Haematology - Leukaemia Acute and Chronic

Question 1

List the four (4) main factors on which the classification of leukaemia is based (2)/ List the four (4) laboratory characteristics used in the diagnosis of haematological malignancies according to the WHO classification that can be used to differentiate CLL from other lymphoproliferative disorders (4x0.5 = 2)

Answer 1

Morphology, Immunophenotype, Cytogenetics, Molecular abnormalities

Question 2

Outline three (3) environmental factors (with examples) that may be involved in the aetiology of leukaemia (3) (Super NB!)

Answer 2

Radiation – Previous radiotherapy and nuclear accidents increase the risk of secondary malignancies including acute leukaemia

Viruses – HIV, HTLV1 and Adult T-Cell Leukaemia/Lymphoma
o Leukemogenicity of viruses have been proven in various animal models & more conclusive proof is now emerging in humans
o HTLV 1 retrovirus is proven to transform human T- cells leading to adult T-cell leukaemia/lymphoma
o Epstein Barr virus is responsible for the development of endemic Burkitt’s lymphoma and has also now been proven to be the etiologic agent in Hodgkin’s lymphoma

Drugs – Prior treatment with chemotherapeutic drugs have increased incidence

Chemicals – Benzene and alkylating agents may cause secondary leukaemia
o Chemotherapeutic agents like alkylating agents which are widely used in treating leukaemia are themselves leukemogenic and can lead to secondary acute leukaemia
o Benzene is myelotoxic and leads to aplastic anaemia in certain cases while others develop acute leukaemia after exposure
o Smoking increases the risk for acute leukaemia

Question 3

Describe three (3) features that determine the phenotype of a leukaemia (4½) (Super NB)

Answer 3

Cell lineage involved: Myeloid vs lymphoid

Proliferative rate: High proliferative rate in acute leukaemias, lower proliferative rate in chronic leukaemias

Degree of differentiation of the daughter cells in the malignant clone.
o Acute leukaemia: Accumulation of undifferentiated cells (blasts)
o Chronic leukaemias: Differentiation to mature cells.

Degree of apoptosis: Reduction in apoptosis may contribute to accumulation malignant cells.

Question 4

Tabulate four (4) fundamental differences between acute and chronic leukaemia (4) (Super NB)

Answer 4

Age: All vs most elderly

Onset: Rapid vs slow

Progression: Immediately life-threatening vs slow (may live for years)

Cell origin: Early immature cells vs more mature cells

Treatment: Intense high dose chemo regimes vs lower less intense/biological/small molecules

Question 5

In your opinion, is Mr Brink more likely to have acute or chronic leukaemia? List 3 features from his case to justify your answer (2)

Answer 5

Acute leukaemia. High blast count, No differentiation, No splenomegaly or lymphadenopathy, Short clinical history.

Question 6

List the investigations that can be used to identify the type of leukaemia (2)

Answer 6

Blast morphology, Cytochemical stains (detect cell enzymes), Immunophenotyping (cell surface antigen detection), Cytogenetic analysis

Question 7

Outline why it is important to determine the type of leukaemia a patient has [1]/ Outline why it is critically important to make an accurate diagnosis of the type of acute leukaemia (1) (Super NB)

Answer 7

Treatment regimen and prognosis differ for different types.

Question 8

Briefly classify the leukaemias (3)

Answer 8

Acute: Lymphoid vs. Myeloid. Chronic: Lymphoid vs. Myeloid

Question 9

An 18-year-old male presents with persistent pallor, fatigue and a sore throat. His GP requests a Full Blood Count (FBC) and a Differential Count (DIFFT). The results are as follows: FBC: WCC 100 HB 6.5 MCV 80 PLT 21. DIFFT: 75% blasts

State the diagnosis (1)

Answer 9

Acute leukaemia

Question 10

List clinical features present that would alert you to consider acute leukaemia in your differential diagnosis (2½)

Answer 10

Tiredness, Epistaxis, Short duration of symptoms, Pallor, Bruises

Question 11

List five (5) clinical features (symptoms and signs) that may be present at diagnosis of acute leukaemia (2) (Super NB)

Answer 11

Anaemia (Tiredness, pallor, etc.), Thrombocytopaenia (Bleeding gums, bruises etc.), Neutropaenia (Opportunistic infections), Hepatosplenomegaly, Lymphadenopathy, Testicular enlargement/ swelling, Bone pain, Gum hypertrophy

Question 12

List the abnormalities in a patient’s Full Blood Count and Differential Count that would make leukaemia a likely diagnosis (2½)

