Chronic Lymphocytic Leukemia Continues To Attract Biology Essay

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Chronic lymphocytic leukemia continues to attract much basic and clinical research interest. Despite recent advances, the disease still has no established cure. Nonetheless, significant strides have been made in our understanding of the genetics, biology, and clinical staging of this disease. This understanding may improve our ability to segregate patients into subtypes that differ in their cytogenesis, propensity toward disease progression, or response to standard or innovative forms of therapy. Finally, several promising new modalities of treatment are being evaluated in clinical trials, involving novel drugs or drug-combinations, monoclonal antibodies, stem cell transplantation, or gene therapy.


Leukemia is a tumor of the white blood cell which created by the bone marrow. Leukaemia originates in developing blood cells, which have undergone a malignant change. This means that they multiply in an uncontrolled way and do not mature as they are supposed to. Because they have not matured properly, these cells are unable to function properly. Most cases of leukaemia originate in developing white cells (Rozman and Monsterrat,1995) .Frequently, people with leukaemia have more white blood cells than normal. There are several different types, and subtypes of leukaemia. Leukaemia can be either acute or chronic. The terms 'acute' and 'chronic' refer to how quickly the disease develops and progresse. Acute leukaemias develop and progress quickly and need to be treated as soon as they are diagnosed. Acute leukaemias affect very immature blood cells, preventing them from maturing properly. Chronic leukaemias develop slowly, during the early stages of disease, and progress slowly over weeks or months. Chronic leukaemias generally involve an accumulation of more mature but abnormal white cells. Leukaemia can also be either myeloid or lymphoid. The terms myeloid and lymphoid refer to the types of cells in which the leukaemia first started (Johnston,2009). When leukaemia starts somewhere in the myeloid cell line, it is called myeloid (myelocytic, myelogenous or granulocytic) leukaemia. When leukaemia starts somewhere in the lymphoid cell line it is called lymphocytic (or lymphoblastic or lymphatic) leukaemia (figure 1, stem cell line).

Therefore, there are four main groups of leukemia;

Chronic lymphocytic leukemia( CLL).

Acute lymphocytic leukaemia(ALL).

Chronic myeloid leukemia (CML).

Acute myeloid leukemia (AML).

Chronic lymphocytic leukaemia (CLL) is a type of slow-growing leukaemia that affects developing B-cells. B-cells (also known as B-lymphocytes) are specialized white blood cells. Under normal conditions they produce immunoglobulins (also called antibodies) that help protect our bodies against infection and disease (Harris, et al, 1999). In people with CLL, lymphocytes undergo a malignant (cancerous) change and become leukaemic cells. It is important to emphasize here that for many people CLL remains stable for many months and years and has little if any impact on their lifestyle or general health. Around 30 - 50 per cent of people diagnosed with CLL never require any treatment for their disease and can survive for many years despite their diagnosis (Chiorazzi et al, 2005). For others, the leukaemic cells multiply in an uncontrolled way, they live longer than they are supposed to and accumulate in the bone marrow, bloodstream, lymph nodes (glands), spleen and other parts of the body. These cells are abnormal and as such they are unable to function properly (Jaglowski and Byrd , 2010). Over time, an excess number of lymphocytes crowd the bone marrow, and interfere with normal blood cell production. The bone marrow produces inadequate numbers of red cells, normal white cells and platelets, making some people with CLL more susceptible to anemia, recurrent infections and to bruising and bleeding easily. Circulating red cells and platelets can also be damaged by abnormal proteins made by the leukaemic cells.

