Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are B-cell non-Hodgkin lymphomas. The standard treatment of CLL/SLL is administering ofatumumab, an anti-CD20 monoclonal antibody used to target the surface biomarker of B lymphocytes. Recent studies indicated that PI3K pathway is activated in most B-cell leukemia. A new oral kinase inhibitor, duvelisib, is developed to target PI3K-delta and PI3K-gamma. In a phase III DUO trial, 319 patients with relapsed or refractory CLL/SLL were randomized 1:1 to receive either duvelisib (25 mg twice daily) or standard of care treatment with ofatumumab. Progression-free survival was 3.4 months longer in the duvelisib group than in the ofatumumab group (13.3 months versus 9.9 months; hazard ratio 0.52). In subgroup analysis, the patients with 17p deletion received duvelisib had significantly longer PFS than those in the ofatumumab group (12.7 months versus 9.0 months; hazard ratio 0.41). The adverse events in the duvelisib group are manageable and consistent with previous studies. The results revealed that duvelisib could be a new treatment for patients with relapsed or refractory CLL/SLL.