Fractionated Varnimcabtagene Autoleucel Induces High Rates of MRD-Negative Complete Remission in Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia
Clinical Summary:
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Design/Population: This multicenter, single-arm phase 2 CART19-BE-02 trial evaluated varnimcabtagene autoleucel, a CD19-directed CAR T-cell therapy incorporating adaptive fractionated dose escalation, in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia who were ineligible for or had relapsed after allogeneic hematopoietic cell transplantation.
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Key Outcomes: Varnimcabtagene autoleucel induced high rates of complete remission with undetectable measurable residual disease by day 28 while demonstrating a relatively low incidence of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.
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Clinical Relevance: These findings support adaptive fractionated CAR T-cell dosing as a feasible strategy to achieve deep remissions while limiting acute toxicity in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia.
Results from the phase 2 CART19-BE-02 trial demonstrated that varnimcabtagene autoleucel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy incorporating adaptive fractionated dose escalation, induced high rates of deep remission with a manageable safety profile in adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
In this multicenter, single-arm trial, 32 adults with first relapsed or refractory CD19-positive B-cell precursor ALL who were either ineligible for allogeneic hematopoietic cell transplantation (HCT) or had relapsed following allogeneic HCT received lymphodepleting fludarabine and cyclophosphamide followed by fractionated varnimcabtagene autoleucel administered in escalating doses (0.1, 0.3, 0.6, and 2.0 × 10⁶ CAR T cells/kg). Each infusion was separated by at least 24 hours and administered only if predefined safety criteria were met. The primary end point was complete response with undetectable measurable residual disease (MRD) at day 28. Safety was a key secondary end point.
After a median follow-up of 8.6 months, 84.4% of patients achieved a complete response with undetectable MRD 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%). One patient experienced grade ≥3 immune effector cell-associated neurotoxicity syndrome with cerebral edema. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome occurred in 2 patients and resulted in 1 post-protocol death attributed to infusion-related uncontrolled sepsis.
As study authors concluded, “[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."
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