Chronic Lymphocytic Leukemia (CLL) is the most common type of leukaemia accounts for approximately 35% of all leukaemia cases and is more common in older men than young people and women (Redaelli, 2004) . The disease is characterized by the accumulation of mature, neoplastic B cells in the peripheral blood, bone marrow and lymphoid tissue . CLL prognosis varies from patient to patient and according to the stage of the disease. Research investigating gene mutations offered some insight into the prognosis of the disease. However, the lack of predictive factors that determine the prognosis of the disease and the response to chemotherapy remain a challenge (Robak, et al, 2009). There is increasing appreciation that there may be an inherited tendency to develop CLL in some patients. The risk for developing CLL in a first degree relative (i.e. father, mother, brother, sister or child) of a patient with CLL is approximately 7 times higher than the population average. However, as the background risk of developing CLL is very low, the vast majority of family members will never develop CLL (Travis et al, 1992). At present, screening for CLL simply because of a positive family history is not recommended. Like other types of leukaemia, CLL is thought to arise from an acquired mutation (or change) in one or more of the special molecules of DNA (called "genes") which encode information that controls the growth and development of blood cells. This change (or changes) will result in abnormal growth (Koduru et al, 1993) . The original mutation is preserved when the affected stem cell divides and produces a 'clone'; that is a group of identical cells all with the same defect. As such CLL is regarded as a clonal blood stem cell disorder (Koduru et al, 1993).

Symptoms of Chronic Lymphocytic Leukaemia

CLL develops gradually and lots of people have no symptoms in the early stages. In these cases the disease may be diagnosed unexpectedly, for example during a routine blood test or physical examination. These may include the following:

Symptoms caused by a lack of normal white cells and normal antibodies such as frequent or repeated infections. Symptoms of anemia due to a lack of normal red cells such as persistent tiredness and fatigue, Weakness, Shortness of breath with minimal exercise and Looking pale. Symptoms caused by a lack of normal platelets for example, bleeding or bruising more easily for no apparent reason, frequent or severe nose bleeds or bleeding gums and the appearance of red or purple flat pinhead sized purple spots on the skin, especially on the legs initially. These are due to small superficial capillary bleeds known as petechiae. CLL can also cause a painless swelling of the lymph nodes (glands) in your neck, under your arms or in your groin. This is usually a result of lymphocytes accumulating in these tissues. The spleen may also be enlarged as it attempts to rid the body of the excess lymphocytes from the circulating blood. Symptoms of an enlarged spleen (splenomegaly) are common and include ; feelings of discomfort, pain or fullness in the upper left-side of the abdomen. An enlarged spleen may also cause pressure on the stomach causing a feeling of fullness, indigestion and a loss of appetite. In some cases the liver may also be enlarged. Other symptoms of CLL may include excessive sweating, especially at night, fevers and unintentional weight loss(Hallek, 2011).

Diagnosis of Chronic Lymphocytic leukeamia

Typically, it is diagnosed by looking at the cells in the blood samples. It is assumed when the blood shows a huge amount of lymphocytes. However, it should confirm by a technique called immunophenotyping (Hallek , 2008). There are some diagnosed methods

Full blood count

The first step in diagnosing CLL requires a simple blood test called a full blood count or full blood examination (FBC or FBE) or complete blood count (CBC). It involves taking a sample of blood from the patients, and sending it to the laboratory for examination under the microscope. The number of red blood cells, white blood cells and platelets, and their size and shape, is noted as these can all be abnormal. In CLL, the lymphocyte count is abnormally high, and needs to be at least 5 x 109L for a diagnosis of CLL. Anemia and thrombocytopenia (a lower than normal platelet count) are common in more advanced disease(Correia et al,2009).


Immunophenotyping, or flow cytometry tests are commonly used to confirm a suspected diagnosis of CLL, and to distinguish it from other similar diseases. This technology uses special markers called antigens found on the surface of cells. These antigens act like flags

identifying the abnormal characteristic of CLL. Antigens are commonly referred to as 'cluster of differentiation' or CD antigens followed by a number. In CLL certain B-cell antigens like CD19, CD20, CD23 and CD5 and other surface markers are almost always expressed on the leukaemic cells (Hardy and Richard, 2008). The presence of these markers helps to define the exact type of CLL you have and distinguishes it from other diseases that can resemble CLL. These include such diseases as prolymphocytic leukaemia, hairy cell leukaemia, mantle cell lymphoma and other types of lymphoma (cancer of the lymphatic system).

