The treatment of chronic lymphocytic leukemia (CLL), the most prevalent leukemia in Western countries, is currently under reconsideration. While in the past treatment strategies primarily concentrated on controlling rather than curing the disease, nowadays the major aim is to achieve a negative state for minimal residual disease (MRD), especially in high risk cases. In recent years, impressive remission rates have been achieved by combining fludarabine with the anti-CD20 antibody rituximab in conjunction with cyclophosphamide (Bosch et al., 2008; Keating et al., 2005). Nevertheless, about 20% of patients with CLL do not respond to these conventional therapies. Moreover, the definition of complete response allows the presence of up to 30% lymphocytes in the bone marrow (BM), which can underestimate the extent of residual disease. Accordingly, the major problem in CLL treatment is still that patients with high-risk disease continue to relapse and require retreatment. Refractoriness to conventional therapies frequently ensues and patients likely die of their disease. New treatment strategies circumventing cellular resistance mechanisms to cytotoxic agents are clearly needed. This review outlines the recent understanding of CLL biology and its exploitation for the development of novel therapeutic approaches.

The Impact of the BCR in CLL

The B-cell antigen receptor (BCR) is the key signaling molecule of B lymphocytes triggering pathways involved in B-cell proliferation, survival, differentiation, anergy, and apoptosis. In CLL, the status of the BCR is of enormous prognostic, biological, and therapeutic relevance, which is reflected in the great variety of emerging novel agents targeting BCR signaling components or downstream effectors (Table 1). The high proportion of CLL patients expressing virtually identical immunoglobulin heavy and light chains and the presence of stereotyped somatic hypermutation patterns across the entire variable region of the immunoglobulin heavy chain gene locus (IgVH) (Messmer et al., 2004; Murray et al., 2008) underpin the hypothesis of an antigenic input in CLL pathogenesis. Moreover, the mutational status of the BCR is one of the strongest predictors of the clinical course of this disease (Damle et al., 1999; Hamblin et al., 1999). While patients with unmutated IgVH tend to have a relatively aggressive clinical course with rapid disease progression and poor outcome, the presence of somatic mutations predicts a rather stable disease. The key to the distinctive tumor behavior between these two prognostic subgroups likely lies in the differential ability of their BCRs to respond to stimuli. In this respect, zeta-associated protein 70 (ZAP-70) and CD38 expression further link biology to disease prognosis. ZAP-70, usually involved in T cell receptor signaling, is aberrantly expressed in high risk CLL subgroups and is associated with aggressive disease. While mutated CLL cells are considered to be anergized as the result of chronic exposure to (auto)antigens in the absence of costimulatory signals (Efremov et al., 2007), unmutated CLL cells maintain a certain BCR signaling competency. The presence of ZAP-70 can enhance and prolong BCR signaling in CLL independent of its conventional tyrosine kinase function, probably serving as an adaptor protein (Gobessi et al., 2007). The negative prognostic marker CD38 (Damle et al., 1999) is another potential modifier of BCR signaling (Deaglio et al., 2006) that influences the proliferation and longevity of the neoplastic clone. Importantly, ZAP-70 represents a limiting factor in the CD38 signaling pathway, acting at the crossroads where BCR signals are enhanced and where migratory signals from chemokine receptors intersect with growth signals mediated via CD38 (Deaglio et al., 2007). A phase I/II clinical trial is currently underway to test an anti-CD38 antibody in multiple myeloma (NCT00574288). However, functional linkage or a specific association of CD38 with signaling competence in CLL has not yet been unambiguously demonstrated and awaits further elucidation.

Pharmacological inhibition of BCR signaling in CLL can be achieved by targeting components of the BCR signaling cascade or modifiers of these components. One such target is Lyn, which binds to the signal transducing subunits of the BCR, and is aberrantly expressed in CLL cells contributing to their apoptosis defects (Contri et al., 2005). The tyrosine kinase inhibitor dasatinib induces CLL cell apoptosis in vitro, with a preference for unmutated and/or ZAP-70 positive high risk groups (Veldurthy et al., 2008). Probably as the result of specific Lyn inhibition, decreased signaling via Akt- and Erk-survival pathways, reduced expression of pro-survival Mcl1- and Bcl-xL, and increased levels of the tumor suppressor p53 are at the core of dasatinib’s therapeutic capacity. Early phase clinical trials for CLL with dasatinib as monotherapy or in combination with rituximab or lenalidomide are currently ongoing (Table 1).

