The combination of fludarabine, cyclophosphamide, and rituximab (FCR) is the only regimen other than allotransplantation shown in studies to result in a significant chance of functional cure in very long-term follow-up for young, fit patients with mutated immunoglobulin heavy chain gene (IGHV) chronic lymphocytic leukemia (CLL), according to current data. The excellent efficacy and tolerability of ibrutinib across a broad group of young, fit patients with CLL prompted investigators to examine whether a time-limited novel agent plus chemoimmunotherapy could result in durable remission for patients with CLL regardless of IGHV status. In the multicenter, single-arm, phase II investigator-sponsored trial, 85 patients (median age, 55 years) received ibrutinib 420 mg daily for 7 days, followed by a combination of ibrutinib with FCR for up to six cycles, and patients who responded continued to receive ibrutinib maintenance therapy. At a median follow-up of 40.3 months, the median number of ibrutinib maintenance cycles was 24 (range, 0-81). According to the intention-to-treat analysis, the rate of complete remission (CR) with bone marrow undetectable minimal residual disease (BM-uMRD) at any point during the study was 55% (47/85 patients). The best rate of BM-uMRD remained at 84% (71/85). After 2 years of ibrutinib maintenance, the rates of CR/CR with incomplete blood count recovery, BM-uMRD, and peripheral blood uMRD in patients with available data were 77% (44/57), 81% (50/62), and 81% (55/68), respectively, with no difference observed according to IGHV status. Progression-free survival and overall survival for all patients were 97% and 99%, respectively. One patient died after 17 months of ibrutinib maintenance due to presumed sudden cardiac death. The most common treatment-emergent grade III or IV adverse events were hematologic.