We report the first prospective study evaluating the efficacy and safety of oral low-dose metronomic chemotherapy PEPC with rituximab and thalidomide in recurrent mantle cell lymphoma. MCL has increased angiogenesis in the tumor microenvironment, and we combined two putative anti-angiogenic regimens, namely PEPC oral chemotherapy 13
, and rituximab with thalidomide 14
. This study is novel in several important aspects: we prospectively combined these regimens, assessed quality of life, and explored a putative mechanism of action (anti-angiogenesis). Additionally, we employed a lower, more tolerable dose of thalidomide compared to the prior RT regimen 14
. The ultimate clinical goal of the study was to develop a novel low-intensity treatment regimen that affords durable response with preservation of quality of life, particularly for elderly patients. The RT-PEPC regimen compares favorably in efficacy and tolerability to data reported from alternative treatment strategies in this patient population 7–12, 15
Subjects in this study generally had unfavorable baseline IPI (72% with IPI score of 3–5) and MIPI scores (12% with intermediate risk, and 80% with high risk), in addition to other clinical features typical for MCL including predominantly elderly patients (median age 68) with advanced stage diseases. Most had progressive disease on bortezomib, the only FDA-approved agent for this setting. Compared to immediate prior therapies, 70% of non-progressors (including CR+PR+SD) achieved longer PFS on RT-PEPC, and 45% had better response quality (i.e., from prior PD or SD to either PR or CR on RT-PEPC). Durable responses generally occurred in complete responders. Most patients would eventually be maintained on PEPC dosing of 1–2 times weekly, and thalidomide dosing of 50–100 mg daily. Treatment was convenient (at home except for rituximab) and well tolerated as reflected by quality of life.
Both metronomic therapy and thalidomide putatively target tumor microenvironment and angiogenesis 18, 19
. Metronomic therapy has broad applicability in lymphoma, including refractory disease 13, 20, 21
. Principal targets of metronomic therapy are thought to be the endothelial cells of the growing tumor vasculature. In addition, metronomic therapy has been shown to suppress the surge of bone marrow-derived endothelial progenitor cells (EPC) mobilization following conventional “maximal tolerated dose” therapy 22, 23
. Metronomic chemotherapy can be combined with new compounds to augment anti-angiogenic effects, as in the RT-PEPC combination. In relapsed breast cancer 24
and aggressive NHL 21
, responses to metronomic regimens appeared to be associated with overall declining levels of circulating endothelial cells, and increased fraction of apoptotic endothelial cells. We explored the correlation of angiogenesis biomarkers to clinical responses in a subset of our study patients. While limited by sample size, nonresponders appeared to have higher baseline VEGF levels, and plasma VEGF levels generally trended down with therapy in both responders and nonresponders. Our data also indicate that CECs declined in response to treatment in both responders and non-responders. A non-statistically significant increase in total CEC was noted at month 1 for 80% of the samples. Since we did not differentiate total CECs from apoptotic CECs, it is possible that this may represent a temporary increase in apoptotic CECs as a result of the treatment. The declining trend of both plasma VEGF and CECs levels in response to therapy may reflect potential anti-angiogenic effect of the RT-PEPC regimen with the caveat that disease in non-responders may have developed resistance via alternative mechanisms. Further investigations with larger sample sizes are needed in trials of conventional or anti-angiogenic treatment strategies to better define the prognostic significance of these angiogenesis biomarkers.
While the precise role of tumor angiogenesis in MCL pathogenesis remains under active investigation, our exploratory correlative study data indicate that MCL has increased angiogenesis in the tumor microenvironment. Consistent with the SWOG S0108 trial 25
, we detected VEGFR-1 over-expression in MCL B-cells compared to normal B-cells. VEGFR-1 expression promotes leukemic proliferation via autocrine fashion and extramedullary metastasis26
. Universal expression of VEGFR-1 in primary MCL cells suggests a role in MCL proliferation and extranodal metastasis. We also demonstrated that VEGFR-2 and VEGFR-3 were primarily expressed in a paracrine fashion by CD34+
neovascular blood and lymphatic vessels in relation to VEGF-A producing lymphoma cells, implicating heightened angiogenesis and lymphangiogenesis in MCL. The presence of both an autocrine loop via VEGF and VEGFR-1 expression on MCL tumor cells, and a paracrine loop between tumor VEGF and neovascular VEGFR-2 supports the strategy of targeting VEGF in MCL. As in solid tumors, single agent bevacizumab has limited activity in MCL 25
, and current approaches involving bevacizumab in combination are under evaluation in MCL and other lymphomas. Other agents targeting angiogenesis and lymphangiogenesis pathways are also in development and our data indicate potential utility in MCL.
The RT-PEPC regimen offers significant and durable clinical activity in MCL while maintaining quality of life, in part by targeting lymphoma microenvironment and angiogenesis. This approach compares favorably to other regimens for recurrent MCL. Novel low-intensity anti-angiogenic approaches warrant further evaluation in MCL and other lymphomas, either as part of a chronic maintenance treatment strategy, or as initial therapy in elderly patients.