Fractionated Varnimcabtagene Autoleucel Achieves High MRD-Negative Response in Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia

Key Clinical Takeaways: 

• Design/Population: This multicenter, single-arm phase 2 trial evaluated varnimcabtagene autoleucel in adult patients with relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia who were ineligible for or had relapsed after allogeneic hematopoietic cell transplantation.
• Key Outcomes: Among patients who received at least 1 fraction of varnimcabtagene autoleucel, 84.4% achieved a complete response with undetectable measurable residual disease by day 28. The fractionated dose-escalation approach was associated with a relatively low incidence of severe cytokine release syndrome and neurotoxicity. 
• Clinical Relevance: These findings support fractionated CAR T-cell dose escalation as a feasible strategy to achieve deep remissions while limiting acute toxicity, potentially expanding access to CAR T-cell therapy in hospital-based settings.

According to results from the phase 2 CART19-BE-02 trial, varnimcabtagene autoleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy using adaptive intra-patient dose escalation, produced high rates of complete remission with undetectable measurable residual disease (MRD) in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

In this multicenter, single-arm study, 32 patients with first relapse or refractory disease who were either ineligible for allogeneic hematopoietic cell transplantation (HCT) or had relapsed following allogeneic HCT received 30 mg/m² of lymphodepleting fludarabine plus 300 mg/m² of cyclophosphamide (once daily for 3 days), followed by fractionated varnimcabtagene autoleucel infusion (0.1, 0.3, 0.6, and 2.0 × 10⁶ CAR T cells/kg), with each fraction administered at least 24 hours apart and contingent on safety criteria. The primary end point was complete response with undetectable MRD at day 28, and a key secondary end point was safety.

At a median follow-up of 8.6 months, 84.4% of patients achieved a complete response with undetectable measurable residual disease by day 28. Treatment-emergent adverse events occurred in 94% of patients. The most common grade ≥3 adverse events included neutropenia (45%), thrombocytopenia (21%), anemia (15%), and cytokine release syndrome (12%). Immune effector cell-associated neurotoxicity syndrome with cerebral edema was reported in 1 patient (grade ≥3 or higher). Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome occurred in 2 patients and led to 1 post-protocol death (infusion-related uncontrolled sepsis). 

“[Varnimcabtagene autoleucel] 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,” concluded Dr Ortiz-Maldonado et al. 

Source: 

Ortiz-Maldonado V, Martinez-Cibrian N, Alserawan L, et al. Varnimcabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia in Spain (CART19-BE-02): A multicentre, single-arm, phase 2 trial. Lancet Haematol. Published online: February 3, 2026. doi:10.1016/S2352-3026(25)00328-X