What is the difference between acute and chronic leukaemias?

Almost everybody knows that there is disease called leukaemia, but only few other than medical professionals and those who has someone with leukaemia knows that leukaemia can be acute and chronic. So, you might wonder, ‘’what is the difference between acute and chronic leukaemias’’. Well this classification is done according to how fast the disease has evolved with time (Kumar P et.al,2009). Therefore, in acute leukaemia the disease progress very rapidly and the patient begins to have symptoms very fast. In chronic leukaemia the changes occurs very slowly. Therefore, it takes a long time for the patient to develop symptoms. In such patients the test results may show the leukaemic changes but the patient may not have single symptom.

Acute leukaemia is more common among young patients and most of them had good outcome if the treatment started quickly. But, it is hard to treat it when it occurs in an elderly patient. On the other hand chronic leukaemia is more common among elderly patients and it is responsible for very few deaths as the disease advances so slowly and most of the time the patient dies due to old age.

Detailed classification and pathogenesis of leukaemia are described in my previous post, Types of Leukaemia. May be you may find some more interesting information about leukaemia there. 

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Treatment of Chronic Lymphocytic Leukaemia

According to Kumar and Clark (2009) thirty percent of patients don’t require any interventions as they are asymptomatic and quiet healthy. The method of treatment depends on the following factors.

·         Stage of the disease – if it is early stage no treatment will be given but the patient will be followed up regularly. Treatment is started immediately in advanced disease.

·         Age of the patient

·         Other illnesses in the patient

·         Toxicity to treatment

The treatment helps to improve symptoms. Aggressive treatment has promised to give an increased survival rate. Patients with following features of advanced diseases are indicated for treatment.

·         Marrow failure

·         Recurrent infections

·         Massive Hepatosplenomegally

·         Fever

·         Night sweats

·         Loss of weight

·         Haemolysis

The treatment methods available in chronic lymphocytic leukaemia can be divided in two main categories. They are,

1.      Supportive treatment

2.      Specific treatment

Supportive Treatment

The following drugs/treatment methods are used.

·         Steroids – for anaemia

·         Splenectomy

·         Chemotherapy and transfusion for thrombocytopenia

·         Antibiotics for ongoing infections and also as prophylaxis because these people are more prone to get recurrent infections because they are immunosuppressed.

·         Allopurinol for hyperuricaemia.

Specific Treatment

Following drugs are used.

·         Chlorambucil

·         Purine analogues

·         Combination therapy with rituximab

·         Allogenic stem cell transplantation

References: Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

What are the Investigations done to diagnose Chronic Lymphocytic Leukaemia?

Following are the investigations carried out in diagnosing.

·         Full blood cout

·         Blood film

·         Bone marrow

·         Immunophenotyping

·         FISH

·         Coomb’s test

·         Immunoglobulins

Symptoms of Chronic Leukaemia

As I mentioned in my previous post, most of the patients with chronic leukaemia are asymptomatic. But some may have the following symptoms.

·         Recurrent infections – this is due to reduction of functioning leukocytes. Now you may wonder how does it happen when there is more than enough white cells to fight infections. It is because those white cells do not work properly.

·         Symptoms of anaemia – these includes fatigability and low exercise tolerance. Their eyes also will be pale if you inspect under their eye lids.

·         Lymph node enlargement – These enlarged lymph nodes are painless.

·         Abdominal discomfort – As with chronic myeloid leukaemia, chronic lymphocytic leukaemia also can lead to spleen enlargement, which is felt by the patient as abdominal discomfort. It you palpate the abdomen carefully; you will feel the enlarged organ.

·         Fever – this is due to infections.

·         Liver enlargement – apart from the spleen liver can also get enlarged.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia is also most commonly seen among older age group people. Therefore, the risk increases as you go older. According to Kumar and Clark (2009)The mean age of presentation is 65and 67 years. The type of lymphocytes that are proliferating are B lymphocytes. As in chronic myeloid leukaemia, this also evolves slowly and therefore, the symptoms are seen at very last stages. The disease can be diagnosed accidently, when a full blood count was done for some other reason.

Once the disease has been diagnosed the patient normally has a chance of survival for 10 years. But, many patients die of old age before there are killed by the disease itself.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Stem Cell Transplantation in Acute Myeloid Leukaemia

Seventy percent of the chronic myeloid leukaemic patients can be cured with stem cell transplantations. As I described in my earliest posts, stem cells are cells that proliferate and give rise to all the other blood cells. Earlier stem cell transplantation was widely used but now it has reduced due to the success rate of therapy with imatinib.

