Chronic Lymphocytic Leukemia

The average age of CLL patients is more than 70 years and it should be noted that a complex clinical picture occurs in more than half of the cases due to coexisting diseases. The CLL itself leads to unspecific symptoms such as general malaise and weakness, possibly also to fever, night sweats and weight loss. In the physical examination, generalized lymphadenopathy and hepato- and/or splenomegaly may be noted. The excessive proliferation of the lymphocytes results in immunological insufficiency and the patients are more susceptible to infections. Recurrent infections of the respiratory tract and urogenital tract are regularly described, and in fact pneumonia and sepsis are the most common causes of death associated with CLL. At the same time there are disturbances in the formation of erythrocytes and thrombocytes, leading to symptoms of anemia and hemorrhagic diathesis, patients are pale, their performance is reduced, they complain of headaches and dizziness as well as palpitations. Epistaxis, gastrointestinal bleeding, and to the formation of hematomas are also common. CLL patients also tend to autoimmune reactions. If these are directed against erythrocytes or blood platelets, the aforementioned symptoms are further intensified.

An acute increase in lymphadenopathy or organomegaly, as well as a worsening of the general condition with accentuation of B symptoms point to a Richter's transformation, a progression to an aggressive Non-Hodgkin lymphoma or - more rarely - to Hodgkin's disease.

Work up includes a detailed history and physical examination.

Laboratory tests

• Complete blood count
• Blood profile
• Lymph node aspiration
• FISH
• Array-based karyotyping
• Matute's CLL Score
• Flow cytometry

Imaging

• Presence of characteristic 'smudge cells' on microscopic view
• Bone marrow biopsy
• CT scan/radiography to stage the disease
• MRI

Test results

CLL is a diagnosed most commonly during routine physical examination and blood work. If the blood work points towards a leukemia, biopsy, cytometry and other such laboratory tests along with imaging studies should be performed to identify and stage the cancer.

Treatment is subjective to the stage of the disease. Since it does not have any definite cure, treatment focuses on improving the quality and quantity of life. Optimum therapy includes a combination of radiotherapy and chemotherapy, which may or may not be accompanied with surgery for existing complications such as a splenomegaly or hepatomegaly. Immunotherapy with antibodies against proteins found on the surface of CLL/SLL cells, such as CD20 and CD52, is finding increasing use [8].

Bone marrow transplant can be a potential cure but success rate is not a 100%. There is increasing interest in the use of reduced-intensity allogenic stem cell transplantation, which offers the prospect of cure for selective patients with a suitable donor [9].

Target therapy

Monoclonal antibody therapy and tyrosine-kinase inhibitor therapy are types of targeted therapy used in the treatment of chronic lymphocytic leukemia.

The overall median survival is about 6 years [3]. Prognosis depends upon the stage of cancer. If the patient is at Stage A/0, prognosis is the best, i.e 12-15 years with treatment. As the stage increases, prognosis of this disease worsens. In case of transformation of CLL into other, more aggressive cancers, prognosis is the worst. Both prolymphocytic and large-cell transformation are ominous events, with most patients surviving less than 1 year [7].

CLL is a type of B cell lymphoma which presents primarily in the lymph nodes [3]. Much like other types of cancers, CLL has no definite known cause. It is an acquired disorder, and reports of truly familial cases are exceedingly rare [4]. However, genetic mutations and more commonly, deletions, may he held the culprit behind this disease.

4 main genetic aberrations are recognised in CLL cells that have a major impact on disease behaviour [5]. These include:

• Deletion of 17p
• Deletion of 13q (most common finding)
• Trisomy 12 
• Deletion of 11q

Occurrence of any one or more of the above 4 aberrations may result in abnormally high rate of development and proliferation of B-cells in the bone marrow and other hematopoietic tissue. This results in crowding of normally developing cells in the marrow as well as crowding of normally maturing cells in the lymph nodes. As a result, the B-cells develop impaired functioning even though the lymphocytic count keeps on increasing.

Incidence

CLL is the most common leukemia of adults in the Western world. There are about 15,000 new cases of CLL each year in the United States [1].

Age and sex

The median age at diagnosis is 60 years, and there is a 2:1 male predominance [1].

