Concepts in Malignant Haematology and Acute Leukaemia

Question 1

Kinetics of normal haemopoiesis?

Answer 1

1. Self-renewal - haemopoietic stem cells are capable of this
2. Proliferation
3. Differentiation or lineage commitment
4. Maturation
5. Apoptosis

NOTE - a normal bone marrow aspirate will reflect this, with different cell types, inc. mature cells

Question 2

How can normal, more mature cells be identified?

Answer 2

Morphology:
• Blood count
• Blood film

Cell surface antigens,e.g: to recognise glycophorin A on red cells

Enzyme expression is a historic technique, e.g: myeloperoxidase on neutrophils

Question 3

How can normal progenitor / stem cells be identified?

Answer 3

Cell surface antigens (using immunophenotyping), e.g: CD34

Cell culture assays

NOTE - cannot differentiate progenitors / stem cells from one another on the basis of morphology alone

Question 4

Pathological characteristics of malignant haemopoiesis?

Answer 4

Increased numbers of abnormal and dysfunctional cells, with a loss of normal activity:
• Loss of haemopoiesis capabilities, e.g: acute leukaemias
• Loss of immune function, e.g: certain lymphomas

Question 5

Why does malignant haemopoiesis occur?

Answer 5

1 / more of the following:
• Increased proliferation
• Lack of differentiation
• Lack of maturation
• Lack of apoptosis

Question 6

Classifications involving proliferation of abnormal progenitors?

Answer 6

Proliferation of abnormal progenitors with block in differentiation / maturation, e.g: acute myeloid leukaemia

Proliferation of abnormal progenitors with no block in differentiation / maturation, e.g: chronic myeloid leukaemia; mature cells are present but are abnormal and present in large quantities

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Question 7

Causes of haematological malignancies?

Answer 7

Genetic, epigenetic and environmental interaction

Somatic mutations in regulatory genes:
• Driver mutations
• Passenger mutations

Recurrent cytogenetic abnormalities, e.g: deletions, chromosomal translocations, etc; not causal in most cases but contributory

Question 8

Difference between driver mutations and passenger mutations?

Answer 8

Driver mutations - in genes that regulate growth; they confer a growth advantage on the cells and are selected during the evolution of the cancer

Passenger mutations (‘noise’) - in less important regions but push the cell towards cancer; do not confer a growth advantage but happened to be present in an ancestor of the cancer cells, when it acquired one of its drivers

Question 9

Consequences of driver mutations?

Answer 9

Can select CLONES, which are populations of cells derived from a single parent cell; this parent cell has a genetic marker (driver mutation or chromosomal change) that is shared by the daughter cells

These clones can diversify but will still contain a similar genetic ‘backbone’

Question 10

Difference between normal haemopoiesis and malignanct haemopoiesis?

Answer 10

Normal haemopoiesis - polyclonal

Malignant haemopoiesis - monoclonal

Question 11

Evidence that haematological malignancies develop, at least partially, due to a genetic input?

Answer 11

Guthrie cards can be screened retrospectively in children who develop acute lymphoblastic leukaemia

With a pair of monozygotic twins, one twin has all and the other has detectable pre-leukaemic cells but does not develop disease

Somatic mutations observed in 10% of persons >65 years of age, without a blood disorder, can predict the risk of haem malignancy subsequently

Question 12

Methods of classifying haematological malignancies?

Answer 12

1. Based on lineage
2. Based on developmental stage (precursor) within lineage
3. Based on anatomical site involved

Question 13

Types of haematological malignancies, with relation to lineage?

Answer 13

Myeloid

Lymphoid

Question 14

Types of haematological malignancies, with relation to developmental stage (precursor) within lineage?

Answer 14

Acute lymphoblastic leukaemia (issue with progenitor cells)

Chronic lymphocytic leukaemia (issue with mature cells)

Question 15

Types of haematological malignancies, with relation to anatomical site involved?

Answer 15

Blood involvement - leukaemia

Lymph node involvement - lymphoma

NOTE:
• Chronic lymphocytic leukaemia can inv. blood and lymph nodes
• Myeloma is a plasma cell malignancy in marrow

Question 16

Differences between acute leukaemia & high-grade lymphomas, compared to chronic leukaemias & low-grade lymphomas?

Answer 16

Acute leukaemias and high-grade lymphomas are histologically, and usually clinically, more aggressive

Question 17

Histological features of aggression?

