Lecture 7 - Leukaemias Flashcards
What are leukaemias and what are some simmilar diseases.
Leukaemias are cancers of the blood - they are a group of closely related malignant conditions affecting the immature blood-forming cells in the bone marrow
Lymphoma is cancer of the lymphatic tissues
Multiple myeloma is cancer that affects plasma B cells
Myelodysplastic syndromes are a group of disease in which the production of blood cells is severely disrupted
Myeloproliferative disorders are a group of conditions in which there is an overproduction of one or more type of blood cell.
List the symptoms of leukaemia.
- Anaemia - Fatigue, breathlessness, paleness
- Thrombocytopenia (low platelets) - excessive bruising, bleeding from mucus membranes and gut, heavy menstrual bleeding (lack of clotting).
- Low white cells (can be high in some stages)
- Persistent infections
- Fevers
- Night sweats
- Abdominal discomfort - swelling of the spleen and liver
Can get low neutrophil count
What are some causes of leukaemia.
Causes of leukaemia
* Majority have no familial pattern
* Childhood leukaemia linked to smoking/drinking in mothers
* Age - increased risk with ageing, except for ALL
* Specific formed linked to some viruses (E.g. EBV, HBV, HIV)
* Chemical (AML and smoking)
* Radiation
* Secondary Leukaemia - cytotoxic chemotherapy
The instance of leukaemia since 1991
Incidence of all Leukaemias (for females and males combined) increased by 13% in the UK between 1993-95 and 2016-2018
How is leukaemia diagnosed.
- Blood counts
- Blood smear - segmented neutrophils, high levels of blast cells.
- Bone marrow aspirate/biopsy
- Chromosome analysis - Karyotype/cytogenic
- Diagnostic imaging (bone marrow)
How are leukaemias classified?
French-American British classification systems (FAB)
Series of classifications of haematologic diseases based on:
* Presence of dysmyelopoiesis
Presence of cytopenia’s in the blood and dysplastic cells in one hematologic cell lines in the blood or bone marrow
* Quantification of myeloblasts and erythroblasts
What are the types of leukaemia?
Types of leukaemia
* Chronic
○ Less aggressive
○ Generally due to overproduction of mature cells
○ Can progress to an acute form
* Acute
○ Aggressive
○ Generally due to blockage in differentiation
○ Lack of mature cell production - blast immature cells released into blood
○ Cells overwhelm system - anaemia as cant hold enough RBCs as too many WBCs
Lymphoid and myeloid types
All associated with aging except ALL
What is myeloid stem cell differentiation?
Cells produced in bone marrow
Pluripotent cell can mature into Myeloid (RBCs and granular leukocytes and Monocyte) or lymphoid stem cells (T-cell, B-cell and natural killer cell)
Discuss Acute Lymphoblastic leukaemia.
Acute lymphoblastic Leukaemia (ALL)
* Neoplasm of precursor B or T lymphoid cells (lymphocytes)
* Cancer of childhood, peak incidence 1-4 years
* Possible risk factors
○ Ionising radiation
○ Pesticide exposure
○ Genetic conditions - down’s syndrome, ataxia telangiectasia
○ Weakened immune system
* 90% cure rates in children
* FAB classification L1-L3
* Blood film - Lymphocytes are immature, large nucleus and little cytoplasm
Discuss Acute Myeloid Leukaemia
- Neoplasm of myeloid stem cells or myeloid blasts
- Most common acute leukaemia in adults
- 30% cure rates only in those suitable for high does induction chemotherapy
- Palliate in majority of elderly cases
- Heterogenous group> FAB classification M0-M7
- Cytogenetic classification e.g. (8:21), (15:17) - acquired cytogenic abnormalities
- Blood smear
○ Very large immature myeloblast with many nucleoli
○ Distinguished by linear “Auer rod” composed of crystallised granules
Describe Acute promyelocytic leukamia
Acute Promyelocytic leukaemia (related to AML)
* FAB classification M3 - hyper-granular, promyelocytic
* Release cytokines that interfere with coagulation cascade - severe bleeding DIC
* Cytogenic classification 15;17 - translocation between chromosomes 15 and 17
* Coagulation problems
* 90% cure rates
* Treatment: All-Trans Retinoic Acid (ATRA) and Arsenic Trioxide
Discuss chronic lymphocytic leukaemia.
- Lymphoproliferative disorder of B lymphocytes (to many in blood)
- Small lymphocytic Lymphoma same disorder but predominantly affects lymph glands
- Majority of cases are characterised by asymptomatic lymphocytosis - don’t know until CBC
- Most common leukaemia in adults
- Symptoms:
○ Lymphadenopathy: swollen lymph nodes
○ Organomegaly: enlarged organs
○ Marrow failure
○ Autoimmune disease - Indolent (slow) course - watch and wait
- Blood film - Marked increase in B cell lymphocytes
- Diagnosis -
○ Immunophenotype (by flow cytometry) - B cell antigens
○ Cytogenic - poor prognosis in individuals with deletions in 17p (p53 gene) and 11q21 - Treatment is to administer drugs that will act on B-cell receptors to repress production of the B-cell
Discuss the staging systems for CLL.
Binet & Rai staging system for CLL
Binet:
Stage A - Lymphadenopathy (enlarged lymph nodes)
Stage B - Lymphadenopathy >3 groups
Stage C - Anaemia and thrombocytopenia
Rai :
Stage 0 - Lymphocytosis only (high number of lymphocytes)
Stage 1 - Lymphocytosis and lymphadenopathy
Stage 2 - Lymphocytosis and enlarged liver or spleen
Stage 3 - Lymphocytosis and anaemia
Stage 4 - Lymphocytosis and thrombocytopenia
What is Chronic Myeloid leukaemia
- Over proliferation of cells committed to the myeloid lineage
- Can be in chronic phase, accelerated phase or blast phase (develop into AML or ALL or both)
- Treatment: tyrosine kinase inhibitors (e.g. imatinib)
- Blood film
○ Numerous granulocytic cells, including immature myeloid cells and band cells (immature neutrophils)
○ Commonly the numbers of basophils and eosinophils, as well as bands and more immature myeloid cells (metamyelocytes and myelocytes are increased
○ Not as many blast cells as in AML - Cytogenic - first human cancer to be associated with consistent chromosomal abnormality - Philadelphia chromosome t(9;22) in >95% of cases
How is leukaemia treated?
Treatment of leukaemia
* Chemotherapy - use of cytotoxic drugs
* Radiotherapy (only with transplantation): use of high energy rays
* Stem cell transplantation - bone marrow transplant
Cytotoxic chemotherapy
* Anti-metabolites - inhibit DNA synthesis
○ Methotrexate - inhibits folic acid metabolism
○ Cytosine arabinoside - inhibits DNA polymerase
* DNA binding - induce DNA damage
○ Daunorubicin - intercalates between base pairs to uncoil helix
* Mitotic inhibitors
○ Vincristine - inhibits tubulin polymerisation and block chromosome separation
○ Vinblastine - Binds to microtubules and prevents purine synthesis
* Others
○ Corticosteroids - directly target leukaemia cells, boost effectiveness of other drugs, reduce side effects of chemotherapy
Trans-retinoic acid - degradation of PML-RAR alpha protein and conversion to transcription activator
