Study Warns on Venetoclax in Double-Hit Lymphoma

Adding the BCL2 inhibitor venetoclax (Venclexta) to chemoimmunotherapy led to worse outcomes and excess mortality in patients with newly diagnosed double-hit lymphoma, phase II results from a randomized trial showed.

Median progression-free survival (PFS) was 28.4 months in patients who received dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) versus 7.7 months in those who received the chemoimmunotherapy regimen plus venetoclax (HR 1.13, 95% CI 0.53-2.37, P=0.75), reported Jeremy S. Abramson, MD, of the Mass General Brigham Cancer Institute in Boston, and colleagues.

Median overall survival has not been reached in either group, and the 24-month overall survival estimates were 72% in the DA-EPOCH-R group compared with 52% in the group that received added venetoclax (HR 2.49, 95% CI 1.03-6.04, P=0.038), they noted in Lancet Haematology.

The excess mortality observed with added venetoclax — six deaths versus one death in the DA-EPOCH-R group — prompted early closure of the trial.

The worse outcomes were primarily due to increased hematologic toxic effects and infections, Abramson and colleagues wrote. “Venetoclax clearly enhances the toxicity of DA-EPOCH-R, and so this combination is not recommended.”

They pointed out that the results in the DA-EPOCH-R group “demonstrate durable remissions in a substantial proportion of patients and provide a valuable benchmark for future studies.”

Double-hit lymphoma, defined as a high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, accounts for about 5% of newly diagnosed cases of diffuse large B-cell lymphoma (DLBCL). It is highly aggressive and is associated with poor outcomes after standard chemoimmunotherapy.

In previous studies, intensive treatment approaches with regimens such as DA-EPOCH-R have shown promise, and it has become a preferred treatment option. However, PFS is still inferior to expected outcomes for patients with DLBCL not otherwise specified, “indicating a considerable need for improvement,” Abramson and team noted.

Venetoclax has previously demonstrated potential benefit in patients with DLBCL when combined with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), including patients demonstrating BCL2 protein overexpression by immunohistochemistry.

This cohort of the open-label ALLIANCE A051701 study included 73 patients with newly diagnosed double-hit lymphoma and an Eastern Cooperative Oncology Group performance status score of 0-2 who were recruited from 41 hospitals and outpatient clinics in the U.S. Between October 2019 and September 2020, they were randomly assigned to receive DA-EPOCH-R alone or DA-EPOCH-R plus venetoclax.

Median age was 65, 55% were men, and 89% were white. Most patients (89%) had double-hit lymphoma with MYC and BCL2 rearrangements, with or without BCL6 rearrangement, and the remaining patients had rearrangements of MYC and BCL6 without BCL2 translocation, but with BCL2 protein expression. Median follow-up was 34.7 months.

Deaths on treatment occurred in one patient in the DA-EPOCH-R group, due to dyspnea, which was possibly related to treatment, and six patients in the DA-EPOCH-R/venetoclax group: four due to sepsis (three at least possibly related and one unrelated) and two due to cardiac arrest (at least possibly related).

Four additional patients in the DA-EPOCH-R/venetoclax group had deaths reported as late adverse events (lung infection with unspecified organism, COVID-19, septic shock, hypoxia) compared with one additional patient in the DA-EPOCH-R group (sepsis).

The most common grade 3-4 non-hematologic adverse event was febrile neutropenia, occurring in 43% of patients in the DA-EPOCH-R/venetoclax group and 37% of those in the DA-EPOCH-R group.