Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL)
Conditions
Keywords
Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL), CAR-T therapy, Chidamide, PD-1 inhibitor
Brief summary
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.
Interventions
DRUGCAR-T Cell Therapy + Chidamide and PD-1 Inhibitor Maintenance
Patients will receive maintenance therapy consisting of Chidamide combined with a PD-1 inhibitor following CAR-T cell infusion. This intervention is designed to upregulate target antigen expression on tumor cells and mitigate antigen escape. By synergistically enhancing the cytotoxic activity and persistence of CAR-T cells, the regimen aims to reduce the risk of relapse and improve long-term clinical outcomes
Sponsors
Daihong Liu
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
\- The patient must meet all of the following inclusion criteria: 1. 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: 1. Partial response (PR) after induction therapy with a standard first-line chemotherapy regimen (e.g., R-CHOP for 4-6 cycles); or 2. Complete response (CR) after standard first-line induction therapy, but with high-risk features present at initial diagnosis. 2. Presence of high-risk features at initial diagnosis, defined as at least one of the following: 1. 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); 2. High-grade B-cell lymphoma with 11q aberration (Burkitt-like lymphoma with 11q aberration); 3. 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; 4. CD5 positivity by immunohistochemistry; 5. Dual expression of MYC and BCL2 by immunohistochemistry (recommended thresholds: MYC ≥ 40% and BCL2 ≥ 50%); 6. TP53 mutation detected by gene sequencing; 7. Molecular subtype MCD or N1 by next-generation sequencing (NGS); 8. 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. 3. Age 18 to 85 years, male or female. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 5. Expected survival of \>3 months from the date of signing informed consent. 6. Hemoglobin (HGB) ≥60 g/L (transfusion permitted). 7. Absolute neutrophil count (ANC) ≥1,000/μL and platelet count ≥45,000/μL. 8. Adequate hepatic, renal, cardiac, and pulmonary function, meeting \*\*all\*\* of the following: 1. Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) (except for patients with Gilbert's syndrome); 2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN; 3. Serum creatinine (Cr) ≤1.5 × ULN \*\*or\*\* creatinine clearance (CCr) ≥60 mL/min (estimated by Cockcroft-Gault formula); 4. Left ventricular ejection fraction (LVEF) ≥50% by echocardiogram (ECHO), with no pericardial effusion and no clinically significant arrhythmias; 5. Baseline oxygen saturation by pulse oximetry \>92% on room air; 6. No clinically significant pleural effusion.
Exclusion criteria
* Patients eligible for CAR-T cell immunotherapy must \*\*NOT\*\* meet any of the following
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1-year progression free survival rate (1-year-PFSR) | 1 years after treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| overall survival (OS) | 2 years after treatment | — |
| progression free survival (PFS) | 2 years after treatment | — |
| time to progression (TTP) | 2 years after treatment | — |
| disease free survival (DFS) | 2 years after treatment | — |
| duration of response (DOR) | 2 years after treatment | — |
| event free survival (EFS) | 2 years after treatment | — |
| recurrence rate | 2 years after treatment | — |
| safety | 2 years after treatment | Evaluate post-CAR-T cell infusion adverse events by analyzing the number of cases, incidence rates, and severity grades of the following key immunotherapy-related toxicities as recorded: Cytokine release syndrome (CRS) Immune effector cell-associated neurotoxicity syndrome (ICANS) Hematologic toxicity Organ toxicity and other immune-related adverse events associated with CAR-T cell therapy. |
| CAR-T cell kinetic parameters in peripheral blood | 2 years after treatment | CAR gene copy number Peak CAR-T cell concentration (Cmax) Time to peak concentration (Tmax) Area under the concentration-time curve from day 0 to day 28 (AUC₀-₂₈d / AUC₂₈d) |
Countries
China
Contacts
CONTACTLi-Ping Dou, Dr.
Outcome results
None listed