Compared to treatment with imatinib, stem cell transplantation has a risk of death due to graft versus host reaction or due to opportunistic infections. Therefore, your physician will weigh the risks upon benefits and decide the most suitable treatment.

You are more likely to have problems with stem cell transplantation, if you belong to any of the following categories.

·         Older age

·         Time of transplantation is delayed even if the disease was diagnosed earlier.

The histocompatibility with the donor is poor.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Treatment of Chronic Myeloid Leukaemia

This is most commonly seen in adult age group (40-60 years). As with all chronic leukaemia, chronic myeloid leukaemia also progress slowly. The possible out comes of a non treated disease are,

·         Blast crisis

·         Myelofibrosis

·         Death – within 3-4 years

Patients with chronic myeloid leukaemia are treated with “imatinib” Ninety five percent of the patients responds very well to this drug and therefore has a good reputation in treatment of chronic myeloid leukaemia. It can be continued for the rest of the life, and good news is that its side effects are also mild and most patients can tolerate them very well. Some of such side effects are listed below.

·         Nausea

·         Headache

·         Rashes

·         Cytopenia

Very few people may develop resistant to imatinib and those patients are treated with second generation tyrosine kinase inhibitors, dasatinib, and nilotinib.

The next method of treatment is Stem cell transplantation, which I will describe in my next post.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

What are the Investigations done to Diagnose Chronic Myeloid Leukaemia

The physician will do a series of investigations starting from the simplest.

·         Full blood count – The results we are looking for are almost equal to those in acute leukaemia, which I have described in one of my previous posts. Simply there will be raised white cell count and low or normal platelet count.

·         Blood film – this is done to identify neutrophilia and myeloid precursors. This will also reveal occasional blasts, increased basophils and eosinophils.

·         Bone marrow aspirate – This is a very specific investigation that is capable of giving very accurate information about the disease. It may show increased cells and myeloid precursors in the bone marrow. The same specimen can be used to look for t(9;22) Philadelphia chromosomal abnormality, which is specific to chronic myeloid leukaemia.

·         FISH – FISH stands for fluorescien in situ hybridization. This technique can detect cytogenetic abnormalities of the cells. This is also used after the therapy to finds out the response to treatment.  

·         Leukocyte alkaline phosphatase – this is an enzyme which usually reduce in amount when some one has leukaemia.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Clinical Features of Chronic Myeloid Leukaemia

Since all chronic leukaemias evolve slowly with time, the patient may not have any symptoms at all. But some may have some of the following symptoms.

·         Symptoms of anaemia – easy fatigability, low exercise tolerance are features of anaemia.

·         Abdominal discomfort – Chronic Myeloid leukaemic patients can develop massive enlargement of the spleen. This leads to abdominal discomfort due to its heavy weight.

·         Weight loss – weight loss is a feature of any chronic illness.

·         Fever and sweating – as I describes in my initial posts there is a high metabolic processes going on in leukaemic tissues. This high metabolic activity creates a lot of energy which is released as heat. As a result the patient begins to have fever and sweating.

·         Headache – this is mainly due to hyperleukocytosis.

·         Symptoms of thrombocytopenia -these symptoms include bleeding, bruising and priapism.

Other than above mentions symptoms of chronic leukaemia, the following signs can also be found if examines carefully.

·         Pallor – look carefully under the lower eyelid, if it is pale in colour then you have developed anaemia. But, don’t jump in to the conclusion that you have leukaemia just because you are pale. Pallor can also be a feature of thousands of other diseases.

·         Palpate the abdomen starting from the right lower part of the abdomen and then gradually palpate lightly towards the left upper part of the abdomen. If you something firm in this path, it is the enlarged spleen.

·         Lymphadenopathy – this is enlarged lymph nodes in the body.

·         There will be retinal haemorrhages, but it needs a special equipment to visualize retinal haemorrhages.    

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

 

Outcome of Acute Lymphoblastic Leukaemia

The outcome of acute lymphoblastic leukaemia depends on several factors.

·         Age – older people have laser survival rates.
·         White Blood Cell Count – Higher the initial number of white cells, high the chances of recurrences in the central nervous system.
·         Immunophenotype – B cell is associated with poor prognosis.
          Pre B cell form has a better prognosis than B cell form.
         T cell form has better outcome than the both mentioned above 
·         Cytogenetic aberrations – patients with t(9;22) or t(4;11) are more prone to have poor outcome.
·         Time to response – high the time taken to achieve complete remission, higher the chances of failure.
 

