Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in China and worldwide. Although standard immunochemotherapy with Rituximab, Cyclophosphamide, Doxorubicin Hydrochloride, Vincristine (Oncovin), and Prednisone (R-CHOP) achieves durable remissions in many patients, approximately 30-40% experience relapse or refractory disease with poor outcomes. Novel strategies are needed for patients who are not candidates for transplantation or who relapse after multiple lines of therapy.
Homoharringtonine (HHT) is a natural cephalotaxine alkaloid extracted from Cephalotaxus species, clinically approved in China for acute and chronic myeloid leukemias. It inhibits ribosomal protein synthesis, modulates oncogenic and epigenetic signaling pathways, and induces apoptosis through mitochondrial and stress-activated pathways. Importantly, HHT downregulates the anti-apoptotic protein Myeloid Cell Leukemia 1 (MCL-1), a critical resistance factor to B-cell lymphoma 2 (BCL-2) inhibitors. This provides a strong mechanistic rationale for combining HHT with a BCL-2 inhibitor, together with rituximab and prednisone, in relapsed/refractory DLBCL.
This prospective, multicenter, single-arm, Phase Ib/II study will evaluate the safety, tolerability, and efficacy of HHT, a BCL-2 inhibitor, rituximab, and prednisone in adult patients with relapsed/refractory DLBCL. Phase Ib will enroll 15-22 patients to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and the recommended phase II dose (RP2D) of HHT. Phase II will enroll 40 patients treated at RP2D to evaluate the overall response rate (ORR) after 3 and 6 cycles per Lugano 2014 criteria. Secondary endpoints include complete remission (CR), partial remission (PR), progression-free survival (PFS), and overall survival (OS). Exploratory analyses will incorporate molecular biomarkers such as genomic profiling, circulating tumor DNA (ctDNA), and spatial transcriptomics.
Age ≥18 years at enrollment, regardless of gender, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-3;
Disease is refractory to or progresses within one year after first-line standard therapy containing anti-CD20 monoclonal antibodies and anthracycline-based chemotherapy, or has failed or relapsed after second-line or later standard treatment regimens, or has relapsed after autologous hematopoietic stem cell transplantation (more than 6 months post-transplant);
At least one measurable lesion present (as defined by the Lugano 2014 response criteria: measurable lesion is defined as a lymph node lesion with a longest diameter >1.5 cm on CT axial imaging, or an extranodal lesion with a longest diameter >1.0 cm, and 18F-FDG PET/CT positive lesion);
Able to provide written informed consent and capable of understanding and complying with all study requirements.
Patients with poor compliance or inability to attend regular follow-up visits;
Presence of severe organ dysfunction, as judged by the investigator, that renders the patient unsuitable for participation in this trial;
Absolute neutrophil count < 1.0 × 10⁹/L, platelet count < 50 × 10⁹/L, or hemoglobin < 80 g/L (excluding cases due to lymphoma bone marrow infiltration);
Other factors, as determined by the investigator, that may lead to forced early withdrawal from the study, such as other serious medical conditions (including psychiatric disorders) requiring concomitant treatment, alcoholism, drug abuse, or family/social factors that may affect patient safety or compliance;