Cytogenetic tests

Cytogenetic tests such as chromosome analysis and fluorescent in situ hybridization (FISH) tests provide information about the genetic make-up of the leukaemic cells, in other words, the structure and number of chromosomes present. These tests may be used to provide more information about the likely course of your disease and the best way to treat it(Hallek,2008). Chromosomes are the structures that carry genes. Genes are collections of DNA, our body's blueprint for life. Certain cytogenetic changes, such as missing, extra or abnormal chromosomes help to confirm the type of CLL you have, the likely course of your disease and the best way to treat it. These chromosomal changes are only found in the leukaemic cells.

Immunoglobulin levels

Blood samples may also be taken to measure the levels of antibodies in patient blood. People with low levels of normal antibodies may be more susceptible to repeated infections and some may benefit from monthly intravenous immunoglobulin (antibody) treatment to reduce the frequency of infections. Blood tests may be repeated at regular intervals to monitor the disease .

Bone marrow examination

A bone marrow examination (biopsy) is used in some cases to help confirm the diagnosis of CLL. It can also provide useful information about the likely course of the disease and to assess how well it is responding to treatment. It involves taking a sample of bone marrow, usually from the back of the iliac crest (hip bone) and sending it to the laboratory for examination under the microscope. The bone marrow examination may be done in the

haematologist's rooms or clinic under local anaesthetic or, in selected cases, under a short general anaesthetic in a day procedure unit. A mild sedative and a pain-killer are given beforehand and the skin is numbed using a local anaesthetic. This is given as an injection under the skin. The injection takes a minute or two, and you should feel only a mild stinging sensation. After allowing time for the local anaesthetic to work, a long thin needle is inserted through the skin and outer layer of bone into the bone marrow cavity. A syringe is attached to the end of the needle and a small sample of bone marrow fluid is drawn out - this is called a 'bone marrow aspirate'. Then a slightly larger needle is used to obtain a small core of bone marrow which will provide more detailed information about the structure of the bone marrow and bone - this is known as a 'bone marrow trephine'. Because you might feel a bit drowsy afterwards, you should take a family member or friend along who can take you home. A small dressing or plaster over the biopsy site can be removed the next day. There may be some mild bruising or discomfort, which is usually managed effectively by paracetamol. More serious complications such as bleeding or infection are very rare.

Other tests

Once a diagnosis of CLL is made, further tests may be done to find out the stage, or extent of the disease in your body and the affect it is having on other organs. They include a combination of blood tests and imaging tests. These tests can also provide important information about your general health and how well your kidneys, liver and other vital organs are functioning. The results may be important in selecting the best treatment for you. They can also be used as a baseline and compared with later results to assess how well patients are progressing.

