Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia

Rossana Maffei, Stefania Fiorcari, Jenny Bulgarelli, Lara Rizzotto, Silvia Martinelli, Gian Matteo Rigolin, Giulia Debbia, Ilaria Castelli, Goretta Bonacorsi, Rita Santachiara, Francesco Forconi, Davide Rossi, Luca Laurenti, Giuseppe A. Palumbo, Daniele Vallisa, Antonio Cuneo, Gianluca Gaidano, Mario Luppi, Roberto Marasca

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Lenalidomide is an IMID immunomodulatory agent clinically active in patients with chronic lymphocytic leukemia (CLL). We evaluated the activity of lenalidomide inside an in vitro coculture system of endothelial and CLL cells. Lenalidomide was able to inhibit CLL survival advantage mediated by endothelial contact. Moreover, the marked increase of in vitro angiogenesis determined by CLL-derived conditioned media was reduced by lenalidomide. We also analyzed peripheral blood collected from 27 patients with relapsed/refractory CLL being treated with lenalidomide within a phase II trial. Plasma levels of VEGF and THBS-1 decreased, whereas Ang2 and Ang increased during treatment. Patients who respond to lenalidomide showed a more pronounced decrease of VEGF and bFGF than did patients with stable or progressive disease (p = 0.007 and p = 0.005). Furthermore, lenalidomide reduced circulating endothelial cells and endothelial progenitors by increasing the percentage of apoptotic cells. Conversely, for six matched bone marrow biopsies available before and after treatment, we did not detect any modification in vessel density, suggesting a possible mechanism of vessel normalization rather than regression. In conclusion, our study provides further evidence that the anti-CLL effect of lenalidomide is mediated through the alteration of microenvironmental elements, implying the modulation of several angiogenesis-related factors and disruption of CLL crosstalk with endothelial cells.
Original languageEnglish
Pages (from-to)126-136
Number of pages11
JournalExperimental Hematology
DOIs
Publication statusPublished - 2014

Keywords

  • CLL

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