Acute Lymphoblastic Leukaemia

Terri Boyer17th October 2006

Overview Disease information:

Aetiology of ALL – proposed theory, contributing factors

Symptoms Complications

Diagnostic approaches - morphology and cytogenetics

Treatment regimes Future directions

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).

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

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.

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

Disease Information

Samples of stained bone marrow aspirations showing the heavy infiltration of ALL leukaemic

blasts in the bone marrow

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.

Causative Agents

Congenital and genetic disorders – Down Syndrome

Radiation - nuclear bombings & Chernobyl disaster

Benzene

Possibly Viruses – population mixing

Clinical Presentation

Typcial symptoms include: Fatigue Presence of Petechiae Bone and joint pain Adenopathsy (swollen lymph nodes) Hepatosplenomegaly (enlarged liver and

spleen)

Clinical Presentation

Image showing the presence of Petechiae.

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

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

Diagnosis

Presentation with symptoms Order Complete Blood Count (CBC) If leukocyte count is above 5-103/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

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

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

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

Risk FactorsLow Risk High Risk

Age between 2-10 years old Low leukocyte count on presentation (<5.0 x109/1) L1 subtype of ALL Female (in children)

Age outside of 2-10 years old High leukocyte count on presentation (>200 x109/1) L2 and L3 subtype of ALL Male (in children)

Treatment Strategy

1. Initial stabilisation of the patient by treating the complications of the disease

2. Remission-induction phase3. 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

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

Side Effects of Treatment

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.