Adding venetoclax to dose-adjusted EPOCH-R (DA-EPOCH-R) did not improve progression-free survival and resulted in excess toxicity and mortality among patients with newly diagnosed double-hit lymphoma, prompting early closure of the double-hit lymphoma cohort of the randomized ALLIANCE A051701 trial. Results reported by Abramson et al were published in The Lancet Haematology.
Double-hit lymphoma is a highly aggressive form of large B-cell lymphoma characterized by rearrangements involving MYC and BCL2 and/or BCL6. Outcomes have historically been poor with standard chemoimmunotherapy, and intensified regimens such as DA-EPOCH-R have become preferred treatment options for many patients. Venetoclax, a BCL2 inhibitor, had previously shown encouraging activity when combined with DA-EPOCH-R in a phase I study.
“In retrospect, the decision to proceed to our [randomized phase II] study proved unfortunate,” the investigators wrote.
Study Details
ALLIANCE A051701 was an open-label, randomized phase II–III trial conducted at 41 hospitals and outpatient clinics across the United States; these results are from the phase II double-hit lymphoma cohort. Patients were aged 18 to 80 years, had newly diagnosed double-hit lymphoma and an ECOG performance status of 0 to 2, and were randomly assigned 1:1 to DA-EPOCH-R alone or with venetoclax.
DA-EPOCH-R consisted of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab administered every 21 days for up to six cycles. Patients in the experimental group also received oral venetoclax at 600 mg daily for 5 days per cycle. The primary endpoint was progression-free survival.
Seventy-three patients were randomly assigned, including 36 to DA-EPOCH-R and 37 to DA-EPOCH-R plus venetoclax. Following central pathology confirmation and eligibility review, 30 and 36 patients, respectively, were evaluable for the primary endpoint. Median age was 65 years; 86% had stage III or IV disease, and 64% had a high-intermediate or high International Prognostic Index score.
Key Findings
At a median follow-up of 34.7 months, median progression-free survival was 28.4 months with DA-EPOCH-R alone and 7.7 months with the addition of venetoclax (HR = 1.13; P = .75). At 24 months, estimated progression-free survival was 53% and 48%, respectively.
Overall survival favored DA-EPOCH-R alone. Median overall survival was not reached in either group, but the 24-month overall survival estimates were 72% with DA-EPOCH-R and 52% with DA-EPOCH-R plus venetoclax (HR = 2.49; P = .038). The investigators attributed the poorer survival with venetoclax largely to the greater number of early deaths in the experimental group.
In the intention-to-treat population, the best overall response rate was 93% with DA-EPOCH-R alone and 67% with the addition of venetoclax (P = .0039). Complete response rates were 77% and 56%, respectively.
Grade 3 or worse sepsis occurred in 13% of patients receiving DA-EPOCH-R alone and 23% receiving venetoclax, while febrile neutropenia occurred in 37% and 43%, respectively. Six patients died during treatment in the venetoclax group compared with one patient receiving DA-EPOCH-R alone; four of the six deaths with venetoclax were due to sepsis and two to cardiac arrest. The excess deaths led investigators to stop enrollment in the double-hit lymphoma cohort early.
Toxicity also affected delivery of DA-EPOCH-R. Dose escalation of the chemotherapy regimen was possible in 70% of patients receiving DA-EPOCH-R alone compared with 22% receiving venetoclax, and 70% vs 51% completed all six cycles. The investigators noted that cytopenias and infections in the venetoclax group limited dose escalation and treatment completion, in addition to contributing to the excess mortality that ultimately led to early closure of the cohort.
“Ultimately, the encouraging activity signal in [phase I] with high complete response rate and progression-free survival was negated in our randomised trial due to substantial excess toxicity, and it serves as a cautionary tale in ongoing clinical trial planning for novel drug combinations,” the investigators wrote.
They added that “venetoclax clearly enhances the toxicity of DA-EPOCH-R, and so this combination is not recommended.” The trial was also the first randomized controlled study in double-hit lymphoma, and the investigators said the outcomes with DA-EPOCH-R alone provide a benchmark for future studies.
Jeremy S. Abramson, MD, of the Center for Lymphoma at Mass General Brigham Cancer Institute, is the corresponding author of the article.
DISCLOSURE: The study was funded by the National Cancer Institute of the National Institutes of Health. For full disclosures of the study authors, visit thelancet.com/haematology.
