Background: There is no standard therapy for recurrent anaplastic glioma (AG). Salvage therapies include alkylator-based chemotherapy (temozolomide [TMZ] or lomustine [CCNU]), re-resection with or without carmustine implants, re-irradiation and bevacizumab. Bendamustine is a novel bifunctional alkylator with CNS penetration but never evaluated in AG. Objective: Assess response and toxicity of bendamustine in bevacizumab naïve recurrent AG following prior radiotherapy (RT) and TMZ in a prospective Phase II trial. Methods: 26 adults (16 males; 10 females: median age 40 years {range 30-65}) with RT and TMZ refractory recurrent AG (14 anaplastic astrocytoma, 7 anaplastic oligodendroglioma, 5 anaplastic oligoastrocytoma) were treated with bendamustine. 12 patients were treated at 1^st and 14 at 2^nd recurrence. Prior salvage therapy included re-resection in 14 (12 with 2^nd and 2 with 3^rd resection), chemotherapy in 11 and re-RT in 2. A cycle of bendamustine was defined as 2 consecutive days of treatment (100mg/m²/day) administered once every 4 weeks (maximum number of cycles 6). Success of treatment was defined as progression free survival (PFS) at 6 months > 40%. Results: Grade 3 treatment-related toxicities included lymphopenia (11 patients), myalgia, pneumonia, diarrhea, leukopenia, allergic reaction and thrombocytopenia in 1 patient each. Three patients had grade 4 lymphopenia. No grade 5 toxicities were seen. One patient discontinued therapy due to toxicity (allergic reaction). Bendamustine dose was delayed in 3 patients (total of 5 events). There were no dose reductions. The median number of cycles of therapy was 3 (range 1-8). Best radiographic response was progressive disease in 12 (46%), stable disease in 13 (50%) and partial response in 1 (4%). Response did not differ by histology. Median PFS was 2.7 months (range 1-52 months), 6-month PFS was 27% and 12-month PFS was 8%. Conclusions: In this small prospective series of patients with recurrent AG refractory to TMZ and bevacizumab naive, bendamustine appears to have modest single agent activity though not meeting pre-specified criteria (40% 6-month PFS) and manageable toxicity. The study was supported in part through research funds provided by TEVA Pharmaceuticals and the National Comprehensive Cancer Network. Clinical trial information: NCT00823797