Protein kinase C (PKC) and phosphoinositol 3 kinase (PI3K) are mediators that control CLL cell survival (Michie and Nakagawa, 2006). While some PKC isoforms (PKCβII) are pivotal for the regulation and outcome of BCR signals important for the progression of CLL (Abrams et al., 2007), other isoforms induce Akt activation independently of BCR-ligation in CLL cells but not in normal B cells, a fact which could be useful for the development of more targeted therapies (Barragan et al., 2006). For example, specific blockade of PKCδ, which is downstream of PI3K and constitutively activated in CLL, results in CLL — but not normal B lymphocyte — apoptosis (Ringshausen et al., 2006). PKC-modulator bryostatin-1 specifically increases CD20-expression on CLL cells thus rendering them more responsive to rituximab (Wojciechowski et al., 2005).

The Impact of the Microenvironment in CLL

Proliferation and survival of CLL cells obviously depend on a complex interplay of distinct cell types, the extracellular matrix, and soluble factors, collectively referred to as the CLL microenvironment. Increasing evidence highlights the considerable and thus far underestimated role of the microenvironment in CLL pathogenesis and stresses the therapeutic value of disrupting these interactions. The current view describes CLL as a dynamic disease characterized by a balance between cells circulating in the blood and cells located in distinct lymphoid niches. The former are morphologically mature CD5+ B lymphocytes resistant to apoptosis, whereas the latter include pro-lymphocytes and paraimmunoblasts. This hypothesized proliferative compartment — the so-called pseudofollicles — are interspersed with T lymphocytes (Ghia et al., 2002). Rather surprisingly for a B cell malignancy, absolute T cell numbers are increased and the peripheral blood CD4+ and CD8+ T cell repertoire is markedly oligoclonal (Serrano et al., 1997). CD4/CD8 ratios are shifted towards CD8 and an additional shift towards activated effector/memory T cells is observed in both CD4+ and CD8+ subpopulations (Kay et al., 1979; Tinhofer et al., 1998; Tinhofer et al., 2009; Totterman et al., 1989). Activation of CD40 on B cells by CD40L induces proliferation, rescues the cells from apoptosis, and induces cytokine secretion. The striking presence of CD4+ CD40L+ T cells in pseudofollicles implies a role of activated T cells in CLL cell proliferation. It is however unclear by which mechanism CD4+ T cells in CLL pseudofollicles acquire the expression of CD40L. The fact that CD38 expression is generally higher within pseudofollicles and proliferative markers such as Ki-67 are increased upon contact with activated CD4+ T cells point to a role of CD38 (Ghia et al., 2003; Patten et al., 2008). The evidence for T cell imbalances in CLL pathogenesis gives rise to a number of potential novel therapies. Inhibition of abl- and src-like kinases by dasatinib was able to revert the complete anti-apoptotic program induced by CD40 stimulation and could contribute to overcoming chemoresistance in microenvironmental niches (Hallaert et al., 2008) (see also below). The anti-CD40 antibody HCD122 demonstrated CLL killing efficacy in vitro (Luqman et al., 2008). Furthermore, CD200 is overexpressed in CLL and has been associated with the induction of regulatory T cells (Kretz-Rommel and Bowdish, 2008).

Other accessory cell types in the tumor microenvironment provide long-term survival benefits. Stromal cells and follicular dendritic cells support the survival of the CLL cells not only by direct integrin-mediated adhesion to the stroma but also by the secretion of soluble factors like chemokines (for review see, e.g., Burger et al. 2009). Homeostatic chemokine receptors such as CCR7 and CXCR4, potentially responsible for the malignant cell positioning in lymphoid follicles and BM, are highly expressed in CLL (Mohle et al., 1999; Till et al., 2002). The ligand of CXCR4, stromal cell-derived factor-1 (SDF-1), and the integrin ligand VCAM, which is binding VLA-4, secreted by marrow stromal cells are indispensable for progenitor and early B cell retention and survival in the BM. Accordingly, CXCR4 and VLA-4 inhibition may be ways of mobilizing progenitor and leukemic cells and overcoming stroma-mediated chemoresistance of CLL cells (Bonig et al., 2009b; Bonig et al., 2009a; Burger et al., 2005). A clinical trial (NCR00694590, Table 1) investigating whether CXCR4 blockage by plerixafor can release CLL cells into the blood, where they are more sensitive to killing by rituximab, is currently in the recruitment phase. In this context, it is also remarkable that the VCAM binding integrin VLA-4 is a novel prognostic marker in CLL (Gattei et al., 2008). VLA-4 expression is closely associated to CD38 expression (Gattei et al., 2008; Hartmann et al., 2009) and these molecules may facilitate the trafficking of CLL cells to BM and/or lymph nodes (Deaglio et al., 2007; Hartmann et al., 2009). Marginal VLA-4/CD38 expression in CLL low risk groups might explain their more favorable clinical course since it restricts circulating CLL cells from entering supportive and pro-proliferative niches. Similar to plerixafor, anti-VLA-4 blocking therapy could be effective in releasing VLA-4 positive CLL cells from the BM and rendering them more susceptible to conventional therapies. Furthermore, vascular endothelial growth factor (VEGF), important for tumor angiogenesis, has a growth promoting and survival effect on CLL cells, and the motility of CLL cells within certain niches seems to be dependent on VEGF interaction with integrin signaling (Till et al., 2005). A CLL clinical trial (NCT00448019, Table 1) testing the efficacy of VEGF blockade (bevacizumab) in combination with fludarabine, cyclophosphamide, and rituximab (FCR) is currently recruiting.

