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First-Line Venetoclax Combinations in Advanced Chronic Lymphocytic Leukemia

With or without ibrutinib, venetoclax–obinutuzumab was superior to chemoimmunotherapy as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL), researchers report. “Time-limited combinations of targeted agents such as venetoclax–obinutuzumab and venetoclax–obinutuzumab–ibrutinib led to longer and deeper responses than the current first-line chemoimmunotherapy standard (fludarabine–cyclophosphamide–rituximab or bendamustine–rituximab),” the authors conclude.

Fit patients with CLL who did not have TP53 aberrations were randomized to 6 cycles of chemoimmunotherapy (fludarabine–cyclophosphamide–rituximab or bendamustine–rituximab) or 12 cycles of venetoclax–rituximab, venetoclax–obinutuzumab, or venetoclax–obinutuzumab–ibrutinib in this phase 3, open-label trial. Ibrutinib could be stopped after 2 consecutive measurements of undetectable minimal residual disease or could be extended.

Based on primary end points of undetectable minimal residual disease (sensitivity, <10−4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival, the study showed: “A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax–rituximab, 229 to venetoclax–obinutuzumab, and 231 to venetoclax–obinutuzumab–ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax–obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax–obinutuzumab–ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P <0.001 for both comparisons), but it was not significantly higher in the venetoclax–rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax–obinutuzumab–ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P <0.001). Progression-free survival at 3 years was also higher with venetoclax–obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P <0.001), but not with venetoclax–rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax–obinutuzumab–ibrutinib (21.2%) than with venetoclax–rituximab (10.5%) or venetoclax–obinutuzumab (13.2%).”

Source: New England Journal of Medicine