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