Trial Ended Early When Venetoclax Plus DA-EPOCH-R Did Not Improve Outcomes in Double-Hit Lymphoma

Adding venetoclax (Venclexta; AbbVie, Genentech) to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) increased mortality without improving progression-free survival (PFS) in patients with newly diagnosed double-hit lymphoma, according to results from the randomized ALLIANCE A051701 trial (NCT03984448). The excess deaths prompted investigators to close the study early and conclude that the combination should not be used in this setting.¹

Need for More Effective Frontline Treatment

Double-hit lymphoma is an aggressive form of high-grade B-cell lymphoma characterized by oncogenic rearrangements involving MYC and BCL2, sometimes accompanied by a BCL6 rearrangement. These genetic changes promote cellular proliferation and resistance to apoptosis, contributing to poorer outcomes than those generally observed with diffuse large B-cell lymphoma (DLBCL) not otherwise specified.²

The terminology and classification of these malignancies have evolved. Under the fifth edition of the World Health Organization classification, the defined entity is DLBCL/high-grade B-cell lymphoma with MYC and BCL2 rearrangements. Tumors with MYC and BCL6 rearrangements—but no BCL2 rearrangement—are classified according to their morphologic and molecular features rather than being included automatically within the same entity.²

Intensive therapy with DA-EPOCH-R has been used for newly diagnosed double-hit lymphoma, but outcomes remain suboptimal for some patients. Venetoclax, a selective BCL2 inhibitor, was considered a rational addition for tumors driven partly by BCL2-mediated resistance to apoptosis.

Earlier findings from the single-arm phase 2 CAVALLI trial (NCT02055820) supported further investigation of venetoclax-based chemoimmunotherapy. In that study, venetoclax plus rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) showed potential activity in previously untreated DLBCL, particularly among patients with BCL2 protein overexpression. The regimen also increased myelosuppression, underscoring the need for randomized safety data.³

ALLIANCE A051701 Shows Excess Mortality

The open-label, randomized phase 2 portion of ALLIANCE A051701 enrolled 73 patients with previously untreated double-hit lymphoma and an Eastern Cooperative Oncology Group performance status of 0 to 2. Participants were recruited from 41 US hospitals and outpatient clinics between October 2019 and September 2020. They received DA-EPOCH-R alone or the same regimen with venetoclax.¹

Most participants (89%) had tumors with MYC and BCL2 rearrangements, with or without a BCL6 rearrangement. The remaining participants had MYC and BCL6 rearrangements without a BCL2 translocation but demonstrated BCL2 protein expression. The median age was 65 years, and median follow-up was about 34.7 months.¹

Median PFS was about 28.4 months with DA-EPOCH-R alone compared with 7.7 months when venetoclax was added. The difference was not statistically significant (HR, 1.13; 95% CI, 0.53-2.37; P = .75). Median overall survival (OS) had not been reached in either group, but estimated 24-month OS was approximately 72% with DA-EPOCH-R and 52% with the venetoclax-containing regimen (HR, 2.49; 95% CI, 1.03-6.04; P = .038).¹

Six patients receiving venetoclax died during treatment compared with 1 patient receiving DA-EPOCH-R alone. In the venetoclax group, 4 deaths were attributed to sepsis and 2 to cardiac arrest. Investigators also reported 4 late deaths in that group, including deaths associated with lung infection, COVID-19, septic shock, and hypoxia. One late death from sepsis occurred in the control group.¹

Toxicity Findings Carry Implications for Pharmacists

The worse outcomes were attributed primarily to hematologic toxicity and infection. Febrile neutropenia was the most common grade 3 or 4 nonhematologic adverse event (AE), occurring in 43% of patients receiving venetoclax and 37% receiving DA-EPOCH-R alone.¹

The findings illustrate that a compelling molecular rationale does not guarantee a favorable clinical benefit-risk profile when a targeted agent is added to intensive chemotherapy. Although febrile neutropenia rates were numerically similar between groups, the difference in fatal infections indicates that routinely reported AE frequencies may not capture the full clinical consequences of compounded immunosuppression.

Oncology pharmacists are positioned to evaluate overlapping myelosuppressive effects, identify infection risks, and support antimicrobial prophylaxis and monitoring when intensive regimens are studied. For current practice, however, the ALLIANCE A051701 results provide direct evidence against adding venetoclax to DA-EPOCH-R for newly diagnosed double-hit lymphoma outside a clinical trial.¹

REFERENCES

1. Abramson JS, Geyer S, Giri S, et al. Venetoclax added to dose-adjusted EPOCH-R for newly diagnosed double-hit lymphomas: phase 2 results from ALLIANCE A051701, an open-label, randomised, controlled, phase 2-3 trial. Lancet Haematol. 2026;13(9):e626-e638. doi:10.1016/S2352-3026(26)00191-2

2. Kurz KS, Ott M, Kalmbach S, et al. Large B-Cell Lymphomas in the 5th Edition of the WHO-Classification of Haematolymphoid Neoplasms-Updated Classification and New Concepts. Cancers (Basel). 2023;15(8):2285. doi:10.3390/cancers15082285

3. Morschhauser F, Feugier P, Flinn IW, et al. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood. 2021;137(5):600-609. doi:10.1182/blood.2020006578