Answer 12

Marked anaemia, Thrombocytopenia, High WBC, Neutropenia, Blasts

Question 13

Identify 4 clinical and 4 laboratory features found in Dylan that alerted Dr Opperman to the possible diagnosis of acute leukaemia [8x½ = 4]

Answer 13

Clinical  Laboratory
Tiredness  Anaemia

Bruising  Thrombocytopaenia

Gum bleeding  Neutropaenia

Lymphadenopathy  Blasts on differential count

Question 14

Patients with acute leukaemia are predisposed to infections. Identify the reason [½]

Answer 14

Neutropaenia

Question 15

List any four (4) specific presenting features and the underlying mechanism thereof in a patient with acute leukaemia (4) (NB)

Answer 15

Anaemia, bleeding tendency, infections. Mechanism = Bone marrow infiltration leading to decreased production of blood cells.

Gum hypertrophy, lymphadenopathy, splenomegaly, CNS disease. Mechanism = Tissue infiltration by leukaemic blasts

Question 16

Outline the mechanisms of the patient’s: (2)

i) Anaemia and thrombocytopaenia (1)
ii) hepatomegaly and splenomegaly (1)

Answer 16

Bone marrow failure owing to marrow infiltration.

Infiltration of liver and spleen by leukaemic blasts

Question 17

List six (6) clinical features commonly associated with ALL (3) (NB)

Answer 17

Bleeding, Infection, Anaemia/Tired, Pain – bone, Lymphadenopathy, Hepatosplenomegaly, Fever, CNS disease

Question 18

Identify 4 clinical features in Mr Brink that would alert you to consider leukaemia in your differential diagnosis. For each, state the laboratory result that you think identifies the cause of the clinical feature (4)

Answer 18

Tiredness (low Hb), Pallor (low Hb), Nose bleeds (low platelets), Petechiae and bruises (low platelets)

Question 19

List ten (10) clinical features (symptoms and/or signs) that may be found in patients with ALL & For each, state the reason why it occurs (15)

Answer 19

Bone marrow failure
Anaemia – pallor, lethargy, dyspnoea
Neutropenia – fever, malaise, infections
Thrombocytopenia – bruises, purpura, epistaxis

Organ infiltration
Bone pain
Lymphadenopathy
CNS disease – meningism (neck stiffness), headache
Testicular swelling
Mediastinal compression – shortness of breath

Question 20

List four (4) clinical features present in Siyamthanda, which would cause you consider leukaemia in the differential diagnosis (4x½ =2)

Answer 20

Tiredness, Bleeding gums, Pallor, Lymphadenopathy, hepatosplenomegaly

Question 21

List four (4) clinical features present in Sarah, which would have alerted you to the possibility of a diagnosis of leukaemia. For each, state the cause of that feature (4)

Answer 21

Sore legs (bone pain) – marrow infiltration

Gums bleeding – thrombocytopenia

Pallor – anaemia from marrow infiltration

Lymph node enlargement – leukaemic infiltration

Splenomegaly – leukaemic infiltration

Question 22

Explain why Vuyo has an enlarged spleen and lymph nodes (1)

Answer 22

These organs are enlarged as a result of infiltration by the malignant cells.

Question 23

List four (4) clinical features in Ms Dastile that would alert you to consider leukaemia in your differential diagnosis.

For each, state the laboratory result which reflects the probable cause of the clinical feature (4)

Answer 23

Tiredness - anaemia
Menorrhagia - thrombocytopenia
Nose bleed
Petechiae
Pallor - anaemia
Enlarged lymph nodes – blasts in blood – leukaemic infiltration
Recurrent infections-decreased functioning WBC

Question 24

List five (5) clinical features present in Ms Siwisa that would cause you to consider leukaemia in the differential diagnosis.
b)	For each symptom or sign state the underlying cause/s (5

Answer 24

Tiredness – anaemia

Swollen gums (hypertrophy) – leukaemic infiltration

Bleeding gums - thrombocytopenia

Petechiae - thrombocytopenia

Splenomegaly – leukaemic infiltration

Question 25

List four (4) common presenting features of CLL

Answer 25

Coincidental (asymptomatic), Lymphadenopathy, Tiredness, Abdominal discomfort (Hepatosplenomegaly), Recurrent infections, Haemolytic anaemia

Question 26

Define the term pancytopaenia [1]

Answer 26

The reduction of all three major haemopoietic cells lines - Erythrocytes (red blood cells), leucocytes (white blood cells), platelets.

