Leukaemia

Question 1

Define leukaemia

Answer 1

cancer of the blood or “white blood”:

• 5% of all cancers are cancers of the blood.
• Blood cancers are the most common cancers in men and women aged 15-24 and the main cause of death in 1-34.
• Leukaemia results from a series of mutations in a single lymphoid or myeloid stem cell.
  
  • Pluripotent hematopoietic stem cell.
  • Myeloid/lymphoid stem cell.
  • Pro-/Pre-T/B lymphocyte.

Question 2

Explain the difference between lymphoid and myeloid leukaemia, and acute and chronic leukaemia

Answer 2

Leukaemia Classification

• Most cancers exist as solid tumours but it is unusual for leukaemia patients to have tumours.
  
  • More often they have leukaemia cells replacing normal bone marrow cells and circulating freely.
• Normal haematopoietic stem cells circulate in the blood and both the stem cells and the cells derived from them can enter tissues, and normal lymphoid stem cells recirculate between tissues and blood.
  
  • Thus, invasion/metastasis cannot be applied normally.

1. Benign leukaemia = chronic.
2. Malignant = acute (aggressive and quick death if untreated).

How to classify leukaemia:

1. Acute (malignant) or chronic (benign).
2. Lymphoid or myeloid origin.

• Lymphoid can be B or T lineage.
• Myeloid can be any combination of granulocytic, monocytic, erythroid or megakaryocytic.

Final classes:

ALL – Acute Lymphoblastic Leukaemia.

AML – Acute Myeloid Leukaemia.

CLL – Chronic Lymphocytic Leukaemia.

CML – Chronic Myeloid Leukaemia.

Question 3

Summarise the genetic features of acute lymphoblastic leukaemia.

Answer 3

An acquired genetic disease, resulting from somatic mutation:

• Arises because of a series of mutations in a single stem cell, some from oncogenic influences, others random errors that accumulate over time. Important leukaemogenic influences include:

1. Proto-oncogene mutations.
2. Novel gene creation – e.g. a chimeric or fusion gene.
3. Dysregulation of a gene – when translocation brings the gene under the influence of a promotor or enhancer of another gene.
4. TSG loss of function – deletion or mutation of both copies.

Inherited causes contributing to leukaemogenesis: Identifiable causes of mutations include:

• Loss of function of a tumour-suppressor gene can also contribute to leukaemogenesis—this can result from deletion or mutation of the gene
• If there is a tendency to increased chromosomal breaks, the likelihood of leukaemia is increased
• In addition, if the cell cannot repair DNA normally, an error may persist whereas in a normal person the defect would be repaired

1. Down’s syndrome.
2. Chromosomal fragility syndromes.
3. Defects in DNA repair.

Inherited defects of TSGs.

1. Irradiation
2. Anti-cancer drugs.
3. Cigarette smoking.
4. ​Chemicals – e.g. benzene.

Question 4

Distinguish between the characteristics of acute and chronic lymphoblastic leukemias

Answer 4

Acute/Chronic Myeloid Leukaemia

• Cell continue to proliferate but they do not mature, leading to:
  
  • Build-up of immature cells.
  • Failure of production of normal functioning end cells such as neutrophils, monocytes, platelets, etc.
• Responsible mutations usually affect transcription factors.
• Often is due to the product of an oncogene affecting proteins.

Chronic myeloid leukaemia (CML):

• Responsible mutations usually affect genes encoding proteins (membrane receptor or cytoplasmic proteins) involved in the signalling pathways from receptors.
• Cell kinetics & function are not as seriously affected as in AML.
  
  • But there is still reduced apoptosis and the cell progressively expands in population.

AML = failure of production of cells.

CML = increased production of cells.

Acute lymphoblastic leukaemia (ALL):

• Increase in very immature cells (lymphoblasts) with a failure of these to develop to mature B/T cells.

