title: Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia.
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 or 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.
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address: rossana.maffei@unimore.it.
authors.forename: Rossana
authors.initials: R
authors.lastname: Maffei
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Fiorcari
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Jenny
authors.initials: J
authors.lastname: Bulgarelli
authors.affiliation: Division of Hematology, Department of Biomedical Sciences, Azienda Ospedaliero-Universitaria Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Rizzotto
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Martinelli
authors.affiliation: Division of Hematology, Department of Biomedical Sciences, Azienda Ospedaliero-Universitaria Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.
authors.forename: Gian Matteo
authors.initials: GM
authors.lastname: Rigolin
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Debbia
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Castelli
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Goretta
authors.initials: G
authors.lastname: Bonacorsi
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Santachiara
authors.affiliation: Division of Hematology and Transplant, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy; Cancer Sciences Unit, CRUK Clinical Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Department of Hematology, Catholic University of the Sacred Hearth, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.affiliation: Division of Hematology, AOU "Policlinico- V. Emanuele", Catania, Italy.
authors.forename: Giuseppe A
authors.initials: GA
authors.lastname: Palumbo
authors.affiliation: Department of Medical Oncology and Hematology, Hospital of Piacenza, Piacenza, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Vallisa
authors.affiliation: Division of Hematology, Department of Biomedical Sciences, Azienda Ospedaliero-Universitaria Arcispedale S.Anna, University of Ferrara, Ferrara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuneo
authors.affiliation: Division of Hematology, Department of Clinical and Experimental Medicine and BRMA, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Luppi
authors.affiliation: Division of Hematology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002470:Cell Survival; D042783:Endothelial Cells / Q000473:pathology*; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D000077269:Lenalidomide