Venetoclax Plus DA-EPOCH-R Trial Halted in Double-Hit Lymphoma Over Excess Mortality
Key Insights
Adding venetoclax to DA-EPOCH-R (search) did not improve progression-free survival and produced excess toxicity and mortality in newly diagnosed double-hit lymphoma (search), prompting early closure of the randomized cohort.
At a median follow-up of 34.7 months, median progression-free survival was 28.4 months with DA-EPOCH-R (search) alone versus 7.7 months with venetoclax, with 24-month overall survival of 72% versus 52%.
Six treatment deaths occurred in the venetoclax group versus one with DA-EPOCH-R (search) alone, four from sepsis and two from cardiac arrest, and dose escalation was possible in only 22% versus 70%.
Adding venetoclax to dose-adjusted EPOCH-R (DA-EPOCH-R (search)) failed to improve progression-free survival and caused excess toxicity and mortality in patients with newly diagnosed double-hit lymphoma (search), leading investigators to close the double-hit lymphoma cohort of the randomized ALLIANCE A051701 trial early. Results from Abramson et al were published in The Lancet Haematology.
The open-label randomized phase II-III trial enrolled patients aged 18 to 80 years with newly diagnosed double-hit lymphoma (search) and ECOG performance status 0 to 2 at 41 US hospitals and outpatient clinics, randomizing them 1:1 to DA-EPOCH-R (search) alone or with oral venetoclax 600 mg daily for 5 days per cycle. Seventy-three patients were assigned, 36 to DA-EPOCH-R and 37 to the combination, with 30 and 36 respectively evaluable for the primary endpoint after central pathology confirmation and eligibility review. Median age was 65 years, 86% had stage III or IV disease, and 64% had a high-intermediate or high International Prognostic Index score.
At a median follow-up of 34.7 months, median progression-free survival was 28.4 months with DA-EPOCH-R (search) alone versus 7.7 months with venetoclax (HR = 1.13; P = .75), and 24-month estimates were 53% versus 48%. Overall survival favored DA-EPOCH-R alone, with 24-month estimates of 72% versus 52% (HR = 2.49; P = .038), which investigators attributed largely to early deaths in the experimental group. Best overall response rate was 93% versus 67% (P = .0039) and complete response rates were 77% versus 56%. Grade 3 or worse sepsis occurred in 13% versus 23% and febrile neutropenia in 37% versus 43%. Six patients died during treatment in the venetoclax group compared with one receiving DA-EPOCH-R alone; four of the six deaths were due to sepsis and two to cardiac arrest. Dose escalation was possible in 70% of patients on DA-EPOCH-R alone versus 22% with venetoclax, and 70% versus 51% completed all six cycles. The investigators concluded that venetoclax enhances the toxicity of DA-EPOCH-R and that the combination is not recommended.
Source: The ASCO Post