Durable responses with the antiangiogenic metronomic regimen RT-PEPC in elderly patients with recurrent mantle cell lymphoma (MCL)

Abstract

8525 Background: Targeting tumor microenvironment and angiogenesis is a novel therapeutic strategy in lymphoma. Two putative anti-angiogenic regimens, RT (rituximab with thalidomide) and PEPC oral metronomic chemotherapy (prednisone, etoposide, procarbazine and cyclophosphamide) are clinically active. We report phase II safety, activity, and angiogenic profiling data with the novel combination RT-PEPC in elderly patients with recurrent MCL. Methods: RT-PEPC includes an induction phase (mo 1–3) of daily thalidomide (50 mg) and PEPC with weekly rituximab x 4. A maintenance phase (mo 4 until progression) continues with daily thalidomide (100 mg), PEPC dosing titrated to ANC > 1K/ul, and rituximab q 4 months. Endpoints included safety, efficacy, and FACT-G quality of life (QoL) assessment. Translational studies assessed the angiogenic phenotypes of tumor cells, and dynamic levels of circulating endothelial and hematopoietic progenitors in response to treatment. Results: Twenty-five pts (19 males) were enrolled, with 22 evaluable (3 never received rx). At study entry, median age (N=25) was 68 yrs (range 52–81), 24 (96%) had stage ≥ III, 16 (64%) had LDH > nl, and 18 (72%) IPI 3–5. The median number of prior therapies was two (range 1 to 7), and 15 pts (60%) progressed on bortezomib. At a median followup of 30 months, overall response rate was 73% (32% CR/CRu, 41% PR, N=22). Median PFS was 12 months, and median OS 22 months. Four CRs of 4+, 28+, 46+ and 48+ months are ongoing. Toxicities included gr 1–2 fatigue, rash and neuropathy as well as cytopenias (by design) including gr 1–2 thrombocytopenia (56%) and gr 3/4 neutropenia (56%). Two thrombotic events and 5 episodes of gr 3–4 infection were observed. QoL was maintained or improved on treatment. Correlative studies demonstrated pre-therapy autocrine angiogenic loop in tumor cells evidenced by expression of VEGFA and VEGFR1. Circulating levels of hematopoietic and endothelial progenitor cells decreased on rx in responders. Conclusions: RT-PEPC has significant and durable clinical activity in MCL, with manageable toxicity and maintained QoL. Novel low-intensity anti-angiogenic approaches warrant further evaluation in MCL and other NHL subtypes, potentially as initial therapy in elderly patients. [Table: see text]