Other blood tests

• Kidney function tests

• Liver function tests

Prognostic factors in Chronic Lymphocytic Leukemia

Scientific staging residue a significant prognostic marker; this and other markers of disease such as beta 2-microglobulin can be integrated into nomograms to measure the threat of development (Wierda, El at, 2007). Traditionally the Rai and Binet staging systems(Molica et al,1975) have been used to estimate prognosis in CLL. Using these systems patients are assigned to one of three major subgroups (good, intermediate or poor prognosis) depending on the number of lymphoid areas affected by the disease (lymph nodes, spleen or liver), and the red cell and platelet counts in the circulating blood. Stage A refers to early disease, where in many cases people haven't got any symptoms and don't require any treatment. Stage B and C refer to more advanced disease which usually requires treatment ( see table 1). A molecular profile can be built from an assessment of the large number of biomarkers that have been identified, the most important being cytogenetic analysis by fluorescent in situ hybridization (FISH), mutational status of the immunoglobulin heavy-chain variable gene (IgVH), use of IgVH, and expression of 70-kDa zeta-associated protein (ZAP70) and CD38. One or more chromosome abnormalities can be found in more than 80% of CLL patients by using FISH, including del13q, del11q, trisomy 12, del17p, and del6q (Krober et al, 2002). The most common abnormality del13q,14 occurs in _ 50% of patients, and isolated del13q is associated with a good prognosis. Two microRNA clusters, mir-15a and mir-16-1, are located within the deleted region at 13q14.7 Del11q and trisomy 12 are each found in approximately 20% of patients. Although_ 10% of patients have del17p at diagnosis, this abnormality is associated with more rapid progression of disease, poor response to therapy, and short survival time ((Bosch et al, 2006) .Cytogenetic changes that occur in CLL can evolve over time, and it is important to reassess these markers at subsequent time points. Fifty percent of CLL patients have undergone somatic hypermutation in IgVH, and these patients have a more indolent clinical course and longer survival than those without somatic hypermutation(Haublim et al, 1999). Analysis of variable region sequences demonstrates that CLL cells use a biased repertoire of V genes with over-representation of certain Ig gene segments, in particular IGHV1-69, IGHV4-34, IGHV3-7, and IGHV3-21(Fais et al,1998). Patients with CLL cells that use IGHV3-21 have relatively aggressive disease, even when the expressed IGHV3-21 is mutated(Mauerer et al,2005). Since it is technically difficult and expensive to determine IgVH mutational status, surrogate markers such as expression of ZAP70 and CD38 have been assessed, and both have prognostic significance. There is not an absolute relationship between ZAP70 expression and IgVH mutational status, with discrepancies occurring in up to 25% of patients(Rassenti et al,2004). Discordant cases may have other biologic features with poor prognostic implications such as del17p, del11q or use of IGHV3- 21(Krober,2006). Some studies have suggested that ZAP70 status is more useful as a predictor of time to progression than mutation status,but this remains controversial. MicroRNA array analysis has revealed a 13- gene signature correlated with ZAP70 status, unmutated IgVH expression and disease progression altered microRNA expression appears to regulate expression of genes controlling apoptosis and cell cycle progression(Calin et al,2004). Although there is a relationship between CD38 and IgVH mutation status this is not absolute, and CD38 expression may vary over time(Montillo et al,2005) High-risk features predictive of disease progression include del17p and del11q, IgVH unmutated status, use of the IGHV3-21 gene segment, and expression of either ZAP70 or CD38. It remains challenging to understand how these biomarkers can be used in clinical practice and whether we should alter treatment on the basis of the detection of high-risk features. Assessment of the impact of these biomarkers remains a vital component of research studies. With improvement in therapy, since some groups respond better to newer treatment combinations, the prognostic significance of some of these parameters will change.

Treatment of CLL

Although greatly evolution has been made in the treatment of chronic lymphocytic leukeamia over the decades, this disease still fatal(Awan, et al, 2010). In 1989 the results of a clinical testing on fludarabine as monotherapy in pretreated CLL patients were published . The response data and toxicity outline were extremely promising (Keating et al, 1989). Consequently, the purine analogue fludarabine has shown effectiveness in CLL therapy. Fludarabine treatment results in a creation of the p53-mediated apoptotic pathway ( Dohner et al, 1995).

First line therapy

Traditionally, chemotherapy with alkylating agents has been the treatment of choice for patients with advanced and progressive CLL (Robak, 2007). Since the introduction of purin nucleoside analogues (PNAs), alkylating agents as chlorambucil, cyclophosphamide and bendamustine may no longer be considered as elective first-line treatment for young healthy patients.