It is good news to know that children with acute lymphoblastic leukaemia have a better outcome. There is 100% complete remission rate.  But if recurrence occurs the outcome will be very bad.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Treatment of Acute Lymphoblastic Leukaemia

As in all leukaemic treatment the first thing in acute lymphoblastic leukaemia is also remission induction. This treatment method is called combination chemotherapy. The following drugs are used in this treatment method.

·         Vincristine

·         A glucocorticoid – dexamethasone, prednisolone

·         An anthracycline - Daunorubicin

·         Asparaginse (crisantaspase)

When the above therapy succeed in achieving complete remission there are some other actions that has to be taken. They are,

·         Consolidation - The second step is consolidation after a successful remission is achieved. The patients will be a number of cytotoxic drugs several times. One such drug is Methotrexate, which is used in high dosage.

·         Allogenic transplantation - In some patients who are at high risk allogenic transplantation is done when they achieve the first remission.

·         Intrathecal Chemotherapy - May have to be continued upto two years depending on the risk. This is under platelet cover and with high doses of systemic Cytosine arabinoside or methtraxate.

·         Cranial irradiation – This now only done for those who are at high risk.

·         Maintanace therapy – Continuation of treatment with methotrexate and mercaptopurine for up to 2 years. A white cell count of 3×10⁹/L is targeted.    


References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Treatment of Acute Myeloid Leukaemia

This is one kind of the acute leukaemias.  When we find out that we have some kind of disease the, the first thing that comes in to our mind is “is it curable?’ So the leukaemic patients also think the same way. For diseases such as cough and cold, the answer is very straight forward and easy, but leukaemia is not such simple disease, so we cannot give a simple straight forward answer.

Leukaemia is a complex disease and as a result of that complexity, there is a wide variety of presentation of the disease. Not only that, the response to treatment also differs from patient to patient.

According to the previous data, acute myeloid leukaemia can be curable in some patients. The next question is ‘who are the people that can be cured?” Well “yes” but for some. Generally adults who are under 60 years old are treated with curative intent, but not all. Those who have other co morbidities (other significant illnesses) are not treated with curative intent.

Out of those who are treated, some may fail to eliminate the disease entirely. The physician categorizes the disease as low risk and high risk. This is done according to the cytological (the cellular) pattern. So if you belong to the low risk group, you will be treated with “Moderately intensive combination chemotherapy”. This always includes an anthracycline. Examples of anthracycline include daunorubicin and cytosine arabinose.  Then at least 4 cycles of treatment will be given for consolidation. These treatments are given at 3-4 week intervals.

Things are a little harder for patients who are grouped as ‘high risk’. This category of patients is treated with curative intent only if they have an HLA-identified sibling. What is meant by “HLA-identified sibling”? HLA can be simplified as a marker of the tissues. Different people differ in their HLA type. If two persons are HLA compatible, it means that their tissues are also more or less identical to each other. So, tissues can be transplanted between such people without getting rejected. Why do they need a HLA-identified sibling?

It is because the treatment may need stem cell transplantation and these stem cells can only be taken from a HLA-identified sibling for it not to be rejected.

Most of the people with acute myeloid belongs to the elderly age group, but it is a very sad situation because those patients cannot be treated with curative intent, because the treatment it self carries a very high morbidity rate for elderly patients. The toxicity of the treatment is very high so that they cannot bear that much of toxicity.

There is another group of patients who are at intermediate risk. In these patients remission is induced by giving consolidating chemotherapy. Thereafter they will be treated with sibling matched allogenic transplantation.   

With all above mentioned interventions, 75% of the patients who are under 60 years of age may achieve complete remissions. If a patient fails to achieve complete remission it could be due to one of the following causes.

1.      Resistant leukaemia

2.      Infection – the disease and the treatment both make the patient Immunocompromised. Therefore, they are more prone to get infections and these infections can be severe enough to cause death.

3.      Bleeding – The patients may become severely thrombocytopenic and that could lead to fatal haemorrhage. This is a rare cause of failure of treatment.

Only half of the patients who successfully achieve complete remission will get completely cured. Recurrence of the disease is sign of bed prognosis because it is very hard to achieve a longer life time when the disease recurs. The prognosis found to be bad even the physicians are able to achieve a second remission. The only thing that improves the survival rate is allogenic transplantation.

Still the patients with acute myeloid leukaemia should not give up their hopes because there are a lot of experimental therapies going on at the time.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

What is Consolidation in Leukaemia and Why it is Important?

I have described what remission induction in my previous posts. This remission induction is followed by consolidation. Simply, consolidation means giving further treatment, so the patient won’t have the disease again. Consolidation is achieved by giving further treatment when the patient remits. If not, the disease will reappear invariably. The following factors determine whether consolidation will be done or not.

