title: Intense reversal of bone marrow angiogenesis after sequential fludarabine-induction and alemtuzumab-consolidation therapy in advanced chronic lymphocytic leukemia.
abstract: OBJECTIVE
  Increased bone marrow (BM) angiogenesis has been demonstrated in several hematologic malignancies. BM angiogenesis is significantly decreased in patients with chronic lymphocytic leukemia (CLL) treated with fludarabine. The anti-angiogenic potential of alemtuzumab in CLL has not yet been investigated. We, therefore, evaluated BM angiogenesis in CLL patients treated sequentially with fludarabine and low doses of alemtuzumab.
  
  
  METHODS
  BM microvessel area was sequentially evaluated in 20 patients with advanced B-cell CLL who received, after a clinical response obtained with fludarabine-induction therapy, alemtuzumab, three times weekly for 6 weeks at a dose of 10 mg.
  
  
  RESULTS
  The complete response rate improved from 45% after fludarabine induction to 90% after alemtuzumab consolidation. The extent of BM angiogenesis decreased continuously after either fludarabine or alemtuzumab (p=0.0002; Kruskal-Wallis test). Thirteen out of 20 (65%) patients changed from having a monoclonal to a polyclonal pattern of IgH sequences after alemtuzumab consolidation. A separate evaluation carried out in patients who achieved molecularly undetectable disease, as defined by polymerase chain reaction negativity, and in patients who remained with minimal residual disease after therapy with alemtuzumab showed a significant reduction of BM microvessel area only in the former (p=0.0002). Finally, molecular responses and a significant reduction of BM angiogenesis were more common in patients who received the cumulative planned dose of alemtuzumab (i.e.,180 mg) than in patients who received reduced doses (p=0.007 and p=0.0001, respectively).
  
  
  CONCLUSIONS
  Overall, these data demonstrate a decrease in BM vascularity that characterized CLL patients who received low doses of subcutaneous alemtuzumab consolidation therapy after a clinical response to fludarabine induction therapy. Such a finding reflects, at least in part, the molecular response and cumulative dose of alemtuzumab.
authors.affiliation: Department of Hematology/Oncology, A.O. Pugliese-Ciaccio, Viale Pio X, 88100 Catanzaro, Italy. smolica@libero.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Molica
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Rosanna
authors.initials: R
authors.lastname: Mirabelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tedeschi
authors.forename: Francesca
authors.initials: F
authors.lastname: Ricci
authors.forename: Silvio
authors.initials: S
authors.lastname: Veronese
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.forename: Enrica
authors.initials: E
authors.lastname: Morra
mesh_terms: D000328:Adult; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001853:Bone Marrow / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000074323:Alemtuzumab; D014740:Vidarabine; C024352:fludarabine