously untreated DLBCL, Eastern Cooperative Oncology Group performance status ≤2, and International Prognostic Index 2 to 5. Venetoclax 800 mg (days 4-10, cycle 1; days 1-10, cycles 2-8) was administered with rituximab (8 cycles) and cyclophosphamide, doxorubicin, vincristine, and prednisone (6-8 cycles) in 21-day cycles. Primary end points were safety, tolerability, and complete response (CR) at end of treatment (EOT). Secondary end points were 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+ subgroups. With a 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+ subgroups (HR, 0.55; 95% CI, 0.34-0.89) vs 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 vs 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+ patient subgroups. •The phase 2 CAVALLI study assessed efficacy and safety of venetoclax + R-CHOP in patients with DLBCL, including Bcl-2+ subpopulations.•Venetoclax + R-CHOP showed potential for improved efficacy vs R-CHOP alone, supporting further investigation of venetoclax in Bcl-2+ DLBCL. [Display omitted]