NexCAR19 (Talikabtagene Autoleucel) in Relapsed/Refractory B-Cell Malignancies (NexCAR19)

Inclusion Criteria71

• Additionally:
• High-grade lymphoma subjects must meet Criteria 14-18.
• Other B-cell lymphoma subjects must meet Criteria 19-24.
• B-ALL subjects must meet Criteria 25-29.
• Age ≥18 years.
• Patients approved for leukapheresis by the CAR-T cell treatment council.
• ECOG performance status <2.
• Life expectancy ≥12 weeks.
• Renal Function: Estimated creatinine clearance ≥60 mL/min (Cockcroft-Gault) → fludarabine/cyclophosphamide lymphodepletion.
• In lymphoma cohort patients with creatinine clearance 30-60 mL/min, bendamustine may be used as an alternative due to cumulative fludarabine toxicity and neurotoxicity risk.
• Liver Function:
• ALT and AST ≤3 × ULN unless attributable to underlying malignancy.
• Total bilirubin ≤2 × ULN except in Gilbert syndrome, isolated unconjugated hyperbilirubinemia, or if attributable to underlying malignancy.
• Hemodynamically stable with LVEF ≥45% (confirmed by echocardiography or MUGA scan).
• Baseline oxygen saturation >92% on room air.
• ANC ≥500/µL (may be waived if cytopenia due to underlying malignancy at investigator discretion).
• Platelet count ≥50,000/µL (may be waived if cytopenia due to underlying malignancy at investigator discretion).
• Negative serum or urine pregnancy test (within 24 hours prior to conditioning therapy) in women of childbearing potential; also negative prior to leukapheresis.
• Sexually active patients (women of childbearing potential and all men) must use highly effective contraception for ≥12 months after CAR-T infusion.
• Written informed consent provided.
• Histologically confirmed previously treated:
• Diffuse large B-cell lymphoma (DLBCL)
• Primary mediastinal B-cell lymphoma
• Transformed indolent B-cell lymphoma
• Follicular lymphoma Grade 3B
• High-grade B-cell lymphoma
• Chemotherapy-refractory disease defined as:
• Primary refractory disease
• Best response to last chemotherapy = PD or SD (biopsy confirmed)
• Progression/relapse ≤12 months after autologous SCT
• Relapse ≤12 months after first-line CR (biopsy confirmed)
• Relapse beyond 12 months if auto-SCT not feasible
• Not eligible for or unwilling to undergo autologous SCT.
• Must have received anti-CD20 monoclonal antibody and anthracycline-containing regimen. Transformed lymphoma subjects must have received ≥2 prior systemic lines.
• Measurable disease per International Working Group (IWG) criteria.
• Histologically confirmed:
• Mantle Cell Lymphoma (Cyclin D1 overexpression or t(11;14))
• Follicular Lymphoma Grade I-IIIA
• Marginal Zone Lymphoma
• Relapsed or refractory disease:
• MCL: ≤5 prior regimens including:
• Anthracycline or bendamustine
• Anti-CD20 antibody
• BTK inhibitor (ibrutinib or acalabrutinib; intolerance allowed)
• FL/MZL: Progression after ≥2 combination chemoimmunotherapy regimens (single-agent CD20 or splenectomy not counted).
• Radiologically measurable disease at screening
• per revised IWG (Cheson 2007): ≥1 measurable lesion
• Previously irradiated lesions measurable only if progression documented
• If only nodal disease: ≥1 node ≥2 cm
• No known active CNS lymphoma involvement.
• Prior therapy toxicities resolved to ≤Grade 1 (except alopecia).
• Prior autologous HCT, POD24 status, and prior PI3K inhibitor therapy allowed.
• Relapsed/Refractory B-ALL meeting one of:
• Primary refractory disease
• First relapse ≤12 months
• ≥2 prior systemic lines
• Post-allogeneic SCT relapse (≥100 days post-transplant; off immunosuppression ≥4 weeks)
• Ph+ disease:
• TKI intolerance
• Relapsed/refractory after ≥2 TKIs
• No alternative TKI option
• Ineligible for allogeneic SCT due to
• comorbidity,
• conditioning contraindication,
• no donor,
• prior SCT,
• or refusal (documented).
• Morphological bone marrow disease.
• CD19 tumor expression documented within 3 months (BM or PB by flow cytometry).
• Absolute lymphocyte count ≥100/µL.
• ≥3 half-lives elapsed since prior immune checkpoint inhibitor or stimulatory therapy