Chronic Leukaemia: CLL & CML Diagnosis and Treatment
What is leukaemia?
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. They also pose a threat of spreading to various other parts.
The term “chronic” …
Chronic means anything that lasts for a longer duration. A chronic form of leukaemia is one 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 and difficult to treat when compared to the acute leukaemia.
What are the types of chronic leukaemia?
There are two main types of chronic leukaemia based on their origin.
Chronic myelogenous/myeloid leukaemia (CML)- this is a type of 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 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. Chronic lymphocytic leukaemia is more difficult to treat and usually can only be managed with radiotherapy and chemotherapy.
What causes chronic myeloid leukaemia?
Chronic myeloid leukaemia is 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 case of chronic myeloid leukaemia, 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 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.
What causes chronic lymphocytic leukaemia?
The exact cause of chronic lymphocytic leukaemia 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 ae considered to be in 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 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 lymphocytic leukaemia.
What are the signs and symptoms of chronic leukaemia?
- Night sweats
- Weight loss
- Bone pain
- Enlarged spleen
- Loss of appetite
Symptoms due to reduced blood cell count:
The leukemic cells replace the healthy normal blood cells. This results in various defects and symptoms.
- 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.
What are the tests done to detect chronic leukaemia?
Certain laboratory tests are performed to confirm a 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 are counted. In patient with chronic myeloid leukaemia, the patient has elevated levels of granulocytes (neutrophils, basophils, eosinophils). In lymphoid leukaemia, 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.
- 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.
What are the stages in a patient with chronic leukaemia?
The staging of a patient is important in order to provide treatment as per their requirements. Once the disease is detected, the patients are categorised and treated based on that.
- The initial stage is the chronic stage. About 80% of the patients who are diagnosed as leukemic 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. 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 accelerated phase if any of these conditions are present. Drug therapy becomes less effective in this stage.
- This is the last stage. This stage is also called the blast crisis. 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.
How is the treatment carried out in a diagnosed patient?
Chemotherapy: alkylating agents, INT alfa 2b, and steroids were used in the earlier stages.
A newer drug that functions by limiting the progression of CML and promoting stem cell proliferation.
Newer drugs that are 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.
What is the outcome of the treatments?
The outcome is called “prognosis”.
Before the usage of tyrosine kinase inhibitors, the prognosis was a survival time of 3-5 years after diagnosis.
Post-discovery of tyrosine kinase inhibitors, the survival rate became 89% after 5 years.