Race

This disease is very rare in the Chinese and related races [2].

Certain bio-markers may be present in CLL. Most common such markers are B-cell CD19 and B-cell CD20. CD23 and CD5 may also be found.

Morphology

Electron microscopy of blood smears show diffuse effacement of lymph node architecture, with the presence of proliferation centres. Stromal cells in proliferation centres seem to express a variety of factors that stimulate the activity of the transcription factor NK-kB, [6], which promote cell growth and survival. This factor, along with others, result in uncontrolled proliferation of B cells.

The leukemic cells have fragile nuclei, so during slide preparation, insertion of a cover slip on top of the sample on the slide crushes the fragile nuclei, resulting in characteristic 'smudge cells' or 'parachute cells'.

Staging

Binet classification

• Clinical stage A: This stage is characterised by less than 3 areas of lymphoid enlargement. There is no anemia or thrombocytopenia.
• Clinical stage B: In this stage, 3 or more than 3 areas of lymphoid enlargement are found. There is no or little evidence of anemia or thrombocytopenia.
• Clinical stage C: In this most serious stage, there is anemia and/or thrombocytopenia regardless of how many areas of lymphoid enlargement are present.

Rai classification

• Stage 0: Only lymphocytosis is present i.e >15,000 mm3.
• Stage I: Lymphocytosis along with lymphadenopathy is present.
• Stage II: Lymphocytosis along with either splenomegaly or hepatomegaly is present. Lymphadenopathy may or may not be present.
• Stage III: Absolute lymphocytosis with anemia is present. Hepatosplenomegaly and lymphadenopathy may or may not be present.
• Stage IV: Absolute lymphocytosis with thrombocytopenia (<100,000/mm3). Lymphadenopathy, hepatosplenomegaly and anemia may or may not be present.

There is no known prevention of this disease. However, routine check ups and examinations may help in preventing the disease from reaching an advanced stage.

Chronic lymphocytic leukemia (chronic lymphoid leukemia, CLL) belongs to the lymphoproliferative disorders and according to the classification of the World Health Organization to the Non-Hodgkin lymphomas and neoplasias of the B lymphocytes. CLL is the most common form of leukemia in the Western world and affects mainly people of advanced age. CLL leads to unspecific symptoms such as general malaise and weakness, fever, night sweats, weight loss and enlarged lymph nodes, spleen or liver. The onset of these symptoms is often insidious and CLL is frequently diagnosed in routine examinations.

CLL is the most common white blood cell cancer in US adults. It is more common in males and occurs most commonly in the late 5th or early 6th decade of life. Common symptoms are enlarged lymph nodes, fever, night sweats, fatigue, weight loss and frequent infections.

1. Robbins and Cotran, Pathological Basis of Disease. 8th ed. Chap 13, 596-638.
2. Davidson's Principles and Practice of Medicine. 16th ed. Chap 14,737-39.
3. Harris NL, Jaffe ES, Diebold J, et al. WHO Classification of neoplasticism disease of the hematopoietic and lymphoid tissues:a report of the Clinical Advisory Committee meeting Airlie-house, Virginia, Nov 1997. J Clin Oncol. 17(12):3835-49
4. Slager SL, Kay NE. Familial chronic lymphocytic leukemia: What does it mean to me? Clin Lymphoma Myeloma. Sep 1,2009;9:S194-S197
5. Dohner H, Stilgenbauer S, Benner A, et al. Genomic Aberrations and survival in chronic lymphocytic leukemia. NEJM 2000 343(26):1910-6
6. Endo T, et al. BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF- kappaB pathway. Blood 109:703, 2007
7. Tsimberiou AM, Keating MJ. Richter's transformation in chronic lymphocytic leukemia. Semin Oncol 33:250, 2006
8. Alinari L, et al. Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic Leukemia. Oncogene 26:3644, 2007
9. Dreger P, Brand R, Hansz J, et al. Chronic leukemia working party of EBMT 2003. Treatment related mortality and graft versus-leukemia activity after allogenic stem cell transplantation for CLL using intensity-reduced conditioning. Leukemia 17(5);841-8

• Chronic Lymphocytic Leukemia
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