arta-based chemo-free bridging/maintenance therapy in car-t treatment for high-risk r/r b-nhl ineligible for hdct and asct

Conditions: B-cell Non Hodgkin Lymphoma

Summary: this is a single-center, open-label, prospective study enrolling high-risk (tumor diameter \> 4 cm) relapsed/refractory b-nhl patients ineligible for hdct and asct. the treatment consists of atra combined with zanubrutinib ± radiotherapy and car-t therapy. based on the efficacy at day 28 post-car-t infusion, patients achieving cr will receive 3 months of atra and zanubrutinib, while those with pr will receive 3 months of zanubrutinib plus 2 years of atra and a pd-1 inhibitor. patients with stable disease or progression will discontinue. the primary endpoint is the 3-month cr rate following car-t infusion.


Eligibility criteria:
inclusion criteria: * willingly sign the informed consent form. * age ≥ 18 years, any gender. * histologically confirmed as b-cell non-hodgkin lymphoma, including: * diffuse large b-cell lymphoma (dlbcl) not otherwise specified (dlbcl-nos) * transformed follicular lymphoma (tfl) * high-grade b-cell lymphoma (hgbl) with myc, bcl2, and/or bcl6 rearrangements * high-grade b-cell lymphoma not otherwise specified (hgbl-nos) * primary mediastinal large b-cell lymphoma (pmbl) * follicular lymphoma grade 3b (fl3b) * patients must have experienced at least one line of treatment for relapsed or refractory disease, meeting the following definitions: * refractory: at least partial response (pr) after the last chemotherapy or relapse within 12 months after autologous transplantation. * relapsed: complete response (cr) after the last chemotherapy, followed by relapse before enrollment, or relapse or progression 12 months or longer after autologous transplantation. * maximum tumor diameter (long axis) \> 4 cm. * evaluator determines that the patient does not meet hdct/asct criteria and meets at least one of the following: * age ≥ 60 years * ecog score = 2 * fev1% or dlco% ≤ 60% * lvef \< 50% * creatinine clearance \< 60 ml/min * alt or ast \> 2× upper limit of normal (uln) * patient unwilling to receive high-dose chemotherapy and autologous stem cell transplantation. * measurable target lesions: lymph nodes ≥ 15 mm in longest diameter, or extranodal lesions \> 10 mm. * expected survival ≥ 12 weeks. * laboratory tests must meet the following requirements at screening: * lymphocyte count ≥ 0.1 × 10\^9/l * hemoglobin ≥ 80 g/l * platelets ≥ 50 × 10\^9/l * alt/ast ≤ 5 × uln and total bilirubin \< 2 × uln * creatinine clearance ≥ 30 ml/min * lung function: ≤ ctcae grade 1 dyspnea, and oxygen saturation (spo2) ≥ 92% in room air. * lvef ≥ 40% * patients with primary central nervous system lymphoma are allowed (secondary cns lymphoma is not allowed). * sufficient venous access for apheresis, and no other contraindications for blood cell separation; female participants of childbearing potential must have a negative pregnancy test at screening. exclusion criteria: * history of allergy to any component of the cellular product or study treatment. * history of allogeneic hematopoietic stem cell transplantation. * history of organ transplantation. * patients with active viral hepatitis requiring treatment, including: * chronic hbv carriers with hbv dna ≥ 500 iu/ml. * positive hcv rna in patients with positive hcv antibodies. * positive hiv antibodies (hiv-ab). * positive treponema pallidum antibodies (tp-ab). * elevated cmv dna or ebv dna above normal limits. * clinical significance of cns diseases * presence of active primary central nervous system lymphoma. * prior treatment with other genetically modified t-cell therapies or car-t therapies. * severe genetic diseases or autoimmune diseases (e.g., systemic lupus erythematosus). * thromboembolic events (e.g., myocardial infarction, pulmonary embolism, deep vein thrombosis) within 6 months prior to screening. * history of malignancies other than the indication for this trial within the last 5 years, except for in situ cancers (e.g., cervical, bladder, breast) or non-melanoma skin cancer. * active infections requiring systemic treatment or uncontrolled infections. * received lenalidomide, calcineurin inhibitors, chemotherapy (e.g., methotrexate, cyclophosphamide, ifosfamide, nitrogen mustard, or melphalan), mycophenolate, thalidomide, immunosuppressive antibodies (e.g., anti-tnf, anti-il6, or anti-il6r), radiation therapy, or any drug that binds fkbp12 (e.g., rapamycin, tacrolimus, everolimus) within 4 weeks prior to pbmc collection. * pregnant or breastfeeding women, or men or women of childbearing potential unwilling to use contraception during the trial and for 2 years after rj car-t 002 cell infusion. * participation in other drug clinical trials (e.g., new drug trials, registrational studies, investigator-initiated trials) within 4 weeks prior to pbmc collection. * researcher's judgment that the patient is unsuitable for the trial (e.g., poor compliance, drug abuse). * vaccination with live or attenuated vaccines within 3 months prior to pbmc collection, or expected vaccination during the trial.