Multicenter phase 2 trial of varnimcabtagene autoleucel for relapsed or refractory B-cell precursor ALL in adult patients in Spain

Varmicabtagene autoleucle (var-cel) is an autologous CD19-directed CAR T-cell therapy. The phase 2 CART19-BE-02 trial, at nine centers in Spain, evaluated var-cel in patients aged 18-70 years with first relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) and an ECOG performance status of 0-2. Patients received a single course of intravenous lymphodepleting chemotherapy, followed by intravenous fractionated var-cel escalation (0.1, 0.3, 0.6, and 2.0 x 10⁶ CAR T cells per kg) separated by at least 24 h, separated by at least 24 h, with each fraction contingent on safety criteria. The primary endpoint was complete response with undetectable MRD (sensitivity of ≤ 10^-5). Among 38 eligible patients, 37 underwent leukapheresis (ITT population), 33 (87%) initiated lymphodepleting chemotherapy (safety population), and 32 (84%) received at least one var-cel fraction (efficacy population). The median follow-up from infusion was 8.6 months (IQR 5.1-14.4), and 27 (84.4%; 95% CI 67.2-94.4) of 32 patients who received at least one dose of var-cel had a complete response with undetectable MRD by day 28. Treatment-emergent adverse events occurred in 31 (94%) of 33 patients. Grade ≥ 3 CRS occurred in four patients (12%), whereas ICANS and cerebral edema was observed in one patients (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). The authors conclude that var-cel induced deep remissions with low incidence of severe CRS and any-grade ICANS, supporting fractionated dose escalation as a strategy that preserves activity and limits acute toxic effects.