Question 27

List three (3) causes of pancytopaenia [1.5]

Answer 27

Bone marrow infiltration (e.g. leukaemia, lymphoma, metastatic tumour), Aplastic anaemia, Infection (e.g. disseminated TB; RVD), Megaloblastic anaemia

Question 28

Following cytotoxic chemotherapy the full blood count showed low haemoglobin, white cell and platelet counts [3]

What is the most likely reason for the patient’s low blood count? [1]

Explain briefly why the patient may now be more susceptible to infections [2]

Answer 28

Cytotoxic effect of chemotherapy preventing bone marrow from replenishing blood cells.

The neutrophil count is markedly decreased. This results in immunosuppression predisposing the patient to opportunistic infections.

Question 29

List three (3) features of bone marrow failure. For each, state the clinical consequences and the method of treatment (4½)

Answer 29

Anaemia with fatigue and pallor – RBC XF

Neutropenia and susceptibility of infections – Antibiotics

Thrombocytopenia causing bleeding – Platelet XF

Question 30

Outline why the antigens present on the surface of leukaemic cells must be analysed in new cases of acute leukaemia (2) (NB)

Answer 30

To determine the cell lineage (½) of leukaemic cells, which is essential for accurate diagnosis (½), treatment (½) & prognosis (½)

Question 31

Outline two (2) molecular mechanisms that may give rise to acute leukaemia (2)

Answer 31

Gain of function of proto-oncogenes, Mutations in tumour suppressor genes, Defects in apoptotic pathway so cells do not die but accumulate.

Question 32

Outline the pathogenesis of Acute Leukaemia (4)

Answer 32

• Malignant transformation occurs at level of haemopoietic stem cell or early progenitor cell.
• Genetic damage results in…
  o Excessive proliferation of malignant cells
  o Reduced apoptosis
  o Block in cellular differentiation
• Together these together result in the accumulation of blasts in the bone marrow, which then may accumulate in blood and other tissues (e.g. spleen, lymph nodes)

Question 33

State three (3) laboratory features that support this diagnosis (AL) (1½)

Answer 33

Low Hb, Low platelets, 89% blasts on peripheral blood

Question 34

List four (4) specialised laboratory investigations you would recommend when investigating a new case of possible acute leukaemia, and for each explain how it would assist you in making an accurate diagnosis (6)

Answer 34

FBC, Morphology, Cytochemistry, Cytogenetics, Bone marrow biopsy, Immunophenotyping, Genetic studies, Renal function & electrolytes, DIC screen (3)

Question 35

List four (4) laboratory investigations that may be used to identify the type of acute leukaemia (4) For each test, state a result that may be found in AML & ALL respectively (8) (Super NB)

Answer 35

AML ALL
Blast morphology on blood or marrow smear
Auer rods No Auer rods

Cytochemical staining of blasts (detect cell enzymes) MPO positive MPO negative

Immunophenotyping (cell surface Ag detection)
CD33 etc. T or B cell markers

Cytogenetic analysis t(15;17), t(8;21) etc t(4;11) or t(8;14)

Molecular analysis (PCR or FISH)

Question 36

Outline two (2) morphological differences between ALL and AML blasts (2)

Answer 36

AML blasts: Cytoplasm with granules and auer rods. ALL blasts: Cytoplasm with no granules and no auer rods

Question 37

State four (4) factors that may influence the prognosis of acute leukaemia. (4x½ = 2)

Answer 37

Age (older patients fare worse than younger), High WBC, Cytogenetics of malignant cells, Time taken to respond to induction chemotherapy

Question 38

List three (3) factors that influence the prognosis in acute leukaemia (1½)

Answer 38

AML
Cytogenetics of the malignant cells
Performance status of patient
Age
Primary vs secondary AML
White cell count at diagnosis
Response to induction chemotherapy
Prognosis is also affected by the type of therapy:

ALL (NB)
Age >35yrs
High white cell count at diagnosis
CNS disease at presentation
Certain cytogenetic abnormalities such as t(9;22) and t(4;11)
If it takes more than 4 weeks of induction chemotherapy to achieve remission

Question 39

Briefly explain why the chromosomal analysis of the leukaemic cell is important in the diagnosis of acute leukaemia. Give one (1) example (3)

Answer 39

The presence of certain cytogenetic abnormalities is important for the diagnosis, treatment and prognosis of the leukaemia. Examples in the computer tutorial.