Chronic lymphoid leukaemia (CLL):

• Leukaemic cells are mature but abnormal.

Question 5

Describe leukemia disease characteristics

Answer 5

• Caused by an accumulation of abnormal cells leading to:
  
  • Leucocytosis, bone pain (acute), hepatomegaly, splenomegaly, lymphadenopathy (if lymphoid), thymus enlargement (if T lymphoid), skin infiltration.
• Metabolic effects of Leukaemic cell proliferation:
  
  • Hyperuricemia and renal failure, weight loss, low-grade pyrexia, hidrosis.
• Crowding out of normal cells leads to – anaemia, neutropenia, thrombocytopenia.
• CT scan picture = intraventricular haemorrhage.
• There is a loss of normal immune function (in CLL)
• Bleeding and gum infiltration

Question 6

Summarise the clinical features of acute lymphoblastic leukaemia.

Answer 6

• ALL is largely a disease of children – highest incidence at age 4.
• B-lineage ALL result from – delayed exposure to common pathogen or, conversely, early exposure to a pathogen protects.
  
  • Evidence also relates to – family size, new towns, socio-economic class, early social interactions and variations between countries.
  • One study showed enterovirus infection gave protection.
• Some leukaemias in children resulted from:
  
  • Irradiation in utero.
  • In utero exposure to certain chemicals – Baygon, Dipyrone.
  • EBV.
  • Rarely – exposure to a mutagenic drug.

Clinical features of abnormal cell accumulation:

• Bone pain.
• Hepatomegaly and splenomegaly.
• Lymphadenopathy.
• Thymic enlargement.
• Testicular enlargement.

Clinical features of crowding out of normal cells:

Anaemia – fatigue, lethargy, pallor, dyspnoea.

Neutropenia – fever and features of infection.

Thrombocytopenia – bruising, petechiae, bleeding

Question 7

Summarise the haematological features of acute lymphoblastic leukaemia.

Answer 7

Haematological features:

• Leucocytosis with lymphoblasts in the blood.
• Anaemia (normocytic, normochromic).
• Neutropenia.
• Thrombocytopenia.
• Lymphoblasts replacing normal bone marrow cells.

Investigations:

• FBC with liver and renal function tests.
• Bone marrow aspirate.
• Cytogenic/molecular analysis.
  
  • Immunophenotyping – find the lineage of the cells.
  • These methods are useful for assessing the prognosis of the ALL.
    
    • Hyperdiploidy (many extra chromosomes) à good prognosis.
    • T(4; 11) reciprocal translocation à poor prognosis as it gives rise to a fusion gene
  • Chest x-ray.

Question 8

Outline leukemogenic mechanisms for acute lymphoblastic leukemia

Answer 8

Mechanisms:

• Formation of a fusion gene – ETV6-RUNX1.
• Dysregulation of a proto-oncogene – TCL3 and TCRA.
• Point mutation in a proto-oncogene.

ETV6-RUNX1 fusion gene can be detected using cytogenic and molecular analysis – FISH.

• Green probe for ETV6 and red for RUNX1.
• Fused colours give yellow.

Example of dysregulation – t(10; 14) (q24; q11) – the TCL3 gene is dysregulated by proximity to the TCRA gene.

Cytogenetics can predict the prognosis of ALL depending on the genetic mechanisms.

Question 9

Discuss treatment options for acute lymphoblastic leukemia

Answer 9

Treatment:

1. Supportive – replace red cells, platelets and antibodies.
2. Systemic chemotherapy.
3. Intrathecal chemotherapy – injecting drug in CSF.

• Childhood ALL survival rates have been increasing gradually.
• Overall survival has been gradually been getting better:
  
  • Approx. 10-year survival was 10% in 60s, now it is 95%.
• Event free survival shows a similar pattern -5%.
• Treatment must be systemic as leukaemia disseminates early in the disease (similar to metastasis).
• ALL has many phenotypes depending upon mutation so treatment varies.