Venetoclax plus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) improves outcomes in BCL2-positive first-line diffuse large B-Cell lymphoma (DLBCL)

first safety, efficacy and biomarker analyses from the Phase II CAVALLI study

Franck Morschhauser, Pierre Feugier, Ian W. Flinn, Robin E. Gasiorowski, Richard Greil, Árpád Illés, Nathalie A. Johnson, Jean-Francois Larouche, Pieternella J. Lugtenburg, Caterina Patti, Gilles Salles, Marek Trněný, Sven de Vos, Farheen Mir, Martin Kornacker, Elizabeth A. Punnoose, Divya Samineni, Edith Szafer-Glusman, Adam Petrich, Arijit Sinha & 2 others Mehrdad Mobasher, Andrew D. Zelenetz

Research output: Contribution to journalMeeting abstract

16 Citations (Scopus)


Introduction: BCL2 overexpression leading to evasion of apoptosis is common in hematologic malignancies. In DLBCL, 50\% of patients (pts) overexpress BCL2 protein, 30\% overexpress BCL2 and MYC (double-expressor [DE]) and 5-10\% have translocations of BCL2 and MYC (double-hit [DH]), all of which are associated with a poor prognosis. We hypothesized that combination of the BCL2 inhibitor venetoclax (Ven) with chemotherapy would improve DLBCL outcomes based on pre-clinical and early clinical data. The Phase Ib part of the CAVALLI (NCT02055820) study assessed the maximum tolerated dose (MTD) of CHOP + rituximab (R) or obinutuzumab (G) with Ven (200-800mg) in non-Hodgkin lymphoma, recommending 800mg of Ven + R-CHOP for Phase II. The single-arm, multicenter Phase II part of CAVALLI investigated the efficacy of Ven + R-CHOP in all first-line (1L) DLBCL pts, by BCL2 immunohistochemistry (IHC) status within cell-of-origin (COO) subtypes, by BCL2 fluorescence in situ hybridization (FISH) and in DE and DH pts, with the intent to compare against a matched pt population in the R-CHOP arm of the GOYA Phase III study. Here we report the first safety, efficacy and biomarker analyses in all pts from this ongoing Phase II study.Methods: Eligible pts (age ≥18 yrs; Eastern Cooperative Oncology Group performance status ≤2; 1L DLBCL; International Prognostic Index score 2-5; ≥1 measurable lesion \gt;1.5cm) were assigned to receive six 3-weekly cycles of R-CHOP + 800mg Ven daily for 10 days (Days 1-10, except Cycle 1: Days 4-10), followed by two 3-weekly cycles of 800mg Ven on Days 1-10 + R on Day 1. The primary endpoint was PET-CT response 6-8 weeks after the last R dose (EoT), according to a modified version of Lugano 2014 criteria. Secondary endpoints were progression-free survival (PFS) and safety.Biomarker analyses in CAVALLI and GOYA were performed in pre-treatment tumor samples including a BCL2 IHC assay (cutoff: 50\% medium/high expression), MYC IHC assay (cutoff 40\% signal), BCL2 and MYC FISH, and COO assay (Nanostring).Results: 211 pts were enrolled; 208 received any treatment and were included in efficacy and safety analyses. Overall, pt characteristics were similar for CAVALLI and GOYA, except CAVALLI enrolled more Ann Arbor Stage IV (65.4\% vs 47.1\ and BCL2 IHC-positive pts (57.7\% vs 50.0\. The EoT complete response rate in all pts did not differ significantly between CAVALLI and GOYA (69.2\% vs 62.8\ respectively; Table 1), but was improved in BCL2-positive subgroups, specifically in BCL2 FISH-positive (70.0\% vs 47.5\ and DH (71.4\% vs 25.0\ pts. With 20 months' median follow-up in CAVALLI, disease progression and death had occurred in 29 and 6 pts, respectively. When compared with GOYA and adjusted for baseline covariates by Cox methodology, PFS improvement was observed in BCL2 IHC-positive pts (HR, 0.53; 95\% CI: 0.30-0.93), including within both activated B-cell (ABC; HR, 0.43; 95\% CI: 0.19-0.94) and germinal center B-cell (GCB; HR, 0.41; 95\% CI: 0.17-0.95) COO subgroups. No PFS benefit was observed in BCL2 IHC-negative GCB pts; the BCL2 IHC-negative ABC subgroup was too small for evaluation (Figure 1).Grade 3-4 adverse events (AEs) occurred in 85\% (176/208) of pts in CAVALLI versus 66\% (373/574) in GOYA; the majority were cytopenias, infections and febrile neutropenia (Table 2). In CAVALLI, 1\% (3/208) of AEs were fatal versus 5\% (30/564) in GOYA but follow-up was longer in GOYA (57 vs 20 months). The higher rate of AEs in CAVALLI led to dose interruptions/discontinuations of both Ven and R-CHOP; 61\% of pts had \gt;90\% relative dose intensity (RDI) of Ven; 73.2\% of CAVALLI pts had \gt;90\% RDI of each of doxorubicin and cyclophosphamide versus 76.4\% for doxorubicin and 77.6\% for cyclophosphamide in GOYA. There were no major differences in grade 3-4 AEs or the RDI of R-CHOP across intention-to-treat and BCL2-positive subgroups. GCSF prophylaxis was recommended, but not uniformly delivered.Conclusions: The addition of Ven to R-CHOP in 1L DLBCL treatment resulted in improved efficacy in BCL2 IHC-positive pts compared with matched GOYA controls. Higher rates of cytopenia, infection and febrile neutropenia were observed in CAVALLI versus the R-CHOP arm in GOYA. These data further support exploration of Ven + R-CHOP in a high-risk population of BCL2-positive 1L DLBCL, including DH pts.
Original languageEnglish
Pages (from-to)782
Number of pages1
Issue numberSupplement 1
Publication statusPublished - 1 Nov 2018
Externally publishedYes
Event60th Annual Meeting of the American Society of Hematology (ASH) 2018 - San Diego, United States
Duration: 1 Dec 20184 Dec 2018

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