Alkylating agents

For many decades, chlorambucil and cyclophosphamide alone or with corticosteroids has been the most frequently used treatment for CLL. Adding steroids in an attempt to improve response rates does not apparently have a direct effect on overall survival. When given as first-line treatment, chlorambucil achieves an overall response rate (ORR) of 60-90% with a complete response rate (CR) in up to 20% of all patients . Jaksic et al. [1997] found an ORR of 89% using chlorambucil at 15 mg/day, which is similar to other results with PNAs. Recent results of a multicentre phase III trial conducted by the German CLL Study Group (GCLLSG) (Eichhors et al,2009) for patients >65 years comparing six cycles of fludarabine (25 mg/m2 for 5 days intravenously every 28 days) to chlorambucil (0.4 mg/kg body weight, increasing to 0.8 mg/kg every 15 days) showed a significantly higher ORR and CR rates of fludarabine (72% vs. 51%, P = 0.003 and 7% vs. 0%, P = 0.011, respectively) but no differences were found in progression free survival (PFS) or overall survival (OS) (19 months vs. 18 months, P = 0.7 and 46 months vs. 64 months, P = 0.15, respectively). Cyclophosphamide has a similar activity to chlorambucil (Robak et al, 2002) and is occasionally used as a single agent when chlorambucil is poorly tolerated at a dose of 2-3 mg/kg/day orally or 20 mg/kg intravenously every 2-3 weeks. Combination therapy of cyclophosphamide with vincristine, doxorubicin and prednisone (COP, CHOP, CVP regimens) has also been studied. However, results from randomised trials did not show superiority of this combination over chlorambucil and prednisone (Raphael et al, 1991) The meta-analysis published by the CLL Trialists Collaborative Group confirmed these results. In contrast, Jaksic et al showed a significant advantage of high doses of chlorambucil over CHOP in terms of ORR (89.5% vs. 75%, P < 0.001) and OS (68 months vs. 47 months, P < 0.005) (Jaksie et al, 1997)

Purine Nucleoside analogues (PNAs)

Fludarabine, cladribine and pentostatin are cytotoxic agents with similar chemical structures to adenosine and deoxyadenosine (Robak, 2002). PNAs share their antitumor mechanism of action, interfering with the DNA synthesis machinery by inhibiting DNA primerse and DNAligase. Studies reported to date show that PNAs are more active than alkylating agents in previously untreated CLL patients in terms of response and time to progression, but their influence on survival is still uncertain . Fludarabine has mainly been found to be very active in previously treated CLL patients. As a single-agent, given at 25 mg/m2 per day for 5 days, Sorensen et al reported a 32% overall response rate (ORR) in previously treated or relapsed CLL patients. Toxicity was mainly haematological (43%), with 22% infections, and neurotoxicity reported in 14% of patients (Sorensen et al, 1997). Evaluation of fludarabine as first-line treatment has been studied both as a single-agent and as part of combination regimens with other cytotoxic drugs. Keating et al. (1998) studied 174 patients with advanced or progressive CLL treated with fludarabine alone or in combination with prednisone with an ORR and CR of 78% and 29%, respectively. In patients with response, the median time to progression was 31 months and the overall median survival was 74 months. Similar results have been obtained with others randomised trials that were confirmed by a meta-analysis published by Steurer et al. (2006). Moreover, an oral formulation has been developed that is equivalent to the intravenous administration in terms of efficacy and tolerability (Ross et al,2004).

