Module 2 - Clinical Overview

Question 1

What is myeloid tissue

Answer 1

Myeloid tissue is a biological tissue with the ability to perform haematopoiesis. It is mainly found as the red bone marrow in bones, and is often synonymous with this. However, myeloid tissue can also be present in the liver and spleen .

Question 2

What is a myeloblast?

Answer 2

The myeloblast is a unipotent stem cell, which will differentiate into one of the cells of the granulocyte series.

Question 3

What is a polymorphonuclear leucocyte?

Answer 3

A granulocyte (called PMN due to the varying shapes of the nucleus, which is usually lobed into three or more segments.)

Question 4

Classification of myeloid disorders

Answer 4

Myeloid, myelomonocytic
Monocytic,
Eyrtholeukaemia
Megakaryocytic

Question 5

Epidemiology of acute leukaemias (AML and ALL)

Answer 5

• AL accounts for 30% of childhood cancers
• ALL is 75% of all childhood leukaemias
• AML > ALL in adults
• M > F
• 90% of ALL and 70% of AML is curable in children
• Minority of adult ALL & AML is curable
• Incidence of AML increases with age but not ALL

Question 6

What are the symptoms in acute leukaemias due to? (5)

Answer 6

symptoms due to:
1.  marrow failure
2. tissue infiltration
3. leucostasis
4. constitutional symptoms
5. other (DIC)
usually short duration of symptoms
(FILO sheets?)

Question 7

What symptoms do you get from marrow failure?

Answer 7

1. neutropenia: infections, sepsis
2. anaemia: fatigue, pallor
3. thrombocytopenia: petechiae, gum bleeds, epistaxis

Question 8

What symptoms arise from tissue infiltration?

Answer 8

enlargement of liver, spleen, lymph nodes, pulmonary infiltrates
gum hypertrophy
bone pain, arthritis
other organs: CNS, skin, testis, any organ
Solid accumulation of AML blasts- granulocytic sarcoma

Question 9

What is leucostasis?

Answer 9

accumulation of blasts in microcirculation with impaired perfusion 
lungs: hypoxaemia, pulmonary infiltrates
CNS:  fluctuation LOC, stroke
Retinal haemorrhages
Priapism
only seen with WBC >> 50 x 109/L

Question 10

What are constitutional symptoms?

Answer 10

fever (and sweats) common - (not associated with rigors, chills, tachycardia,hypotension, not relieved by anti-pyretics, mediated by cytokines acting as endogenous pyrogens)
weight loss less common
Anorexia (cancer cachexia-cytokines, excess lactate)
fatigue

Question 11

Lab features of ALs

Answer 11

WBC usually elevated, but can be normal or low
blasts in peripheral blood
normocytic anaemia
thrombocytopenia
neutropenia
DIC- associated with some subtypes of AML
Features of tumour lysis- raised uric acid & LDH, raised K and PO4, low Ca

Question 12

Why is bone marrow examined?

Answer 12

necessary for diagnosis
useful for determining type
useful for prognosis
Acute leukemia is defined by the presence of
> 20% blasts in bone marrow (% of nucleated marrow cells)
CSF always examined for CNS involvement

Question 13

What is important to remember with ALL treatment?

Answer 13

Treatment to prevent CNS relapse is key

Question 14

Aetiology of AL?

Answer 14

The aetiology of leukaemia is unknown however somatic acquired genomic instability is one of the hallmarks of cancer.

• OG mutations and TSG alteration
• Host factors
• Environmental factors

Question 15

What is the Two-hit model of leukaemogenesis?

Answer 15

First hit: Loss of function of transcription factors needed for differentiation

eg. AML1-ETO
CBFb-SMMHC
PML-RARa

Second hit:
Gain of function mutations of tyrosine kinases

eg. FLT3, c-KIT mutations
N- and K-RAS mutations
BCR-ABL
TEL-PDGFbR

Question 16

What are “host factors” referring to?

Answer 16

Hereditary cancer predisposition syndromes- loss of genomic stability due to increased chromosomal breakage, defective DNA repair E.g.:

Fanconi anaemia- increased chromosomal breakage
Diamond-Blackfan anaemia- ribosomopathy
Dyskeratosis congenita- shortened telomeres
Bloom’s syndrome, Li-Fraumeni syndrome, NF-1

Question 17

Which chromosomal abnormalities can cause ALs?

Answer 17

Trisomy 21- Down’s syndrome

• High risk of specific type of AML in the first 5 years
• Mutations in TF GATA-1, thought to control megakaryocyte and erythroid maturation
• Potential oncogenes on chr 21, complex interactions contributing to leukaemogenesis

Trisomy 8
- Risk of leukaemia related to aneuploidy

Question 18

What other host factors have been linked to causing ALs?

Answer 18

IMMUNODEFICIENCY - An unusually high incidence of lymphoid leukemia and lymphoma has been described in patients with hereditary immunodeficiency states (ataxia-telangiectasia and sex-linked agamaglobulinemia).
Usually related to T and B-lymphocyte gene rearrangement.
CHRONIC BONE MARROW DYSFUNCTION-
Patients with CBMD syndromes have an increased risk of acute leukemic transformation.
Examples include the myelodypalstic syndromes, myeloproliferative disorders, aplastic anemia and PNH

Question 19

What environmental factors can cause leukeamia?

Answer 19

Ionizing radiation (linked to chronic and acute leukaemias)
Benzene and aniline dyes- need prolonged exposure
Cytotoxic drugs: alkylating agents, platinum-based agents and topoisomerase II inhibitors
Lifestyle factor- smoking
Viruses
-EBV- Burkitt lymphoma/leukaemia
- HTLV-1- Adult T-cell leukaemia/lymphoma

Question 20

What supportive care is needed in leukaemic pnts?

Answer 20

Support for bone marrow- blood products, antibiotic prophylaxis
Delivery of therapy- central venous catheters
Management of complications
- Infectious- neutropenic sepsis
- Bleeding
- Organ involvement and/or toxicity
- Mass effect