Acute Leukaemia

Dr N Holland

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

Incidence

4/100 000 population/year Incidence and type of acute

leukaemia varies with age

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

Types of Acute Leukaemia

Acute Lymphoblastic Leukaemia

Primitive lymphoid neoplasms Immunophenotyping and genetic

techniques of more value in classification than cytochemistry (and morphology)

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

Precursor B cell ALL

Cure rates (disease free survival) >70% in childhood precursor B-cell ALL

However, distinct sub-groups are recognised which are associated with better/worse prognosis

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

Examples of molecular abnormalities in lymphoid leukaemias

t(9;22) – the Philadelphia chromosome

t(9;22)

Philadelphia Chromosome – CML ALL

• Translocation t(9;22)Breakpoint cluster region – chr 22Abelson oncogene – chr 9 (tyrosine kinase)

• Results in the formation of a chimeric fusion gene (bcr:abl) on chromosome 22.

t(9;22)• Translated into an abnormal protein

product • Abl assumes an abnormal cytoplasmic

location• Inappropriately active• Cell can grow and divide

independently of normal growth factors

Poor prognostic factors in ALL

Age WCC Immunophenotype Cytogenetics Hyperploidy Response to induction

chemotherapy

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

Pathogenesis

2 co-operating mutations: Class 1:

Proliferative E.g. tyrosine kinase e.g. FLT3 abnormality

Class 2: Differentiation block Transcription factor

Acute Myeloid Leukaemia:WHO Classification

Four distinct subgroups recognised AML with recurrent genetic

abnormalities AML, myelodysplasia related AML and myelodysplastic syndromes

therapy related AML not otherwise categorised

Example of importance of molecular abnormality in myeloid leukaemia

t(15;17) – Acute Promyelocytic Leukaemia

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

APL t(15;17)

Normal RARa Activity

Transcription of genes required for differentiation are suppressed

Normal RARa Activity cont.

Transcription of genes required for differentiation can occur.

In APL

APL is characterized by t(15;17), which produces the abnormal fusion gene

PML-RARa.

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.

Acute Promyelocytic Leukaemia Translocation t(15;17) Chromosome 17: retinoic acid receptor

alpha (RARα) Retinoic acid binds RARα and causes

the expression of genes essential for differentiation of promyelocytes

In the presence of the translocation t(15;17), the cells are unresponsive to physiological doses of retinoic acid

Acute Promyelocytic Leukaemia C’td 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

Importance of Molecular Abnormalities in Leukaemias

Diagnosis – CML – t(9;22) APL – t(15;17)

Prognosis – ALL with Philadephia chr – poor prognosis

• Treatment selection STI-571 – CML ATRA – APL Bone marrow transplant

• Minimal residual disease

References

Evans L et al. Non-Hodgkin Lymphoma. The Lancet 2003; 362:139-146

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