INTEGRACIÓN DE ELEMENTOS EN TORNO AL PATRIMONIO

The stage of the disease and prognosis determine the necessity of treatment in CLL. There are several treatment options as follows.

1.6.1 Chemotherapy

The common nitrogen mustard alkylating agents used for CLL treatment are chlorambucil and cyclophosphamide to induce cell death through p53 independent pathway. Induction of apoptosis by chlorambucil was related to increasing p53 and MDM-2 proteins whereas patients who had p53 mutations, increased cell apoptosis via p53 independent manner (Begleiter et al.,1996). The combination of chlorambucil and prednisolone produced initial response rates between 60%-90% and complete remission in 60% of patients analysed (Keating

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et al.,1998). Particularly patients who are resistant to alkylating agents are treated

with fludarabine, which is a purine analogue and potent inhibitor of DNA repair (Dillman et al.,1989). Moreover, it was reported that combination of fludarabine and cyclophosphamide (FC) give a higher response rate than fludarabine alone (O’Brien,1998). Rai et al., (2000) reported that fludarabine was superior to chlorambucil in previously untreated CLL patients in terms of rate of complete remission, overall rate of response, duration of response and progression-free survival. Another group has demonstrated that 2-chlorodeoxyadenosine (2- CDA)+prednisolone is an effective treatment for CLL patients who resist to chlorambucil+predinisolone and for patients who had early relapse after treating with alkylating agents (Robak et al., 2000). Fludarabine had a superior activity compared to CAP regimen (cyclophosphamide, doxorubicin and prednisone) and chlorambucil in terms of complete remission rate and remission duration (Dilman

et al., 1989; Rai et al.,2000).

Chemotherapy treatment of CLL was reported to relate with p53 mutations and selective drug resistance mainly associated with alkylating agents (Sturm et al., 2003). They suggested that p53 mutations may be related to DAN-damaging therapies which result in p53 inactivation. In vitro or in vivo drug resistance can be caused by several biological factors including abnormal p53 function, overexpression of bcl-2 and incubation of tumour cells with interleukin-4 (IL-4) (Dohner et al.,1995; Thomas et al., 1996). It was reported that chlorambucil could delay the disease progression whereas no effect on survival. However, analysis of the percentages of chlorambucil treated and untreated CLL patients progressed into stage B suggested that early exposure to the drug may select for resistant clones which may be related to poor prognosis of patients who have no response to early therapy (Dighiero et al., 1998).

1.6.2 Immunotherapy

Receptors on CLL are targeted via antibody-dependent cellular cytotoxicity (ADCC), causing apoptosis of CD20+ _{B cells and clearance of immune complexes}

(Shaw et al., 2003). Rituximab is the first monoclonal antibody approved for CLL treatment directed to CD20 phosphoprotein. Due to low density of CD20 on CLL cells, Rituximab treatment has a weak response in CLL patients (O'Brien et al., 2001). CD52, a ubiquitous antigen in CLL with heterogeneous density is targeted by Campath-1H (alemtuzumab). Campath-1H has a significant effect on CLL cells

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in the blood and bone marrow, but its effectiveness on targeting cells in secondary lymphoid tissues is lower confirming their protection by microenvironmental interactions with NLC and other stromal cells (Bentz et al., 1995). CD52 is expressed by both B and T lymphocytes and monocytes. It is reported that Campath-1H is concomitant with a significant incidence of opportunistic infections associated with T-cell immunodeficiency. Monoclonal antibodies are effective in the management of minimal residual disease (MRD) and the administration of moderate amounts of Campath-1H can clear residual tumour (Montillo et al., 2002; Ferrajoli et al., 2003;). Furthermore, when CD20 monoclonal antibody, rituximab is used as a single agent, it can induce only partial responses. The response is mainly limited to the lymph nodes and of short duration (Itala et al., 2002; Hainsworth et al., 2003). Therapeutic outcome of rituximab can be improved when it is used with other drugs such as fludarabine mono-phosphate (fludara) or fludara and cyclophosphamide (Ferrajoli et al., 2003).

1.6.3 Haematopoietic stem cell transplantation

Allogenic and Autologous stem cell transplantation (SCT) are increasingly considered for treatment of patients with CLL. Autologous stem cell transplantation (ASCT) may increase the response rate and prolong the time to progression, but in comparison with chemotherapy, it does not show a longer survival (Sutton et al., 2011). Since they have done their trial before monoclonal antibodies are started to use, it is important to analyse whether incorporation of rituximab into front line therapy can improve the results or including rituximab as an additional treatment after ASCT. The efficacy of ASCT depends on the administered cytotoxic therapy and it can improve patients' outcome with defined poor-risk features (Dreger and Montserrat, 2002). Allogenic stem cell transplantation from related and well-matched or partially matched unrelated donors could increase long-term MRD-negative survival in 50% of poor-risk CLL patients studied independently of the underlying genomic risk profile (Dreger et

al., 2010).

1.6.4 Novel therapies

Recent studies have shown that autologous CD19 redirected T cells expressing genetically modified chimeric antigen receptor (CART19) (Figure 1.8) are very effective in targeting CD19 on CLL cells through transduction of chimeric antigen receptor linked to potent signalling domains (Porter et al., 2011). A patient's T

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cells are genetically modified and transferred back to the patient's body mediating killing of malignant and normal B cells (Davila and Brentjens, 2013). It was reported that CLL patients with TP53 deletions have short remissions after standard therapies (Dohner et al., 1995) and for CLL patients who have advanced stages of the disease, the only approach is allogenic bone marrow transplantation to induce long-term remission (Gribben et al., 2011). However, allogenic bone marrow transplantation is associated with potent graft-versus-tumour effect contributing to morbidity especially in older patients (Sorror et al., 2008; Gribben

et al., 2011). Genetically modified autologous T cells may avoid this limitation and

unlike antibody-mediated therapy, chimeric antigen receptor modified T cells have the potential to replicate in vivo. This can lead to long-term persistence and sustained tumour control (Porter et al.,2011).

Figure 1.8: The chimeric antigen receptor (CAR). Most CARs consist of three parts, the antigen binding domain of a scFv, transmembrane region (TM) of a protein such as CD8 and a signal transduction domain associated with a T cell receptor. Antigen binds with scFv and the two signal transaction domains mediate T cell activation (Davila and Brentjens, 2013).