Haematologica
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Haematologica, Vol 92, Issue 10, 1367-1374
Copyright © 2007 by Ferrata Storti Foundation
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Chronic Lymphocytic Leukemia

Intense reversal of bone marrow angiogenesis after sequential fludarabine-induction and alemtuzumab-consolidation therapy in advanced chronic lymphocytic leukemia

Stefano Molica, Marco Montillo, Domenico Ribatti, Rosanna Mirabelli, Alessandra Tedeschi, Francesca Ricci, Silvio Veronese, Angelo Vacca, Enrica Morra

From the Department of Hematology-Oncology, A.O. Pugliese-Ciaccio, Catanzaro (SM, RM), Department Hematology, Niguarda Ca’ Grande Hospital, Milano (MM, AT, FR, SV, EM), Department of Human Anatomy and Histology, University of Bari (DR), Department of Biomedical Sciences and Human Oncology, University of Bari, Italy (AV)

Correspondence: Stefano Molica, MD, Medical Oncology Unit, Dept. of Hematology/Oncology, A.O. Pugliese-Ciaccio, Viale Pio X, 88100 Catanzaro, Italy. E-mail: smolica{at}libero.it

Background and Objectives: 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.

Design and 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).

Interpretation and 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.

Key words: alemtuzumab, antiangiogenesis, CLL, fludarabine, molecular response, prognosis.






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