An interesting agent for CLL immunomodulation is lenalidomide. Lenalidomide and related compounds have shown promising anti-neoplastic activity in various tumor types (List, 2007; Richardson, 2005). Lenalidomide is clinically active as a single agent in CLL and small lymphocytic leukemia in previously unsuccessfully treated patients (Chanan-Khan et al., 2006; Ferrajoli et al., 2007).

The Impact of Aberrant Apoptotic Signaling Pathways in CLL

The intrinsic cell death pathway is regulated by the balance between pro-apoptotic and anti-apoptotic members of the Bcl-2 family. CLL has long been characterized by an overexpression of the anti-apoptotic molecule bcl-2 but paradoxically high levels of pro-apoptotic molecules Bim, Bmf, and Noxa have also been observed (Del, V et al., 2007; Del, V and Letai, 2008; Mackus et al., 2005). The mainstay of therapeutic strategies in CLL is still cytotoxic chemotherapy with alkylating agents or purine analogs triggering a DNA damage response via p53 leading to a prominent cell-death signal. The problem encountered in using these strategies is that a number of CLL patients harbor defects in the p53 pathway (Dohner et al., 1995; Gryshchenko et al., 2008; Zenz et al., 2008). The challenge is therefore to bypass such resistance by engaging p53-independent cell death pathways.

Probably the most important death sensory molecules are the so called “BH3-only” proteins (e.g., Bim, Bid, Bmf, Puma, Bad, and Noxa), a name derived from their short homology with members of the classical Bcl2 family of cell death regulators. BH3-only proteins are fundamental to the initiation of apoptosis by virtue of their ability to bind some or all anti-apoptotic Bcl-2 family members. Building on this concept, a number of BH3 mimetics have been developed to specifically neutralize the anti-apoptotic Bcl-2 family members (see Table 1). The most promising small-molecule BH3 mimetic to date is ABT-737, along with its second-generation orally bioavailable derivative, ABT-263 (Tse et al., 2008). Although BH3 mimetics generally lack impressive single-agent efficacy, they show a high synergism with some of the currently used therapeutic compounds such as the tyrosine kinase inhibitors imatinib and erlotinib/gefitinib. Furthermore, a number of approaches have been taken to directly modulate the core components of the Bcl-2 cell-death machinery. The Bcl-2 antisense molecule oblimersen is the most advanced agent in clinical testing, with encouraging phase I/II and phase III data in CLL reported (O’Brien et al., 2007; O’Brien et al., 2005).

Summary

The rapidly growing number of modulators of BCR components and the cell death machinery currently in CLL clinical trials demonstrates how a better understanding of disease biology facilitates the design of novel treatment strategies. Targeting the immune and microenvironmental interactions in CLL might additionally provide the means to relieve protection that CLL cells derive from these interactions and create synergisms with conventional therapies. Novel strategies may also help in the aim to maintain an MRD-negative state post-chemotherapy, which is associated with superior long-term survival in CLL.

Acknowledgments

We thank Josefina Pinon for helpful discussion and proofreading. The work of the authors is supported by FWF grants L488-B13, P19481-B12, and SFB 021-P11 and ÖNB grant 13420 and grants of the Province of Salzburg.

(Correspondence should be addressed to Dr. Richard Greil: r.greil@salk.at.)

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