Chidamide-based Combination With PD-1 Blockade: A Synergistic Strategy to Improve CAR-T Cell Therapy Outcomes for B-cell Lymphoma.
B-cell non-Hodgkin lymphoma (B-NHL) is one of the most common malignancies in China, with approximately 100,000 new cases diagnosed annually. Although immunochemotherapy, novel small-molecule targeted agents, and hematopoietic stem cell transplantation have significantly improved outcomes for patients with B-cell malignancies, nearly half of patients still experience drug resistance and relapse. In high-risk aggressive B-cell lymphoma, the 5-year survival rate remains around 50%. Previous clinical guidelines recommended autologous hematopoietic stem cell transplantation as first-line consolidation therapy for high-risk patients; however, multiple studies have demonstrated that even after autologous transplantation, nearly half of these patients relapse and succumb to the disease. Chimeric antigen receptor T (CAR-T) cell therapy has achieved objective response rates of approximately 50% in relapsed/refractory lymphoma, particularly in B-cell subtypes. Nevertheless, limitations such as tumor immune antigen escape, immunosuppressive effects of the tumor microenvironment (TME) on CAR-T cells, and T-cell exhaustion continue to restrict the durability and efficacy of CAR-T-mediated cytotoxicity. This study evaluates the incorporation of chidamide (an HDAC inhibitor) combined with a PD-1 inhibitor as maintenance therapy following CAR-T cell immunotherapy in patients with relapsed/refractory high-risk aggressive B-cell lymphoma. By implementing an early intervention strategy-prompt administration of CAR-T cell therapy after induction treatment for relapsed/refractory high-risk aggressive B-cell lymphoma-and subsequent maintenance with chidamide plus a PD-1 inhibitor, the approach aims to reduce relapse rates and improve overall survival. These strategies are intended to address the current unmet clinical need for improved outcomes in relapsed/refractory high-risk aggressive B-cell lymphoma, where prognosis remains poor despite existing therapies.
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• The patient must meet all of the following inclusion criteria:
• Histologically or cytologically confirmed CD19 and/or CD22-positive large B-cell lymphoma (LBCL) according to the WHO 2016 classification, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL), and related entities, with one of the following:
‣ Partial response (PR) after induction therapy with a standard first-line chemotherapy regimen (e.g., R-CHOP for 4-6 cycles); or
⁃ Complete response (CR) after standard first-line induction therapy, but with high-risk features present at initial diagnosis.
• Presence of high-risk features at initial diagnosis, defined as at least one of the following:
‣ High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit) confirmed by fluorescence in situ hybridization (FISH);
⁃ High-grade B-cell lymphoma with 11q aberration (Burkitt-like lymphoma with 11q aberration);
⁃ International Prognostic Index (IPI) score of 2-5; age-adjusted IPI (aa-IPI) score of 2-3; or National Comprehensive Cancer Network-IPI (NCCN-IPI) score of 4-8;
⁃ CD5 positivity by immunohistochemistry;
⁃ Dual expression of MYC and BCL2 by immunohistochemistry (recommended thresholds: MYC ≥ 40% and BCL2 ≥ 50%);
⁃ TP53 mutation detected by gene sequencing;
⁃ Molecular subtype MCD or N1 by next-generation sequencing (NGS);
⁃ Relapsed/refractory B-cell lymphoma, meeting one of criteria ①-④ plus criterion ⑤:
∙ Less than 50% tumor reduction or disease progression after ≥4 cycles of standardized chemotherapy;
• Relapse within 6 months after achieving CR with standard regimen;
⁃ ≥2 relapses after CR;
‣ Relapse after hematopoietic stem cell transplantation;
∙ Must have received adequate prior therapy, including at least an anti-CD20 monoclonal antibody and anthracycline-containing combination chemotherapy.
• Age 18 to 85 years, male or female.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Expected survival of \>3 months from the date of signing informed consent.
• Hemoglobin (HGB) ≥60 g/L (transfusion permitted).
• Absolute neutrophil count (ANC) ≥1,000/μL and platelet count ≥45,000/μL.
• Adequate hepatic, renal, cardiac, and pulmonary function, meeting \*\*all\*\* of the following:
‣ Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) (except for patients with Gilbert's syndrome);
⁃ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN;
⁃ Serum creatinine (Cr) ≤1.5 × ULN \*\*or\*\* creatinine clearance (CCr) ≥60 mL/min (estimated by Cockcroft-Gault formula);
⁃ Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO), with no pericardial effusion and no clinically significant arrhythmias;
⁃ Baseline oxygen saturation by pulse oximetry \>92% on room air;
⁃ No clinically significant pleural effusion.