Answer 17

Large cells with high N : C ratio

Prominent nucleoli

Rapid proliferation

Question 18

Clinical features of aggression?

Answer 18

Rapid progression of symptoms

Question 19

Examples of haematological malignancies?

Answer 19

Acute myeloid leukaemia

Acute myeloblastic leukaemia

Chronic myeloid leukaemia

Chronic lymphocytic leukaemia

Question 20

What is acute leukaemia?

Answer 20

A rapidly progression clonal malignancy of the marrow or blood, with maturation defects(s)

Excess of ‘blasts’ (≥50%) in either the peripheral blood or bone marrow, due to block in differentiation & maturation

There is a decrease/loss of haemopoietic reserve

Question 21

2 types of acute leukaemia?

Answer 21

Acute myeloid leukaemia (AML) -

Acute lymphoblastic leukaemia (ALL) - malignant disease of primitive lymphoid cells, i.e: of lymphoblasts

Question 22

Occurrence of ALL?

Answer 22

Most common childhood cancer

Question 23

PC of ALL?

Answer 23

Due to marrow failure (pancytopaenia):
• Anaemia
• Infections
• Bleeding

Leukaemic effects:
• High count with obstruction of circulation
• Extramedullary inv. of areas outside the marrow and blood, e.g: CNS, testis

Bone pain

Question 24

Occurrence of AML?

Answer 24

More common in the elderly (>60 years of age)

May be ‘de novo’ or secondary

Question 25

PC of AML?

Answer 25

Can be similar to ALL (with marrow failure) Various sub-groups of AML may have characteristic presentation, e.g: • DIC (coagulation defect) • Gum infiltration

Question 26

Ix for acute leukaemia?

Answer 26

1. Blood count and film 2. Coagulation screen 3. Bone marrow aspirate: • Morphology - what do the cells look like? • Immunophenotype (flow-cytometry) - are there lineage-specific proteins on the cell surface? • Cytogenetics • Trephine - piece of bone that allow better assessment of cellularity; it is helpful when the marrow aspirate is sub-optimal

Question 27

Blood film results with acute leukaemia?

Answer 27

Reduction in normal Presence of abnormal; this include abnormal blast cells with a high N : C ratio

Question 28

What are Auer rods?

Answer 28

Blood film characteristic of AML EXAMS

Question 29

For a definitive diagnosis of AML or ALL, what is required?

Answer 29

Immunophenotyping is required NOTE - even if cells from AML and ALL look alike. they express lineage-assoc. proteins; this differentiation is important, as AML and ALL have different treatments

Question 30

Curative treatment of acute leukaemia?

Answer 30

Multi-agent chemotherapy

Question 31

Curative treatment of ALL?

Answer 31

``` Chemo can last up to 2-3 years; there are different phases of treatment, of varying intensity: • Induction • Consolidation • Intensification • Maintenance ```

Question 32

Curative treatment of AML?

Answer 32

Normally intensive treatment, with 2-4 cycle of chemotherapy (5-10 days of chemo followed by 2-4 weeks of recovery); there is prolonged hospitalisation

Question 33

What is a Hickman line?

Answer 33

Used to remove blood samples OR Deliver chemotherapy

Question 34

Issues assoc. with marrow suppression?

Answer 34

1. Anaemia 2. Neutropaenia: • Infections 3. Thrombocytopaenia: • Bleeding - purpura and petechiae

Question 35

Particular infection concerns in neutropaenic patients?

Answer 35

Gram -ve bacteria can cause fulminant life-threatening sepsis

Question 36

Complications of treatment?

Answer 36

N&V, hair loss Liver, renal dysfunction Tumour lysis syndrome (during 1st course of treatment) Infection: • Bacterial - empirical treatment with broad-spectrum antibiotics if the patient has NEUTROPAENIC FEVER (important) • Fungal - consider if prolonged neutropaenia and persisting fever unresponsive to anti-bacterial agents • Protozoal, e.g: PJP (more relevant in ALL therapy) Late effects, e.g: • Infertility • Cardiomyopathy with anthracyclines

Question 37

Outcomes of treatment?

Answer 37

May patients enter remission; may not be durable, depending on the type of acute leukaemia and many patients relapse Some patients die of treatment-related toxicity

Question 38

Other treatment options?

Answer 38

Targeted treatments, e.g: molecular targeting with kinase inhibitors for ALL with the Philadelphia chromosome Allogeneic stem cell transplantation in select patients