1. Acute Lymphoblastic Leukaemia Terri Boyer 17 th October 2006

2. Overview Disease information:  Aetiology of ALL – proposed theory, contributing factors  Symptoms  Complications Diagnostic approaches - morphology and cytogenetics Treatment regimes Future directions

3. Acute Lymphoblastic Leukaemia Is the: “neoplastic proliferation of a clone of myeloid or lymphoid cells characterised by uncoupling proliferation and maturation” (Bain, Clark and Lampert, 1996, 88).

4. Disease Information Over several subtypes of ALL –  myeloid v lymphoid  chronic v acute 300 each year are diagnosed with ALL 60% of cases are in children 0-14yrs

5. Clinical features of leukaemic cells Monoclonal origin - derived from a single clone Acquired gene mutation Deregulation or uncoupling of critical cellular functions – proliferation, differentiation and apoptosis Leukaemic cells are more robust and survive condition other cells do not, such as stress and growth factor deprivation which forces other cells to go into apoptosis.

6. Disease Information >90% of lymphoid cells present in the bone marrow  normal bone marrow has only 10% Proliferation of immature lymphoid blasts:  Crowd the bone marrow - markedly hyper cellular  Blasts do not function normally

7. Disease Information Samples of stained bone marrow aspirations showing the heavy infiltration of ALL leukaemic blasts in the bone marrow

8. Etiology Precise etiology is unknown Research indicates assault to the immune system occurs in utero – causing a chromosomal translocation. Proto-oncogenes – code proteins that regulate cell signal transduction, gene transcription, cell cycle etc. Anti-oncogenes – vital to suppress tumour growth are suppressed.

9. Causative Agents Congenital and genetic disorders – Down Syndrome Radiation - nuclear bombings & Chernobyl disaster Benzene Possibly Viruses – population mixing

10. Clinical Presentation Typcial symptoms include:  Fatigue  Presence of Petechiae  Bone and joint pain  Adenopathsy (swollen lymph nodes)  Hepatosplenomegaly (enlarged liver and spleen)

11. Clinical Presentation Image showing the presence of Petechiae.

12. Clinical Presentation  Repeated fevers/infections  Abnormal bleeding or bruising easily  Swelling or discomfort in the abdomen  Listlessness or breathlessness  Severe joint pain and in some cases spinal cord compression.  Pallor  Weight loss/lack of appetite

13. Disease Information Failure of normal haematopoiesis most serious consequence. Complications:  Anaemia – reduced erythrocyte numbers  Thrombocytopenia – reduced platelet numbers  Patients are immunocompromised – immature lymphoid blasts cannot function  Infiltration of organs – accumulation of leukocytes in liver, spleen, lymph nodes, abdomen

14. Diagnosis Presentation with symptoms Order Complete Blood Count (CBC) If leukocyte count is above 5-10 3 /ul in adults and 5.0-20 for children Bone marrow aspiration - >30% blasts present in bone marrow will result in definitive diagnosis of Acute Leukaemia Samples stained to sub classify ALL

15. ALL Subtypes L1 ALL:  Blasts are small and relatively uniform  Round nucleus and regular cellular outline  Nucleoli are absent or inconspicuous and the nuclear- cytoplasmic ratio is high, chromatin pattern is fairly homogenous L2 ALL:  Lower nuclear cytoplasmic ratio typically with prominent nucleoli  Macroblasts sometimes two and a half times larger are identifiable L3 ALL:  Large, relatively round cells  Nuclei finely dispersed  Cytoplasm is strongly basophilic, contains prominent vacuoles

16. L1-ALL: Complete replacement by small/medium sized blasts with scanty cytoplasm and round nuclei with dense chromatin. L2-ALL: Pleiomorphic blasts with variable amounts of cytoplasm, twisted irregular nuclei and multiple indistinct nucleoli. ALL-L3: Large lymphoid blasts of with high nuclear to cytoplasmic ratio, dark- blue cytoplasm, and small lipid-containing vacuoles in the cytoplasm and over the nucleus. ALL-L3 are high grade B cell malignancies. FAB Classification of ALL

17. Alternate Diagnostic Methods Labelled probes – labelled proteins bind to the surface of cancerous leukaemia cells Microarrays:  Advance molecular understanding of ALL  Advanced knowledge base of the mechanisms of sensitivity and resistance to chemotherapy

18. Risk Factors Low RiskHigh Risk Age between 2-10 years old Low leukocyte count on presentation (<5.0 x10 9 /1) L1 subtype of ALL Female (in children) Age outside of 2-10 years old High leukocyte count on presentation (>200 x10 9 /1) L2 and L3 subtype of ALL Male (in children)

19. Treatment Strategy 1. Initial stabilisation of the patient by treating the complications of the disease 2. Remission-induction phase 3. Intensification (consolidation) treatment 4. Prolonged continuation (maintenance ) therapy Treatment typically lasts for a period of 3 years Children between 1-10 respond better then adults and infants

20. Side Effects of Treatment Low blood counts Anaemia Neutropenia Thrombocytopenia Fatigue Infection/Fever Mouth Sores Nausea and Vomiting Hair Loss Pain Depression Reproductive/Sexuality difficulties

21. Side Effects of Treatment

22. Future Directions Research needs to identify the exact causative agent/s triggering the onset of ALL. Development of less toxic and more effective drugs are needed to reduce toxicity, latent complications and improve patients quality of life during treatment. Research identifying why children respond better to treatment would also be beneficial.