According to a phase 2 study presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, adding venetoclax to rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone (R-CHOP) treatment for patients with diffuse large B-cell lymphoma (DLBCL) with expression of MYC and BCL2 (double expressor lymphoma [DEL]) did not improve progression-free survival (PFS), and caused higher toxicity.

Investigators included 119 patients with untreated DEL aged ≥ 18 years. Patients were randomized on a 1-to-1 basis to R-CHOP, including 60 patients (arm 1) or R-CHOP-venetoclax, including 59 patients (Arm 2). DEL was defined as MYC expression ≥40% and BCL2 expression ≥50%, without double-hit cytogenetics. Venetoclax at a dosage of 800 mg was given orally days 4 to 8 of cycle 1, and days 1 to 5 of subsequent cycles, for up to 6 cycles. The noted primary end point was PFS with 84% power to detect a hazard ratio (HR) of 0.518 corresponding to a 2-year PFS rate of 65% in arm 1 and 80% in arm 2 (1-sided α=0.20).

Trial results demonstrated that most patients were non-germinal center B cell-like (non-GCB) by immunohistochemistry (arm 1, 72%; arm 2, 58%), high-intermediate/high risk IPI (arm 1, 54%; arm 2, 51%) and ECOG performance status 0 to 1 (arm 1, 95%; arm 2, 86%). Additionally, BCL2 rearrangements were detected in 25% and 33% of patients in arm 1 and arm 2, respectively. Most patients completed therapy per protocol (84% in arm 1, 75% in arm 2). The median follow-up was 27 months.

It was noted that no difference in PFS was observed with 12-month PFS estimates of 77% in Arm 1 and 76% in Arm 2 [HR = 0.98 (95% confidence interval [CI], 0.48 to 2.01), P = 0.95]. The end of treatment (EOT) overall and complete response (CR) rates among patients with an EOT assessment were 87.5% and 70% in arm 1, and 90% and 82% in Arm 2. Study authors wrote that the overall survival (OS) was not statistically significantly different with 12-month OS estimates of 94% in arm 1 and 79% in arm 2 [HR = 1.27 (95% CI, 0.57 to 2.79), P = 0.56].”

Safety measurements showed that grade ≥3 adverse events occurred more frequently in arm 2 (42% vs 76%). The most commonly increased grade ≥3 events included neutropenia (20% vs 47%), anemia (4% vs 25.5%), thrombocytopenia (5.5% vs 24%), febrile neutropenia (7% vs 16%) and fatigue (0% vs 11%). No grade 5 adverse events on treatment were reported on arm 1, and 3 were reported on arm 2 (lung infection and sudden death NOS, both of which were possibly related, and respiratory failure, which was unlikely to be related).

“Adding venetoclax to R-CHOP in DEL [patients] did not improve PFS and resulted in increased toxicity,” concluded Jeremy Abramson, MD, Massachusetts General Hospital, Boston, Massachusetts and colleagues.

“The study did not meet its primary endpoint in phase [2], and so did not proceed to phase [3],” they added.

Source:

Abramson J, Geyer SM, Pederson L, et al. Randomized phase II/III study of R-CHOP +/- venetoclax in previously untreated MYC/BCL2 double expressor diffuse large B cell lymphoma (DLBCL): Alliance A051701. Presented at the ASCO Annual Meeting. May 31-June 4, 2024; Chicago, IL. Abstract 7012