Targeting Angiogenesis in Mantle Cell Lymphoma: Clinical Efficacy and Correlative Studies of a Phase II Trial of RT-PEPC (Rituximab, Thalidomide and Metronomic Oral Chemotherapy with Prednisone, Etoposide, Procarbazine and Cyclophosphamide) in Relapsed/Refractory Disease.

BACKGROUND: Targeting tumor microenvironment and angiogenesis is a novel therapeutic strategy with preliminary evidence of efficacy in lymphoma. Combination of rituximab with thalidomide demonstrated significant activity in a pilot study in MCL. We combined these agents with a metronomic oral chemotherapy of prednisone, etoposide, procarbazine and cyclophosphamide to comprise the RT-PEPC regimen. We report phase II safety and activity of RT-PEPC in recurrent MCL, and present angiogenic profiling of MCL patients. METHODS: Patients with recurrent MCL after chemotherapy were enrolled. The RT-PEPC regimen includes an induction phase (months 1–3) of daily thalidomide (50 mg) and oral PEPC (prednisone 20 mg, etoposide 50 mg, procarbazine 50 mg, and cyclophosphamide 50 mg), with weekly rituximab x 4 (375 mg/m2/week). Subjects then enter a maintenance phase (months 4–24), continuing on daily thalidomide (100 mg), PEPC dosing titrated (weekly to alternate day schedule) to maintain absolute neutrophil count > 1K/ul, and maintenance rituximab every 4 months for 2 yrs or until disease progression. Study endpoints included safety, efficacy, and FACT-G quality of life assessment. Translational studies of the angiogenic phenotypes of primary tumor cells and tumor vasculature are ongoing to correlate with treatment response. RESULTS: Fourteen patients (10 males) were enrolled, with 11 subjects evaluable for response. The median age (n=14) is 70 yrs (range 56–81). At study entry, ten patients (71%) had stage IV disease, ten had elevated serum LDH, and ten had IPI score 3–5. Twelve patients (86%) had two or more prior therapies; eight (57%) had progressive disease on bortezomib. Of the evaluable patients, the overall response rate is 82% including 27% CR and 55% PR. Non-responders experienced stable disease for 6 and 11 months, respectively. Median time to progression has not been reached at a median follow-up of 10.5 months (range 3+ to 20+ months). This response rate exceeds the prospectively defined interim efficacy criteria for continued accrual. Treatment-related toxicities are mild to moderate, with grade 1–2 fatigue, rash and neuropathy being most common. By design, hematologic toxicity includes grade 1 anemia (10%), grade 1–2 thrombocytopenia (45%), and grade 3 neutropenia (73%). One episode each of pulmonary embolism, stroke, and pneumocystis pneumonia were observed and resolved with treatment. All patients maintained or improved quality of life parameters on treatment. Ongoing correlative studies indicate increased angiogenesis in MCL (pre-therapy) at the tumor cellular level via vascular endothelial growth factor receptor 1 expression by immunohistochemistry and qPCR analysis, and at the tumor vascular stromal level where enhanced hemangiogenesis support neo-vascular assembly. CONCLUSIONS: RT-PEPC has significant clinical activity in MCL with a manageable toxicity profile in chronic use. Novel low-intensity anti-angiogenic approaches warrant further evaluation in MCL and other lymphoma subtypes.