Acute Leukaemia

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Acute Leukaemia

• Dr N Holland

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What are the Acute Leukaemias?

• Leukaemia
• Meaning white blood
• Malignancy
• Uncontrolled proliferation of blood cell
  precursors
• Acute
• Rapid onset and progression
• Proliferation of blasts /primitive cells

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Incidence

• 4/100 000 population/year
• Incidence and type of acute leukaemia varies with
  age

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What determines the type of malignancy that
develops?

• Type of cell in which original mutation occurred
• E.g. Myeloid or lymphoid progenitor etc.
• Type of mutation
• Accumulation of mutations

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Types of Acute Leukaemia
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Acute Lymphoblastic Leukaemia

• Primitive lymphoid neoplasms
• Immunophenotyping and genetic techniques of more
  value in classification than cytochemistry (and
  morphology)

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Acute Lymphoblastic Leukaemia

• Predominantly a disease of childhood
• 75 of cases occur in children under 6 years
• Second peak does occur in the 6th to 7th decade
• WHO Precursor B cell and Precursor T cell
  neoplasms

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Precursor B cell ALL

• Cure rates (disease free survival) gt70 in
  childhood precursor B-cell ALL
• However, distinct sub-groups are recognised which
  are associated with better/worse prognosis

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Precursor T-cell ALL

• Constitutes 15 of childhood leukaemia
• Considered high risk ALL in childhood
• More common in adolescents and males
• Frequently presents with high WCC
• Commonly present with mediastinal mass and/or
  pleural effusion

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Examples of molecular abnormalities in lymphoid
leukaemias

• t(922) the Philadelphia chromosome

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t(922)

• Philadelphia Chromosome
• CML
• ALL
• Translocation t(922)
• Breakpoint cluster region chr 22
• Abelson oncogene chr 9 (tyrosine kinase)
• Results in the formation of a chimeric fusion
  gene (bcrabl) on chromosome 22.

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t(922)

• Translated into an abnormal protein product
• Abl assumes an abnormal cytoplasmic location
• Inappropriately active
• Cell can grow and divide independently of normal
  growth factors

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Poor prognostic factors in ALL

• Age
• WCC
• Immunophenotype
• Cytogenetics
• Hyperploidy
• Response to induction chemotherapy

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Acute Myeloid Leukaemia

• 70 of Acute Leukaemia
• FAB classification of AML
• Adopted since 1976
• Uses morphology, cytochemistry and
  immunophenotype (flow cytometry)
• Does not include the genetic findings
• AML M0 M7
• The WHO classification
• Incorporates all the available information to
  define entities
• Diagnosis 20 or more blasts in marrow

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Pathogenesis

• 2 co-operating mutations
• Class 1
• Proliferative
• E.g. tyrosine kinase e.g. FLT3 abnormality
• Class 2
• Differentiation block
• Transcription factor

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Acute Myeloid LeukaemiaWHO Classification

• Four distinct subgroups recognised
• AML with recurrent genetic abnormalities
• AML, myelodysplasia related
• AML and myelodysplastic syndromes therapy related
• AML not otherwise categorised

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Example of importance of molecular abnormality in
myeloid leukaemia

• t(1517) Acute Promyelocytic Leukaemia

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Acute Promyelocytic Leukaemia

• AML M3
• Medical emergency due to the high incidence of
  haemorrhagic phenomena
• Abnormal, heavily granulated promyelocytes
  accumulate which have procoagulant activity
• DIC
• Specific therapy

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APL t(1517)
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Normal RARa Activity
HDAC
RARa
RARE
RARa
HDAC
RARE
Transcription of genes required for
differentiation are suppressed
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Normal RARa Activity cont.
RA
HDAC
RARa
RARE
RA
RARa
RARa
HDAC
RARE
RARE
Transcription of genes required for
differentiation can occur.
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In APL

• APL is characterized by t(1517), which produces
  the abnormal fusion gene
• PML-RARa.

RA
RARa
PML
HDAC
RARE
The PML-RARa does not respond normally to
Retinoic Acid exposure (i.e.does not release the
DNA when exposed to Retinoic Acid at
physiological levels). Transcription of genes
required for differentiation is therefore
suppressed.
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Acute Promyelocytic Leukaemia

• Translocation t(1517)
• Chromosome 17 retinoic acid receptor alpha
  (RARa)
• Retinoic acid binds RARa and causes the
  expression of genes essential for differentiation
  of promyelocytes
• In the presence of the translocation t(1517),
  the cells are unresponsive to physiological doses
  of retinoic acid

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Acute Promyelocytic Leukaemia Ctd

• However, high doses of retinoic acid
  (pharmacological doses) cause transcription of
  genes essential for differentiation
• ATRA (all-transretinoic acid) pharmocological
  preparation - causes differentiation of the
  abnormal promyelocytes
• APL first example of clinically successful
  differentiation therapy

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Importance of Molecular Abnormalities in
Leukaemias

• Diagnosis
• CML t(922)
• APL t(1517)
• Prognosis
• ALL with Philadephia chr poor prognosis
• Treatment selection
• STI-571 CML
• ATRA APL
• Bone marrow transplant
• Minimal residual disease

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References

• Evans L et al. Non-Hodgkin Lymphoma. The Lancet
  2003 362139-146
• Jaffe ES et al. Pathology and genetics neoplasms
  of the haemopoietic and lymphoid tissues. In
  Kleihaus P eds. World Health Organization
  classification of tumours. Lyon IARC Press, 2001
• Postgraduate Haematology. Hoffbrand AV, Lewis SM.
  Fourth edition. 1999
• Williams Haematology. Beutler E et al. Sixth
  edition. 2001