·         Type of leukaemia

·         Patient risk factors

·         The patients tolerance of treatment

Why consolidation is important?

Even though remission induction means bringing the bone marrow and the blood in to normal state, there could be still some leukaemic cells remaining in the bone marrow, undetected. So, these cells can multiply and the disease can relapse. Therefore, there should be a way to prevent these cells from raising their heads. This is where consolidation comes into play. The continuation of the treatment prevent the disease from relapsing again.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Treatment for acute Leukaemia

The following treatment options are available for the patient with acute leukaemia.

1.      Palliative Therapy

2.      Curative Therapy

3.      Active Therapy

Palliative Therapy

Palliative therapy involves both chemotherapy and radiotherapy. The patient is given the opportunity to stay at home as much as possible.

Curative Therapy

This is only done if the benefits outweigh the risks; since the treatment itself carries a considerable morbidity (also read Why Everybody with Acute Leukaemia is not Treated with Curative Intent). The cure can never be guaranteed or even expected in some of the cases. So, it is a controversial issue whether to start treatment of not. This is carefully discussed among the physician and the patient. 

 Curative therapy is given only in specialized centers which handles only about 10 such cases per year. Therefore the patient may have to be transferred to one of such centers. It also involves long term hospitalization. In the first instance the patient will have to be hospitalized for about a month and subsequent admission for several days to weeks. So the patient may have to discuss about their work pale/education, etc.

Even after the successful therapy life won’t be the same for some of the patients.

 Active Therapy

This involves supportive care and specific treatment. 

Supportive Care

Supportive care is targeted at providing comfort to the patient. It treats only for the symptoms. So the each symptom is treated separately.

·         For anaemia – most of the symptoms in leukaemia is due anaemia. So, it is corrected by repeated blood transfusion (packed red cells). Everybody with leukaemia is not transfused with blood. Only those who have severely reduced haemoglobin are transfused.

·         For thrombocytopenia – as mentioned in my previous posts, thrombocytopenia means reduced platelet counts. Their reduction in number results in bleeding tendencies. So the patients bleeding tendencies should be controlled. The exact platelet count is determined before the beginning of the treatment and the decision whether to transfuse or not is taken according to the platelet count. The platelet counts requiring transfusion in uninfected is <10×10⁹ /L and that in infected is <20×10⁹ /L.

·         For leucopenia – As I have mentioned in my previous posts the reduction of white blood cells leads to higher risk of infections. So these infections should be treated. Some of the patients may not have already developed any infections but still they should be treated prophylactically. Prophylaxis means treating in order to prevent a disease. Prevention does not only involve medication. It also contains education of patients, relatives and staff about hand washing and other hygienic activities. That’s why such patients are isolated in hospitals. Appropriate antifungals and antibiotics will be chosen by the physician and prescribed.

Infected patients are treated therapeutically with appropriate antifungals and antibiotics.

·         Another problem they might develop is hyperuricaemia. This condition is treated with hydration and prophylactic alopurinol and rasburicase. So, the patient will be asked to drink plenty of water.  

Specific treatment 

This is targeted in bringing the blood and bone marrow to their normal state. The therapy it self impairs bone marrow function. Therefore, it carries the risk of life threatening bone marrow function. Therefore, the treatment is carried out in a hospital where the patient has his/her separate room, lavatory facilities and lesser risk of infection.

A venous catheter is inserted in to the patient and Cytotoxic drugs are administered through this line. Remission induction and consolidation are achieved.

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Why Everybody with Acute Leukaemia is not treated with a Curative Intent

Since acute leukaemia is a rapidly developing disease, it is fatal unless treated as soon as possible. Untreated patient can die within month. Therefore, quick treatment is mandatory. It is very hard to predict the response to the treatment because different people respond differently. Some may get cured, and some may have recurrences. Some of they may even not respond at all. Unsuccessful therapy could be either because the patient cannot withstand the treatment or because the type of leukaemia he/she is having is incurable.

Treatment methods available to cure the disease also carry a very high morbidity rate. This is because the drugs given to the patient can themselves harm the patient’s normal body cells in the process of killing the malignant cells. Therefore curative treatment is given only for those who have low risk (possibly curable) leukaemia.

Childhood Acute lymphoblastic Leukaemia is considered as low risk leukaemia and they are treated with curative intent. Even for them the treatment brings considerable morbidity. The morbidity is even more if the same treatment is given for the high risk groups. So, the physician will weigh the risks against benefits and offer the most suitable treatment option. 

