Front-Line Ibrutinib plus Rituximab for Chronic Lymphocytic Leukemia

The oral Bruton tyrosine kinase inhibitor (TKI) ibrutinib (IBR) has demonstrated high activity in previously untreated and relapsed patients with chronic lymphocytic leukemia (CLL; NEJM JW Oncol Hematol Feb 2016 and N Engl J Med 2015; 373:2425; NEJM JW Oncol Hematol Sep 2014 and N Engl J Med 2014; 371:213).

Now, investigators have conducted a planned interim analysis of an industry-funded, multicenter, open-label, randomized phase III trial, in which 529 previously untreated CLL patients (age, ≤70 years) were randomized 1:2 to standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) for 6 cycles versus TKI therapy with IBR (420 mg/d in 4-week cycles) plus rituximab (R) in cycles 2–6. Patients with del(17p) were excluded owing to known poor response to FCR.

Three-year progression-free survival (PFS; the primary endpoint) was improved with IBR-R versus FCR (89.4% vs. 72.0%; hazard ratio, 0.35; P<0.001), as was overall survival (OS; 98.8% vs. 91.5%; HR, 0.17; P<0.001); 3-year PFS was significantly improved with IBR-R versus FCR for patients with the unfavorable biomarkers del(11q22.3) and IGHV unmutated status but was similar for those with the prognostically favorable IGHV mutation. Conversely, the rate of complete remission was lower with IBR-R versus FCR (17.2% vs. 30.3%), as was the rate of minimal residual disease negativity at 12 months (8.3% vs. 59.2%). Toxicities included atrial fibrillation in 7.4% of IBR-R recipients and 3.2% of FCR recipients and grade 3 hemorrhage in 1% of IBR-R recipients. There were 10 deaths among FCR recipients, most due to CLL progression or treatment-related toxicity, and 4 deaths among IBR-R recipients.