Investigations

INVESTIGATIONS
• Blood test - General investigations may show anaemia or low platelet count. The peripheral white blood cell count can vary between 50-200 x 10/9 per litre. The peripheral blast count is less than 10% in the chronic phase. You will have a blood test which checks the number and stage of development of all the different types of blood cell. If the blood test shows that leukaemia cells are present, the doctor will want to take a sample of your bone marrow to confirm a diagnosis.
• Bone marrow biopsy – from the hip bone or sternum. Takes around 15-20 minutes. The type of leukaemia present can be diagnosed by identifying the abnormal WBCs. The bone marrow can also be examined to see if the Philadelphia chromosome is present. It can take up to a week to get results.
• Laboratory test – to detect the BRC-ABL Philadelphia chromosome.

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Signs and SYmptoms

Chronic Myeloid Leukemia
Signs and Symptoms
Patient Presents with:
- Fatigue (caused by the anaemia)
- Low Grade Fevers and Sweats
- Fullness in the abdomen caused by an enlarged spleen
- Weight loss
- Bone pain
- General Weakness (caused by the anaemia)
- Excess bruising or bleeding due to less functional platelets

what is massive splenomegaly

What is massive splenomegaly?

Splenomegaly is enlargement of the spleen. However, massive splenomegaly is usually defined as a spleen extending into the left lower quadrant or pelvis or spleen which has crossed the midline of the abdomen. Massive spleen is weigh at least 500 to 1000g. Once the spleen is palpable in physical examination, it has usually reached twice its normal size.

Cause of massive splenomegaly:

1. Myeloproliferative disease:

a. Chronic myeloid leukemia

b. Polycythemia vera: clonal expansion of haematopoiesis. Lab findings include increased WBC and platelet counts.

2. Gaucher disease: autosomal recessive lyosomal glycolipid storage disorder due to insufficient acid beta-glucosidase enzyme. This leads to clinical manifestation of hepatosplenomegaly, anemia, thrombocytopenia and bone disease.

3. Lymphoma:

a. Chronic lymphocytic leukemia

b. Hairy cell leukemia: uncommon chronic B-cell lymphopoliferative disease.

c. Thalassemia major: b-Thalassemia major is a hereditary anemia resulting from decreased production of b-globin chains. Decreased b-chain synthesis results in excess free a chains that form insoluble tetramers and precipitate within the RBC, causing increased fragility and cell death.

Pathophysiology of CML

Pathophysiology of CML

· Due to growth and replication of an abnormal clone

· Philadelphia chromosome
o 9-22 reciprocal translocation
§ ABL – 9
§ BCR - 22
o BCR-ABL gene fusion
§ ABL – tyrosine kinase
§ BCR – break cluster region (normal function unknown)
§ Leads to disregulated tyrosine kinase activity (ABL)
o BCR-ABL fusion protein expressed
§ Increased activity
§ Causes the leukaemia
§ Normally, ABL acts in the nucleus - inhibits the retinoblastoma gene à inhibits cell growth
§ In CML, ABL acts mainly in the cytoplasm à constitutive tyrosine kinase activity – cellular transformation and deregulated growth (inhibition of apoptosis)

· Initially - Expansion of semi-mature granulocytes (Myeloid stem cell line)
o production of immature cells
· Acquisition of additional genetic mutations
o ‘blastic crisis’
o Can cause acute myeloid or acute lymphatic leukaemia

