"Bendamustine monotherapy induces high response rates and STAT3 inhibition in high burden T-cell large granular lymphocytic leukemia".

T-cell large granular lymphocytic leukemia (T-LGLL) is a rare chronic lymphoproliferative disorder characterized by clonal expansion of cytotoxic CD3⁺ large granular lymphocytes (LGLs). Current first-line therapy relies on immunosuppressive agents such as methotrexate, cyclophosphamide, and cyclosporine A; however, these treatments are associated with suboptimal response rates and often require prolonged administration. Bendamustine, a bifunctional alkylating agent with purine analogue-like properties, is widely used in B-cell malignancies and has a favourable safety profile. We evaluated the efficacy and safety of bendamustine monotherapy in a retrospective cohort of 12 patients with treatment-naïve or relapsed/refractory T-LGLL and high burden disease. STAT3 mutations were detected in six patients. The main indications for treatment were severe neutropenia and severe/symptomatic anemia. After a median follow-up of 47.5 months, all patients achieved a clinical response, with a median time to response of 3 months and a complete response rate of 67%. Responses were observed irrespective of STAT3 mutational status. The estimated 3-year progression-free survival, duration of response and overall survival were 56.2%, 61.3% and 90.9%, respectively. Bendamustine was generally well tolerated: fewer than half of patients experienced grade 3-4 adverse events, mostly hematologic, and two patients discontinued treatment for toxicity. Ex vivo studies on patients' leukemic LGL demonstrated direct cytotoxic activity of bendamustine, associated with inhibition of STAT3 phosphorylation and induction of apoptosis. These findings support bendamustine as an effective and well-tolerated single-agent therapeutic option in high burden T-LGLL and support its further evaluation in prospective clinical studies.