The present invention discloses a pharmaceutical composition for treating B-cell lymphoma, including a PI3K/AKT signaling pathway inhibitor and a chemotherapeutic drug, and further including a monoclonal antibody targeting CD20, such as rituximab. The pharmaceutical composition provided by the present invention is particularly suitable for the treatment of relapsed/refractory B-cell lymphoma. Given the critical role of cancer stem cells (CSCs) in the process of metastasis and drug resistance, the present invention proposes a new pro-differentiation therapy (PDT) strategy to cope with CSCs, i.e. to determine the decisive signaling pathway that maintains stem cell sternness and then promotes CSC differentiation by interfering with the pathway. Differentiated cells are eventually sensitive to conventional therapies, such as chemotherapy. In this situation, the PI3K/AKT signaling pathway inhibitor in combination with an R-CHOP regimen has a good effect on the treatment of drug-resistant diffuse large B-Cell lymphoma (DLBCL).