Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma

Abstract

Background: Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL).

Methods: RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells.

Results: Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF levels and circulating endothelial cells trended down with treatment.

Conclusions: RT-PEPC had significant and durable activity in MCL with manageable toxicity and maintained QoL. Novel, low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.

(c) 2010 American Cancer Society.

Figures

Figure 1. RT-PEPC treatment schedule

Treatment consisted of induction and maintenance phases. Patients received weekly rituximab × 4 at month 1, daily thalidomide at 50 mg (months 1–2, then dose-escalated to 100 mg if tolerated after month 2) and daily PEPC with prednisone 20 mg, etoposide 50 mg, procarbazine 50 mg, and cyclophosphamide 50 mg during induction. PEPC was put on hold when ANC dropped to

Figure 2. Response measurements in two representative patients

CT images from baseline and at 6 months were compared for study subjects RT#4 (A, B) and RT#14 (C, D). Tumor sizes (long axis) were marked with yellow lines.

Figure 3. Kaplan-Meier survival curves

A: Overall survival (OS) curve and progression-free survival (PFS) curve. B: PFS based on response status.

Figure 4. FACT-G quality-of-life (QoL) assessment

The FACT-G total score and modified trial outcome index (TOI) were measured at baseline, every 2 months until month 6, and every 6 months until disease progression to assess the impact of the metronomic therapy on QoL.

Figure 5. Angiogenesis and lymphangiogenesis characterization in MCL

A. VEGFR-1 is expressed by MCL B-cells (A1) and neovessels (v = vessel) (A2) by immunofluorescence analysis, and appears to be overexpressed in neoplastic B-cells (n=5) compared to normal B-cells (n=5) and MCL cell line Jeko-1 by quantitative PCR analysis (A3). B. VEGFR-2 expression in neovasculature. B1: VEGFR-2 immunohistochemistry on frozen tissue section. B2: A majority of VEGFR-2+ tumor endothelial cells coexpress CD34 by immunofluorescence analysis (white arrows). B3: VEGFR-2 vessels (V) are situated in proximity to VEGF-producing tumor cells (B3). C. Lymphangiogenesis as marked by VEGFR-3+ (C1), podoplanin+ (C2) and Lyve-1+ (C3). Some lymphatic vessels appear to co-express CD34. Black arrows point to CD34+podoplanin+ vessels, and asterisks point to CD34+lyve-1+ vessels.

Figure 6. Individual profiles of VEGF (A) and total CECs (B) over time

Individual time course of plasma VEGF and total CECs (dotted lines) with linear regression (solid lines) in a subset of patients.