Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with low malignancy. It's essence is clonal proliferation of malignant transformed mature lymphocytes (in 95 % cases its B-lymphocytes). These lymphocytes do not undergo apoptosis as fast as in their physiological form – gradual increase in the amount of lymphocytes is caused not only by uncontrolled proliferation, but mainly due to their inability to apoptose. In the pathogenesis of the disease there is an increased expression of the gene bcl-2, resulting in inhibition of apoptosis of pathological lymphocytes. Pathological lymphocytes are characterised by monoclonal surface Ig (proved by immunofluoresence ) that are unable to respond to antigenous stimulus (level of antibodies in plasma is usually lowered, because pathological B-lymphocytes produce TGF-β inhibiting the proliferation of physiological B-lymphocytes, which causes an increased risk of infection complications, and may have an autoimmune development hemolytic anaemia and thrombocytopenia).

Microscopical image
náhled|150px|vpravo|Bone marrow of an adult male with distinct lymphocytosis; lymphocytes − sparce pale cytoplasm, immature nucleolus

Bone Marrow
The leukemic infiltrate looks like dispersed lymphoid nodules and variously expressed infiltration in the septa (interstitial, reticular infiltration), but can even progress to massive infiltrate with replacing the original myeolopoiesis (adverse diagnostic feature).

Extramedullar tissue

 * 1) nodes – wiped out structure monotonous lymphoid infiltration, sometimes with dispersed immature cells (so called paraimmunoblasts), infiltration of the nodes is obvious (unlike in CML);
 * 2) spleen – infiltration in sinuses (red pulp), distinction between the red and white pulp is no longer evident
 * 3) liver – infiltration in the portobili (in CML, the infiltrate is mainly in the sinuses).

Macroscopical image
Macroscopical findings on the organs are usually less obvious than in CML.

Main features:
 * enlargement of nodes (generalized lymphadenopathy – cervical, axillary and inguinal nodes) a spleen (splenomegaly), in advanced stages the liver, prostate etc. are also infiltrated;
 * anaemia;
 * thrombocytopenia.

T-CLL is not morphologically different from B-CLL with the exception of Sézary syndrome, where the infiltration is extensive from tumour cells predominantly in the skin, the cells are big, with a broken down nucleus (cerebriform nucleus).

A variant of CLL is prolymphocytic CLL, where large lymphoid cells appear in the blood and bone marrow with distinct nucleoli.They are referred to as prolymphocytes and the prognosis of this state is worse than in the typical CLL.

Clinical picture of the patient
CLL is a disease affecting mainly the older age group (more than 65 years), more commonly affects males. Patients are asymptomatic for a long time. Lymphocytosis can be an accidental finding during a preventive examination.

Further findings may include:
 * lymphadenopathy, splenomegaly, hepatomegaly;
 * infiltration of different areas of the body: retroperitoneum, mediastinum (nodes).

Examination methods

 * peripheral blood − absolute lymphocytosis > 5 · 109/l lasting longer than 3 months, may also include anaemia and thrombocytopenia;
 * immunophenotyping − determination of the characteristics of cells according to the receptors on their surfaces (CD19, CD23, CD38, ZAP-70);
 * Examination of the bone marrow − usually is not necessary for the dtermination of the diagnosis but is done before the start of treatment;
 * cytologic examination (deletions, trisomies) − present in up to 80 % of patients;
 * biochemical testing − LDH, beta-2-microglobulin, thymidinkinase;
 * X-ray of the chest (always);
 * Ultrasound of abdomen − determination of adenopathies, hepatosplenomegaly;
 * CT of chest, abdomen and the small pelvis − before start of tehrapy.

Clinical stages and variants, prognosis
In clinics there are 2 classification systems, Raie or Binet.

Negative prognosis factors:
 * short LDT (lymphocyte doubling time) < 12 months (time, in which the tumour population doubles);
 * not mutated state of the heavy chains of immunoglobulins;
 * elevated enzymes − LDH, ThK;
 * surface markers CD38 and ZAP-70;
 * cytogenetics − deletion of 17p;
 * range of bone marrow infiltration > 35% of population is formed by tumour cells.

Differential diagnosis
Conditions which may resemble CLL:
 * prolymphocytic leukemia,
 * hairy cell leukemia,
 * lymphoma of small lymphocytes,
 * monoclonal B-lmyphocytosis,
 * splenic lymphoma.

Complications of CLL
Amongst the complications of CLL is the development of anaemia and/or thrombocytopenia, which may occur by 2 mechanisms:
 * 1) oppression of the normal hematopoietic tissue by the influence of the expansion of the tumour process;
 * 2) autoimmune − the production of antibodies against erythrocytes and/or thrombocytes (therapy − corticoids).

Therapy
As long as the CLL patient is asymptomatic, it remains untreated, but it is controlled. If it were to come to a progression of the disease, the treatment is initiated according to its clinical stage and prognosis (comorbidities). The signs of the progression of the illness are suddenly appearing symptoms (fast weight loss, fatigue, night sweats, febrile, short doubling time, appearance or worsening of the hepatosplenomegaly, signs of the progression of medullary oppression − anaemia, thrombocytopenia). Standardly a combination of treatments is used FCR (immunochemotherapy): According to the clinical stage, general state of the patient and prognostic factors we are able to choose from the following therapy scheme:
 * fludarabin − purine analogue;
 * cyclophosphamide − alkaline substance;
 * rituximab − monoclonal antibody anti CD20.
 * 1) intensive therapy − FCR combination, if unsuccessful, one can also use the monoclonal antibody alemtuzumab (anti CD52);
 * 2) easy therapy − FCR − lite, i.e. the same drugs, but smaller dosage;
 * 3) palliative treatment − radiotherapy.

Video summary – Chronic leukemia
https://www.youtube.com/watch?v=Wn3fylOqUZU&t=22s

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 * Acute myeoloid leukemia
 * Chronic myeloid leukemia
 * Hairy cell leukemia
 * Chronic lymphadenosis of marrow (slide)