Chronic Leukaemia: CLL & CML Diagnosis and Treatment
Leukaemia is, simply put, the cancer of the white blood cells. The uncontrolled, rapid multiplication of white blood cells causes various problems in the human body. Despite being large in quantity, they are incapable of performing a function. Leukaemia also pose a threat of spreading to various other parts.
The term “chronic” …
Chronic means anything that lasts for a longer duration. A chronic leukaemia is the type of leukaemia which is not as aggressive as its acute counterpart but lasts for a very long time without getting completely cured. It is usually many years before they are identified and symptoms show up. It is also much slower to progress and difficult to treat when compared to the Acute Leukaemia.
There are two main types of chronic leukaemia based on their origin.
Chronic myelogenous/myeloid leukaemia (CML)- This is a type of chronic leukaemia which involves all the granulocytes. Granulocytes are a component of white blood cells in which the cytoplasm contains granular structures. There are three granulocytes – neutrophils, basophils, and eosinophils. Any defects involving them is called myelogenous or myeloid. It is due to the presence of a chromosome called “Philadelphia chromosome”.
Chronic lymphocytic leukaemia (CLL) – This is a type of chronic leukaemia which involves the lymph nodes and the lymphocytes of the white blood cell. It is a malignant manifestation of the lymph nodes which produce a large number of immature white blood cells. This type of chronic leukaemia is more difficult to treat and usually can only be managed with Radiotherapy and Chemotherapy.
Chronic myeloid leukaemia is the first cancer to have been associated directly with chromosomal abnormalities. The only known risk factor is the age of the patient which increases after the age of sixty-five years. Ionizing radiation is also suspected to be a causative agent.
So, what really happens in the chromosomes?
Chromosomes are parts of the cell which carry genetic information. In cases of chronic leukaemia namely CML, there is a chromosomal translocation. This means that a part of one chromosome gets dislocated and re-attached to another part of another chromosome. This is known as the Philadelphia chromosome.
A portion of the 22nd chromosome relocates itself onto the 9th chromosome. This leads to the formation of an abnormal protein which has a high molecular weight. It can also add on other phosphate groups to the free chains.
This gene does not require any activation. It activates other proteins which control the cell cycle and the rate of cell division.
The exact cause of chronic leukaemia of lymphocytic origin (CLL) is not known although a genetic shift is the general causative agent. The genetic mutation of the DNA results in rapid multiplication of the white blood cells which do not mature fully. They are also incapable of performing their function despite being present in such high numbers. Their lifespan is increased. All these factors lead to an overall increased accumulation of white blood cells in the blood.
The risk factors associated with chronic lymphoid leukaemia are:
Age: The older the patient, greater the risk of developing chronic lymphocytic leukaemia. Patients over the age of 60 are considered to be at higher risk.
Race: People of the white race have a greater tendency to develop leukaemia.
Family history: If the patient has a history of CLL or any other form of chronic leukaemia in their family, the risk of developing it is also increased.
Chemical Agents: Some chemical agents found in insecticides and herbicides (like Agent Orange) are known to cause chronic leukaemia or CLL.
Some specific symptoms associated with chronic leukaemia are:
Anaemia: The reduction of red blood cells leads to weakness, dizzy spells, paleness, tiredness and fatigue. The red blood cells carry oxygen with the help of haemoglobin. When the number reduces, it leads to reduced oxygen levels in the tissues.
Leukopenia and neutropenia: Despite having a high leukocytic count, all the leukemic cells are immature and do not perform any of the functions.
This leads to increased susceptibility to infections. Also, it takes a long while to recover from the infections and recurrent infections may also occur.
Thrombocytopenia: The reduced number of platelets is called thrombocytopenia. Platelets perform the function of aiding clot formation. In this condition, there are increased bleeds for a prolonged duration. There is also frequent bruising, ecchymosis, petechiae on the skin.
Certain laboratory tests are performed to confirm the diagnosis of chronic leukaemia.
Complete blood picture and smear: The patient’s blood is taken and visualised under the microscope. A rough estimate of each cell per unit surface is counted. In the patient, with chronic leukaemia of myeloid origin or CML, the patient has elevated levels of granulocytes (neutrophils, basophils, eosinophils). In chronic leukaemia of lymphoid origin or CLL, the lymphocytic cells are in abundance.
Apart from the number, the slide can also show the abnormalities in size, shape, abnormal nuclear forms which can be seen under the microscope. All these defective cells indicate the genetic changes in the patient and the non-functionality of the cells.
Coagulation tests: In case of reduced platelet count, the coagulation tests, bleeding time and clotting time estimate will be altered. Note that this test is only supplemental and alone does not decide any diagnosis of chronic leukaemia.
Bone marrow biopsy: the chromosomal observation shows that the patient has the Philadelphia chromosome, where a part of chromosome 22 is translocated to chromosome 9. There is a change in the size of the chromosome which makes it easier to identify the chronic leukaemia.
The staging of a patient is important in order to provide treatment of chronic leukaemia as per their requirements. Once the disease is detected, the patients are categorised and treated based on the stage of chronic leukaemia.
The initial stage is the chronic stage of chronic leukaemia. About 80% of the patients who are diagnosed as Leukaemic are in this stage. It is in this stage that the patient shows mild symptoms like fatigue, bone pain, hip/joint pain. Fatigue and tiredness is the most frequently experienced symptoms.
This stage is followed by the accelerated stage of chronic leukaemia. If the patient has not responded well to the treatment for CML, the condition rapidly worsens in an accelerated state. Symptoms are more noticeable. WHO has a set of criteria to fall under accelerated stage:
10-19% myeloblasts in blood or bone marrow.
>20% basophils in blood or bone marrow.
Platelet count is < 100,000, unrelated to therapy
Platelet count is >1,000,000, unresponsive to therapy
Cytogenic evolution with new abnormalities in addition to the Philadelphia chromosome.
Increasing splenomegaly or white blood cell count, unresponsive to therapy.
The patient is considered to be in the accelerated phase of chronic leukaemia if any of these conditions are present. Drug therapy used to treat chronic leukaemia becomes less effective in this stage.
This is the last stage. This stage is also called the blast crisis stage of chronic leukaemia. The patient has more than 20 per cent of the cells as lymphoblast or myeloblast cells. The symptoms are similar to that seen in acute myeloid leukaemia. The condition is diagnosed so if any of these signs are present:
>20% myeloblasts or lymphoblasts in the blood or bone marrow.
Large clusters of blast cells in the bone marrow biopsy
Development of a condition called chloroma where there is an accumulation of leukemic cells outside the bone marrow.
Chemotherapy: Alkylating agents, INT alfa 2b, and steroids were used in the earlier stages. A newer drug functions by limiting the progression of CML and promoting stem cell proliferation. Newer drugs are also being used in treatment-resistant cases of CML.
Stem Cell Transplantation: The replacement of the defective bone marrow with the healthy bone marrow of either a donor or of self may be carried out. This cannot be done on all patients. It is the most tried out therapy for chronic leukaemia patients.
The outcome is called “prognosis”.
Before the usage of tyrosine kinase inhibitors, the prognosis of chronic leukaemia was a survival time of 3-5 years after diagnosis.
Post-discovery of tyrosine kinase inhibitors, the survival rate of chronic leukaemia became 89% after 5 years.
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