Question 40

List four (4) types of chromosomal abnormalities that may be found in acute leukaemia (2)

Answer 40

Hyperdiploidy, Hypodiploidy, (gain or loss of chromosomes), Deletions, Translocations

Question 41

Outline 4 (four) medical interventions (other than chemotherapy) used in the management of Acute Leukaemia (4)/ Outline three (3) complications of acute leukaemia and/or its treatment, stating the management in each case (3) (Super NB)

Answer 41

Anaemia: Red blood cell transfusions (filtered irradiated packed red cells to maintain Hb >8g/dl)

Thrombocytopenia: Platelet transfusions if indicated

DIC: Supportive – FFP and cryoprecipitate

Prevention of infections (Neutropenia)
o Nursed in a single room in a special unit with reverse isolation.
o Regular handwashing by staff and visitors
o Avoiding contact with anybody with an obvious infection.
o Fresh fruit and raw vegetables are not allowed.
o Antibiotic and antifungal prophylaxis are given in most units.
o Special attention to mouth care prevents oral infections.

Prompt treatment of infections: Immediate empiric antibiotics after blood cultures and cultures from other sites like sputum and urine have been sent off. If no response within 72 hours, anti-fungal treatment should be added

Prevention of gout and tumour lysis syndrome  Hydration, alkalinise urine, allopurinol

Prevention of nausea due to chemotherapy  Anti-emetics

Question 42

Name the type of acute leukaemia that is most common in children (½) (NB)

Answer 42

Acute lymphoblastic leukaemia

Question 43

CML is a clonal disorder of the myeloid cell line. Briefly explain the genetic abnormality underlying this disorder (4)

Answer 43

Reciprocal translocation between chromosomes 9 & 22. (t(9;22)/ (1) Philadelphia chromosome) with formation of BCR-ABL fusion gene (1). Gene product has enhanced tyrosine kinase activity (1) with constitutive activation of various signal transduction pathways (1)

Question 44

List four (4) peripheral blood features seen in the chronic stable phase of this disease (2)

Answer 44

Leukocytosis, peaks in myelocytes and neutrophils, no significant dysplasia, occasional blasts (usually less than 2%), basophilia (invariable), eosinophilia (common), platelet numbers normal or increased.

Question 45

Explain the mechanism of action of imatinib (Gleevec) in CML (3)

Answer 45

Blocks the ATP binding site on the BCR/ABL fusion protein. Prevents:
Phosphorylation of tyrosine residues on the BCR/ABL substrate

Phosphorylation of downstream effector molecules

Transcription of genes that drive proliferation & prolonged survival

Thus effectively prevents cellular proliferation in CML

Question 46

Write short notes on the BCR/ABL fusion gene (5)

Answer 46

Results from translocation of genetic material between chromosomes 9 and 22

The fusion gene has enhanced tyrosine kinase activity

This results in increased (granulocyte) proliferation, decreased adherence of bone marrow haemopoietic cells to the stroma and prolonged survival.

If found BCR/ABL positive on molecular testing, this result is in keeping with the diagnosis of CML or ALL

Question 47

A 55-year-old man presents with left upper quadrant abdominal pain and is found to have splenomegaly. FBC shows: White cell count 60x109/l (N = 4-10), Hb 9.5g/dl (13-17), Platelets 400x1012/l (137-373). The peripheral blood smear shows predominance of granulocyte precursors (promyelocytes, myelocytes and metamyelocytes). Basophils and eosinophils are also increased.

List four (4) differential diagnoses (½x4 = 2)

Answer 47

CML, Severe bacterial infection, Malignancy (G-CSF secreting), Acute blood loss/shock, Tissue trauma/surgery, Severe inflammation/infection

Question 48

List the investigations you would perform to determine the diagnosis (½x4 = 2)

Answer 48

Bone marrow biopsy, cytogenetics, FISH, PCR BCR/ABL, Cultures, Imaging for tumours

Question 49

Briefly describe three (3) mechanisms that may result in anaemia in patients with CLL. For each describe a clinical finding or one special investigation and its result that may suggest this is a cause of anaemia (3x2 = 6) (NB)

Answer 49

Immune haemolysis (typically warm AIHA): Reticulocytosis, + DAT, increased LDH/ unconjugated bilirubin, low haptoglobin, spherocytes and polychromasia on PB smear

Pure red cell aplasia (immune mechanism): Low reticulocyte count, bone marrow biopsy with reduced/ absent RBC precursors

Reduced erythropoiesis due to bone marrow infiltration: Low reticulocyte count, bone marrow biopsy with lymphocytic infiltrate and reduced haematopoiesis

Splenic sequestration of RBCs (hypersplenism): Splenomegaly clinically/ radiologically

Question 50

List two (2) reasons for the predisposition to infection in CLL (2x½ =1)

Answer 50

Hypogammaglobulinaemia, Neutropenia, Defective cellular immunity

Question 51

Not all patients with CLL require chemotherapy. List two (2) indications for treatment (1x2 = 2)

Answer 51

Bulky lymphadenopathy, problematic organomegaly, bone marrow infiltration with cytopenias, autoimmune manifestations.