Добавление венетоклакса к терапии DA-EPOCH-R при лимфоме двойного удара повысило смертность и не улучшило выживаемость

TOPLINE Adding venetoclax to dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for newly diagnosed double-hit lymphoma increased treatment-related mortality and toxicity without improving efficacy. Median progression-free survival was 7.7 months with venetoclax vs 28.4 months with DA-EPOCH-R alone. Six on-treatment deaths occurred with venetoclax, whereas one on-treatment death occurred with DA-EPOCH-R alone, primarily due to sepsis and cardiac arrest. METHODOLOGY - Patients with double-hit lymphoma have poor outcomes after standard chemoimmunotherapy. Although intensified regimens such as DA-EPOCH-R are commonly used, outcomes remain suboptimal. Venetoclax, an oral BCL2 inhibitor, has shown activity in some B-cell lymphomas; however, whether its addition to chemoimmunotherapy improves frontline outcomes in this population is still unclear. - To evaluate the safety and efficacy of adding venetoclax to chemoimmunotherapy, researchers conducted a randomized phase 2 trial involving 66 patients aged 18-80 years (median age, 65 years; 55% men) with newly diagnosed double-hit lymphoma (high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements). - Patients were randomly assigned to receive DA-EPOCH-R alone (n = 36) or DA-EPOCH-R plus venetoclax (n = 37); DA-EPOCH-R was administered on a 21-day schedule for up to six cycles; venetoclax 600 mg was given orally once daily on days 4-8 of cycle 1 and days 1-5 of cycles 2-6. - The majority of patients had MYC-BCL2 double-hit lymphoma (89%), advanced-stage disease (86%), or a high-intermediate-risk or high-risk international prognostic index score (64%). - The primary endpoint was progression-free survival; the secondary endpoints included overall survival, event-free survival, and safety. The median follow-up duration was 34.7 months. TAKEAWAY - Progression-free survival did not improve with venetoclax. Among patients evaluable in the DA-EPOCH-R group (n = 30) and the DA-EPOCH-R plus venetoclax group (n = 36), the median progression-free survival was 28.4 months and 7.7 months, respectively (hazard ratio [HR], 1.13; P = .75). - Overall survival was worse with venetoclax ‒ 24-month estimates were 72% with DA-EPOCH-R vs 52% with DA-EPOCH-R plus venetoclax (HR, 2.49; P = .038); however, event-free survival was similar between groups (10.2 vs 6.2 months; HR, 1.08; P = .83). - Treatment-related mortality rate was higher with venetoclax. During treatment or within 30 days of ending treatment, six grade 5 events occurred in the venetoclax group, whereas one such event occurred in the DA-EPOCH-R group; four additional deaths were reported as late adverse events in the venetoclax group vs one in the DA-EPOCH-R group. Overall, 10 deaths occurred in the venetoclax group (five from sepsis, two from other infections, two from cardiac arrest, and one from hypoxia) vs two in the DA-EPOCH-R group (one from sepsis, one from dyspnea). - Febrile neutropenia occurred in 15 of 35 patients (43%) in the venetoclax group vs 11 of 30 patients (37%) in the DA-EPOCH-R group. Grade 3 or worse sepsis occurred in eight (23%) patients vs four (13%) patients, including four grade 5 sepsis events with venetoclax vs none with DA-EPOCH-R alone. IN PRACTICE "Outcomes for patients with double-hit lymphoma are not improved with the addition of venetoclax to DA-EPOCH-R and remain inferior to those of patients with large B-cell lymphoma without double-hit lymphoma treated with standard chemoimmunotherapy," the authors of the study wrote. SOURCE The study, led by Jeremy S. Abramson, MD, Mass General Brigham Cancer Institute in Boston, was published online in The Lancet Haematology. LIMITATIONS The study was closed early due to safety concerns, limiting the sample size and statistical power. The trial design allowed patients to receive one cycle of chemotherapy before enrollment, which may have introduced heterogeneity. The study population was predominantly White, potentially limiting generalizability to other racial and ethnic groups. DISCLOSURES The study was supported by grants from the National Cancer Institute of the National Institutes of Health. Several authors reported consulting fees, honoraria, research support, or other financial relationships with pharmaceutical companies, including AbbVie, Genentech, Roche, and others. Full disclosures are reported in the original article. This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.