Lancet Haematol

Background: Varnimcabtagene autoleucel (var-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy with adaptive intra-patient dose escalation and was approved in Spain in 2021 for patients older than 25 years with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia. We report activity and safety from var-cel's pivotal trial in this patient population.

Methods: This multicentre, single-arm, phase 2 trial was conducted at nine academic centres in Spain. Eligible patients had CD19+ B-cell precursor acute lymphoblastic leukaemia in the first relapse or refractory disease, either ineligible for allogeneic haematopoietic cell transplantation (HCT) or with relapsed disease after allogeneic HCT; centralised measurable disease in peripheral blood or bone marrow, or both, using flow cytometry; were aged 18-70 years; and had an Eastern Cooperative Oncology Group performance status of 0-2. Patients received a single course of intravenous lymphodepleting chemotherapy with fludarabine (30 mg/m2 per day for 3 days) plus cyclophosphamide (300 mg/m2 per day for 3 days), followed by intravenous fractionated var-cel escalation (0·1, 0·3, 0·6, and 2·0 × 106 CAR T cells per kg) separated by at least 24 h, with each fraction contingent on safety criteria. The primary endpoint was complete response with undetected measurable residual disease (MRD; sensitivity of ≤10-5) determined by flow cytometry by day 28 from var-cel administration, assessed in the efficacy population (defined as all patients who received at least one var-cel fraction). Safety was analysed in patients that initiated lymphodepletion. This study is registered with ClinicalTrials.gov, NCT04778579 (completed).

Findings: Between May 19, 2021, and July 6, 2023, 50 patients were assessed for eligibility, 12 were ineligible, and 38 were enrolled. 37 (97%) of 38 underwent leukapheresis (ITT population), 33 (87%) initiated lymphodepleting chemotherapy (safety population), and 32 (84%) received at least one var-cel fraction (efficacy population). Five patients who underwent leukapheresis did not receive var-cel due to rapid disease progression (n=3), death due to veno-oclusive disease (n=1), and persistent COVID-19 (n=1). Patients receiving var-cel had a median age of 40 years (33-48); of whom, 16 (50%) were female and 16 (50%) were male. By data cutoff (Jan 18, 2024), the median follow-up from infusion was 8·6 months (IQR 5·1-14·4) and 27 (84·4% [95% CI 67·2-94·7]) of 32 patients who received at least one dose of var-cel had a complete response with undetected MRD by day 28. Treatment-emergent adverse events occurred in 31 (94%) of 33 patients. The most common grade 3 or higher adverse events were neutropenia in 15 (45%) patients, thrombocytopenia in seven (21%), anaemia in five (15%), and cytokine release syndrome in four (12%). Immune effector cell-associated neurotoxicity syndrome and cerebral oedema was observed in one patient (3%; grade ≥3), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome occurred in two (6%; one resulted in death after protocol violation due to infusion during uncontrolled sepsis).

Interpretation: Var-cel induced deep remissions with low incidence of severe cytokine release syndrome and any-grade immune effector cell-associated neurotoxicity syndrome, supporting fractionated dose escalation as a strategy that preserves activity, limits acute toxic effects, and supports a hospital-based approach that could expand access to CAR T-cell therapy.

Funding: Instituto de Salud Carlos III Subdirección General de Evaluación y Fomento de la Investigación Sanitaria and Fondo Europeo de Desarrollo Regional, CaixaResearch, Servei Català de la Salut, Servicio Madrileño de Salud, Servicio Murciano de Salud, Salud de Castilla y León, Servicio Andaluz de Salud, and Servicio Navarro de Salud-Osasunbidea.

Translation: For the Spanish translation of the abstract see Supplementary Materials section.