Diagnosis of Chronic Myeloid Leukaemia

Diagnosis of Chronic Myeloid Leukaemia
Usual peripheral blood findings in chronic myeloid leukaemia at diagnosis
* Raised white blood cell count (30-400 x 109/l). Differential shows:
Granulocytes at all stages of development
Increased numbers of basophils and eosinophils
Blast (primitive) cells (maximum 10%)–never present in the blood of normal people
* Haemoglobin concentration may be reduced; red cell morphology is usually unremarkable; nucleated (immature) red cells may be present
* Platelet count may be raised (300-600 x 109/l)\
The diagnosis of chronic myeloid leukaemia in chronic phase can be made from study of the peripheral blood film, but the marrow is usually examined for confirmation.
Marrow examination shows increased cellularity. The distribution of immature leucocytes resembles that seen in the blood film. Red cell production is relatively reduced. Megakaryocytes, the cells giving rise to platelets, are plentiful but may be smaller than usual.
Cytogenetic study of marrow shows the presence of the Ph chromosome in all dividing cells.
The patient's blood concentrations of urea and electrolytes are usually normal at diagnosis, whereas the lactate dehydrogenase is usually raised. Serum urate concentration may be raised.
Sarah
References
http://www.bmj.com/cgi/content/full/314/7081/657

Complications of CML

At the time of diagnosis, >80% of patients are in chronic phase, which is asymptomatic in many patients.

If CML is left untreated, the natural progression is rapid and fatal, with a median survival of about 3 to 5 years in patients.

As patient progresses into accelerated phase and blast phase, he/she would experience symptoms that often are secondary to splenomegaly: abdominal fullness, pain from splenic infaraction. The spleen may be so enlarged that it may fill the abdominal cavity and extend into the pelvis. Hepatomegaly is also frequently present. Infection and bleeding, which are not common in the chronic phase, are eventually picked up as the disease progresses.

Leukocytosis is a common feature, up to the excess of 300 x 109 /l. The leukocytes are abnormal, with no or severely reduced content of alkaline phosphatise.

The increased numbers of blast cells >30% in blood and bone marrow, marked anaemia and thrombocytopenia are signs of the acute, terminal phase of the disease. This is when the myeloid cells have eventually lost the ability to differentiate, in which clinical features are very close to those of acute leukaemia.

Incidence

Incidence vs Prevalence

The "prevalence" of a condition means the number of people who currently have the condition, whereas "incidence" refers to the annual number of people who have a case of the condition.

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Incidence: CML has an incidence of around 1–2 cases per 100,000; in
Australia, there are probably more than 200 new cases per year

Prevalence: 1300 prevalent cases/Australia.

Joske, D. J. L. (2008). "Chronic myeloid leukaemia: the evolution of gene-targeted therapy." Medical Journal of Australia 189(5): 277-82.

Definition

Leukemia, chronic myeloid

Chronic myeloid leukemia (CML) is a cancer of blood cells, characterized by replacement of the bone marrow with malignant, leukemic cells. Many of these leukemic cells can be found circulating in the blood and can cause enlargement of the spleen, liver, and other organs.

CML is often suspected on the basis on the complete blood count, which shows increased granulocytes of all types, typically including mature myeloid cells. Basophils andeosinophils are almost universally increased; this feature may help differentiate CML from a leukemoid reaction. A bone marrow biopsy is often performed as part of the evaluation for CML, but bone marrow morphology alone is insufficient to diagnose CML

CML is usually diagnosed by finding a specific chromosomal abnormality called the Philadelphia (Ph) chromosome (see figure), named after the city where it was first recorded. The Ph chromosome is the result of a translocation—or exchange of genetic material—between the long arms of chromosomes 9 and 22 . This exchange brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the proto-oncogene ABL (Ableson leukemia virus) on chromosome 9. The resulting hybrid gene BCR-ABL codes for a fusion protein with tyrosine kinase activity, which activates signal transduction pathways, leading to uncontrolled cell growth.

Tasks

Tasks
• CML
o Definition - Ari
o Incidence - Nathan
o Eitiology - Rushmi
o S and S - abmu
o Ix - Georgia
o Diagnoses - Me
o Mx - Jacqui
o Marrow transplant - sam
o ComplicationsDillys
o Prognosis - Kylie
o
Task
• What is massive splenomegaly? - Hasif
• Types of anaemia - Steph
o Hypo/normo, hypochromic
o Macro/norma/ chormic cytic
• Why some people can’t donate blood - lional