Monoclonal antibodies

C-1 Rituximab

CD20 is a 297-amino acid transmembrane phosphoprotein expressed as a cell-surface antigen on more than 90% of mature B-cell leukaemias and lymphomas. Rituximab is a chimeric anti-CD20 monoclonal antibody with action against leukaemia cells mediated by different mechanisms: antibody-dependent cell-mediated cytotoxicity, complement-dependent lysis and induction of apoptosis. However, rituximab has poor efficacy in CLL at conventional doses (375 mg/m2 weekly), and some studies have suggested that higher doses may be more effective (Byrd,et al, 2005). However the real interest lies in the effect of the rituximab combination with PNAs . In a phase II randomised study, Byrd et al. (2005) obtained an ORR rate of 90% with 47% CR in patients treated with a concurrent regimen of rituximab plus fludarabine compared to a 77% ORR and 28% CR in patients that were treated with a sequential regimen. PFS and OS were also significantly higher in the rituximab group (P < 0.0001 and P < 0.0006, respectively). Keating et al. [2005] investigated this association in the FC combination, including 224 treatment-naive CLL patients and obtained an ORR rate of 95%, a CR rate of 70% and 80 months of median time to progression. Hallek et al. (2009) presented the results of a phase III trial carried out by the GCLLSG including 817 patients with progressive CLL randomised to FC or FCR as first-line therapy. The CR rate was significantly higher in the FCR arm (45% vs. 23%) and the PFS was significantly longer (43 months vs. 32 months). Recently, Hallek et al.( 2009) presented inASH2009 an update of these results showing differences in PFS (64.9% vs. 44.7%, P < 0.001) and OS (87.2% vs. 82.5%, P = 0.012) favourable to FCR arm. FCR was significantly more myelotoxic but it was not superior in terms of complications in the form of infection or toxic deaths. However, FC regimen should be used with caution in elderly patients due to its high risk of myelosuppression. For this group, reducing fludarabine and cyclophosphamide doses and increasing doses of rituximab could be a valid option (Foon et al, 2009). Other combinations should be considered for future studies, including pentostatin and rituximab or regimens that can be used in patients with limited myeloid reserve, such as rituximab plus high-dose methylprednisolone . We can conclude that the combination of rituximab plus PNAs, with or without cyclophosphamide, results in higher ORR, CR rates an median duration of response compared with PNAs alone, and should be used as a standard first-line therapy in young patients with symptomatic and/or progressive CLL.

C-2 Alemtuzumab

CD52 is a small cell-surface glycoprotein highly expressed on most normal and malignant B and T lymphocytes, compared with other blood cell types (Fabion et al,1993). Alemtuzumab (Campath 1-H®) is a humanised anti-CD52 monoclonal antibody that fixes complement and depletes normal lymphocytes and lymphoma cells (Hale et al,1983). It has been extensively evaluated in various clinical settings, including refractory disease, front-line therapy, and as part of combination and consolidation strategies. The effectiveness of alemtuzumab in treatment-naïve patients was first reported by Osterborg et al in 1996. The same group reported the results of a phase II trial (Lundian et al,2002). Including 38 treatment-naive patients who were given alemtuzumab subcutaneously, achieving 19% CR and 68% PR. Hillmen et al(2007), confirmed these results in a prospective randomised phase III trial (CAM 307) comparing alemtuzumab (30 mg iv three times a week for a maximum of 12 weeks) and chlorambucil (40 mg/m2 orally every 28 days up to a maximum of 12 cycles), obtaining an ORR rate of 83% with alemtuzumab vs. 55% with chlorambucil. Alemtuzumab had superior PFS with a 42% reduction in risk of progression or death (HR = 0.58; P = 0.0001). Moreover, this study demonstrated the superiority of alemtuzumab for CLL patients with poor cytogenetic risk. In this respect, alemtuzumab is an agent with demonstrated clinical activity in patients with genetic abnormalities (p53 mutations and 17p deletions). Lozanski et al(2004), presented a randomised study comparing 21 patients first-line treated with chromosome 17p deletion with either chlorambucil or alemtuzumab. Both ORR rate and PFS were higher in the alemtuzumab group and there were no differences in OS due to the small number of patients. When given for relapse, alemtuzumab attained an ORR rate of 40% and median PFS of 9 months in patients with chromosomal aberrations. Combination therapy of alemtuzumab with cytotoxic agents, mainly fludarabine, has also been assessed in several studies, showing encouraging results (Kennedy et al, 2002). Wierda et al. (2008), tested the combination of alemtuzumab and fludarabine cyclophosphamide- rituximab (CFAR regimen) in 63 patients with advanced CLL. The ORR was 94% and CR was 69%. In the subgroup of patients (n = 13) with 17p deletion, ORR was 77% and CR was 54%, and no differences were detected in time to progression and survival after 16 months of follow up. However, this regimen was more myelosuppressive so, as is described in the management guidelines for the use of alemtuzumab in CLL (Osterborg et al,2009), combination therapy should only be offered in the context of controlled clinical trials.

