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ANTIANGIOGENIC THERAPY IN CLL
Despite the development of many new therapies in the last decades targeting specific pathways or
molecules, CLL remains an incurable disease. Angiogenesis is a common process in cancer, which helps the
growth and dissemination of malignant cells. As in other tumors, angiogenesis provides CLL cells with
nutrients and survival signals to facilitate disease progression [20-22] . Targeting angiogenesis thus seems a
useful therapeutic strategy against CLL [Table 2]. This section summarizes the results obtained with these
antiangiogenic treatments in CLL.

Fludarabine
Fludarabine is a purine analogue and a frontline treatment in CLL, alone or combined with other
compounds such as rituximab and/or cyclophosphamide [1,7,8,146] . The antiangiogenic role of fludarabine was
first assessed by Molica et al. who measured the microvessel density in the bone marrow samples of CLL
[147]
patients and found that this density decreased after fludarabine treatment. The same authors later evaluated
the effect of combining fludarabine with alemtuzumab (anti-CD52 antibody) and found an even more
significant reduction of angiogenesis in the bone marrow of CLL patients who had received this
treatment . In another study, the combination of fludarabine with the γ-secretase inhibitor PF-03084014
[148]
[149]
resulted in a synergistic induction of apoptosis and the impairment of angiogenesis and cell migration .
Importantly, these synergistic effects were specific for Notch1-mutated CLL cells, known to represent a
[149]
high-risk form of the disease .
Endothelin receptor inhibitor
CLL cells express high levels of endothelin receptors, which regulate CLL cell-microenvironment
[150]
[98]
interactions and angiogenesis . Maffei et al. reported that inhibiting endothelin receptors with
macitentan impaired CLL cell survival, migration, and proliferation. Macitentan also reduced VEGF
expression by decreasing HIF-1α accumulation, thus directly affecting angiogenesis .
[150]
Lenalidomide
The use of inhibitors of the transcription factor NF-κB for the treatment of hematological tumors has been
proposed for a long time. Thalidomide was a first-generation drug which downmodulated the levels of
angiogenic molecules, such as tumor necrosis factor-α and VEGF [151,152] . Indeed, these two angiogenic factors
were downregulated in CLL patients treated with thalidomide in combination with fludarabine .
[153]
Lenalidomide is a thalidomide analog frequently used as a therapeutic agent in hematological malignancies,
including multiple myeloma, myelodysplastic syndrome, and CLL . In CLL, lenalidomide was shown to
[154]
be very efficient in patients with relapsed or refractory disease [155,156] . Lenalidomide has antiangiogenic and
antitumor activity as it downregulates cytokines such as VEGF in CLL patients . However, a clinical trial
[157]
has reported the appearance of venous thrombosis in approximately 18% of the patients receiving
lenalidomide, together with the upregulation of soluble vascular endothelial adhesion molecule 1, tumor
necrosis factor-α, and C-reactive protein . Other clinical trials have shown that lenalidomide increases the
[158]
efficiency of fludarabine and rituximab, although this effect appears to be dependent on specific clinical
features of the patients [159-161] .

Bevacizumab and VEGF receptor inhibitors
Bevacizumab (Avastin, AVA) is a monoclonal antibody targeting VEGF with proven antiangiogenic
properties in multiple hematologic malignancies, such as acute myeloid leukemia, CLL, and non-Hodgkin’s
lymphoma [162-164] . Despite its potential relevance in the clinic, the administration of bevacizumab, as a single
[165]
agent, to CLL patients has shown no significant improvement in clinical trials . However, when
bevacizumab was given to CLL patients in combination with other conventional therapies (pentostatin,
cyclophosphamide, and rituximab), clinical trials have shown that it prolongs the progression free and