Can Venetoclax Plus R-CHOP Improve Outcomes in Aggressive DLBCL?

Researchers found that venetoclax plus the regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) improved outcomes in BCL2-positive diffuse large B-cell lymphoma (DLBCL) patients, according to a study (abstract 782) presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 1–4 in San Diego.

In blood cancers, BCL2 overexpression mediating evasion of apoptosis is frequent. In DLBCL, 50% of patients overexpress the BCL2 protein, 30% overexpress BCL2 and MYC, and 5% to 10% harbor translocations of BCL2 and MYC (double-hit [DH])-all correlated with a poor prognosis. In the current study, the investigators led by Franck Morschhauser of Centre Hospitalier Universitaire in Lille, France, hypothesized that the combination of the BCL2 inhibitor venetoclax and chemotherapy could ameliorate DLBCL outcomes based on early data.

In the single-arm, multicenter, phase II part of the CAVALLI trial, the researchers analyzed the efficacy of 800-mg venetoclax plus R-CHOP in all first-line DLBCL patients. They compared these data with a matched patient population in the R-CHOP arm of the phase III GOYA study. They reported the first safety, efficacy, and biomarker analyses in all patients from the ongoing CAVALLI study.

The primary endpoint was PET/CT response 6 to 8 weeks following the last rituximab dose (end of treatment), and secondary endpoints included progression-free survival (PFS) and safety.

In total, 208 patients who received any treatment were assessed for safety and efficacy, with patient characteristics mostly similar between CAVALLI and GOYA. Of note, grade 3/4 adverse events were observed in 85% of CAVALLI patients vs 66% of GOYA patients, with most being cytopenias, infections, and febrile neutropenia.

The end-of-treatment complete response rate in all patients did not significantly differ in CAVALLI and GOYA, but did improve in BCL2-positive subgroups. Furthermore, when compared with GOYA and adjusted for baseline covariates via Cox methodology, the researchers observed PFS improvement in BCL2 immunohistochemistry (IHC)–positive patients (hazard ratio, 0.53; 95% CI, 0.30–0.93).

“The addition of venetoclax to R-CHOP in first-line DLBCL treatment resulted in improved efficacy in BCL2 IHC–positive patients compared with matched GOYA controls,” the researchers concluded. “These data further support exploration of venetoclax plus R-CHOP in a high-risk population of BCL2-positive first-line DLBCL, including DH patients.”

In an interview with Cancer Network, Chan Cheah, MD, a hematologist and clinical researcher at Hollywood Private Hospital and Sir Charles Gairdner Hospital, commented on the implications of these findings. “The results of the study and biomarker analysis suggest that patients with BCL2 overexpression by immunohistochemistry or FISH seem to have a benefit from the addition of venetoclax. I think this provides rationale to explore this combination in a phase III study.”