Emerging drugs for CLL

Recently, several newagents are being explored with interesting results in the treatment of CLL patients. These novel therapies are being evaluated in preclinical studies and early phases of clinical trials. Novel mAbs, immunomodulating agents, novel PNAs, bcl-2 inhibitors, protein kinase inhibitors and small molecule signal transduction inhibitors that affect the genetic and epigenetic tumour pathway generation should be considered in this new era in the future treatment of CLL. Here some example of these drugs

5.1- Anti-CD20 mAbs

Obinutuzumab (GA-101) is a novel third generation (mAb) derived from humanization of the parenteral B-Ly1 mouse antibody. GA-101 binds to the CD20 epitope with high affinity showing also superior caspase-independent apoptosis induction than rituximab. It was administered as a single agent in patients with CD20+ malignant disease in a phase I/IIa trial (Salles et al, 2008), with promising results.

5.2- Lumiliximab

Genetically engineered macaque-human chimeric anti- CD23 IgG1_ mAb that binds CD23 inducing several antiproliferatives functions including apoptosis. Byrd et al(2007), assessed in a phase I trial the safety, efficacy and pharmacokinetics of lumiliximab in 46 patients with refractory/ relapsed CLL. MAb was given as 6 regimens including the lowest dose of 125 mg/m2/week for 4 weeks up to the highest dose of 500 mg/m2 3 times per week for 4 weeks with reduction in absolute lymphocyte count and lymphadenopathy in 91% of the patients.

5.3- Anti-CD40

Dacetuzumab is another anti-CD40 mAb that induces cytotoxicity against CLL cells. Furman et al(2010), reported the results of a phase I study with 12 patients obtaining 5% ORR with maximum doses administered between 3 and 8 mg/kg/week.

5.4- Bcl-2 family inhibitors

Oblimersen is a synthetic, 18-base, single-strand phosphorothioateDNAoligonucleotide designed to down regulate bcl-2 mRNA expression. Initial phase I/II study (OiBrien et al, 2005), included 40 relapsed/refractory CLL patients that received oblimersen at doses ranging from 3 to 7 mg/kg/day as 5- day continuous intravenous infusion every 3 weeks. Recently updated with a significant 5-year survival benefit (HR 0.60; P = 0.038) in the patients treated with FC and oblimersen who obtained CR or PR (OiBrien et al,2009).

5.5- Obatoclax (GX15-070)

This agent inhibits several anti-apoptotic bcl-2 family proteins and can promote the release of cytochrome C from mitochondria isolated from leukaemia cells. OˇıBrien et al. reported the results of a phase I trial (OiBrien et al,2009), with 4% of ORR (one patient achieved PR).


CLL is now acknowledged to be a highly complex and variable disease. Much has been learned about its biology over the last 10-15 years, and significant progress has been made in its treatment. These developments have also made the treatment of CLL more complicated.although the subject can appear confusing, things can be simplified by thinking about each of the key treatment questions as they arise. For decades, alkylating agents have been considered the treatment of choice in first-line treatment of progressive and symptomatic CLL patients. More recently, purine-analogues have demonstrated to be highly active in previously treated and in refractory or relapsed patients, especially when administered in combination, and have become the first-line treatment in young patients without associated comorbidity. Monoclonal antibodies are another promising therapeutic modality. Alemtuzumab may be an effective treatment for fludarabine-refractory patients and further evaluation will define its role as first-line treatment. Haematopoietic stem cell transplantation has recently opened new perspectives in the management of CLL patients. Non-myeloablative allogeneic transplant appears to be a promising therapy for elderly patients, due to its lower toxicity. Future clinical trials should improve identification of high-risk patients, who may be candidates for these novel therapeutic strategies, in an attempt to offer appropriate individualised treatment.