Following leukaemias are considered as probably incurable 

1.      Acute myeloid leukaemia with adverse cytogenetic features in elderly

2.      Secondary acute myeloid leukaemia

3.      Recurrent acute leukaemias

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Investigations Done in Acute Leukaemia, Learn to Interpret Yourself

The investigations starts from the simplest and easiest test and thereafter more complex and precise investigations will be done. 

1.      Full blood count

This is the easiest, fastest and more feasible investigation done when acute leukaemia is suspected. So, if you have a full blood count report you may want to interpret it yourself. At a glance it may look a bit difficult, but once you have understood the symbols and their meanings, it will become easier. Once you learn to interpret one report, then you will be able to interpret and compare subsequent blood reports.

Let me take you through a full blood count report of a female patient with acute leukaemia. It will help you to understand your report clearly.   

		Normal Values
Total WBC	63×109 /L	4-11 ×109 /L
Neutrophils	02%
Lymphocytes	18%
Monocytes	0%
Eosinophils	0%
Basophils	0%
Haemoglobin (Hg)	10.4 g/dl	11.5-16.5g/dl
Red Blood Cells (RBC)	3.79×1012 /L	3.8-5.8×1012/L
MCV	82 fl	80-96 fl
PCV	31.1
MCH	23.735	27-32 pg
MCHC	33.5 g/dl	32-36 g/dl
Platelets	79×109	150-400×109/L

      Let’s discuss one by one. First let’s take WBC. WBC means white blood cells. As I have mentioned in my first post, there are several types of white blood cells. This is a patient with acute lymphocytic leukaemia. As you can see the number of white blood cells is way higher than the normal value. That is because the abnormally proliferated white blood cells are released in to the blood stream. One may think that white blood cells are involved in immunity and it is better to have a lot of white blood cells in the blood stream. But it is not because these extra cells are abnormal. They have had not got enough time to mature. So they don’t function normally. So, the excessive white blood cells do not help with immunity.

Next to WBC are shown the percentages of each type of white blood cells (Neutrophils, Lymphocytes, Monocytes, Eosinophils, and Basophils). By looking at this report we can only say that there is more than normal amount of white blood cells in the blood stream. To find out correctly the type of leukaemia, we should do a test called differential count (Blood Film). This test reveals the morphological types of the blood cells. In this patient it was found that there are blast cells in the blood stream. Blast cells are cells arising in the initial steps of the haemopeisis. This favors more towards the acute type of leukaemia. (In chronic leukaemia the predominant cells are more mature ones).

Also look at the haemoglobin level and the platelet number. They are also less than the normal amounts. It is because the proliferating cells have reduced the space available for the production of red blood cells and platelets.

2.      Bone marrow aspirate

Once the above abnormalities are found, a bone marrow aspirate is done to confirm and categorize the type of disease the patient have. This is a very painful procedure. The aspirate will be sent to the lab and the report will come with the following results.

a.      Increased cellularity

b.      Reduces erythropoeisis (the process of red blood cell production) – This is why there is less red blood cells in the blood stream.

c.       Reduced megakaryocytes – Platelets are produces by the megakaryocytes. This is why there is less number of platelets in the blood stream.  

d.      Replacement of blast cells.

3.      Chest X-ray – mediastinal widening. This is mainly done in T- lymphocytic leukaemia to see whether there is any enlargement of the thymus causing the mediastinum to grow wider.

4.      CSF (Cerebro-spinal Fluid) – This is done in acute lymphoblastic leukaemia, after blood is cleared from blast cells after therapy and to see whether there is any more in CSF.

                          

Before starting treatments the following investigations will be also done to assess the general condition of the patient.

1.      Biochemistry

a.      Serum urate

b.      Renal and liver biochemistry

2.      Cardiac function

a.      ECG

b.      Echo

c.       Cardiac MRI

 

 

References : Kumar P and Clark M, 2009. Clinical Medicine. 7th ed.

Diagnostic Process of Acute Leukaemia

How do doctors diagnose you as having Acute Leukaemia? In medicine diagnosis of a disease is done in three major steps. They are,

1.      History  

History is what the patient comes and complains to the doctor. Then the doctor gathers more information by asking questions from the patient. Most of the time a clinician can come to diagnosis only by the information he gather from the history. So, in history he will ask questions to see whether you have the symptoms of acute leukaemia that I have described in my previous post.

2.      Examination

Then he will examine you to find the signs of leukaemia. The things he will look for is described in my previous post.  

3.      Investigation

The investigation process involved in diagnosing acute leukaemia will be discussed in my next post.