1 / 32

Acute Leukaemia

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

lok
Download Presentation

Acute Leukaemia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Acute Leukaemia Dr N Holland

  2. 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

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

  4. 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

  5. Types of Acute Leukaemia

  6. Acute Lymphoblastic Leukaemia • Primitive lymphoid neoplasms • Immunophenotyping and genetic techniques of more value in classification than cytochemistry (and morphology)

  7. 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

  8. 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

  9. 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

  10. Examples of molecular abnormalities in lymphoid leukaemias • t(9;22) – the Philadelphia chromosome

  11. t(9;22) • Philadelphia Chromosome – • CML • ALL • Translocation t(9;22) Breakpoint cluster region – chr 22 Abelson oncogene – chr 9 (tyrosine kinase) • Results in the formation of a chimeric fusion gene (bcr:abl) on chromosome 22.

  12. 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

  13. Poor prognostic factors in ALL • Age • WCC • Immunophenotype • Cytogenetics • Hyperploidy • Response to induction chemotherapy

  14. 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

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

  16. 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

  17. Example of importance of molecular abnormality in myeloid leukaemia • t(15;17) – Acute Promyelocytic Leukaemia

  18. 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

  19. APL t(15;17)

  20. Normal RARa Activity HDAC RARa RARE RARa HDAC RARE Transcription of genes required for differentiation are suppressed

  21. Normal RARa Activity cont. RA HDAC RARa RARE RA RARa RARa HDAC RARE RARE Transcription of genes required for differentiation can occur.

  22. In APL • APL is characterized by t(15;17), 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.

  23. 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

  24. 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

  25. 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

  26. 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 IARCPress, 2001 • Postgraduate Haematology. Hoffbrand AV, Lewis SM. Fourth edition. 1999 • Williams Haematology. Beutler E et al. Sixth edition. 2001

More Related