Leukaemia + Lymphoid Malignancies Flashcards
Define leukaemia (1)
Groups of diseases characterised by overproduction of WBCs or their precursors
What is the clinical presentation of leukaemia? (5)
Varies b/w type Symptoms due to loss of normal blood cell production - abnormal bruising (platelet) - repeated or abnormal infection (WBC) - anaemia (RBC)
How do we classify leukaemias? (4)
Acute vs chronic
Lymphoid vs myeloid
What does lymphoid refer to? (2)
Involves cells of lymphocyte lineages
Mainly B-cell, more rarely T-cell
What does myeloid refer to? (3)
Involves cells of non-lymphocyte lineages
Common neutrophils/their precursors
(Can be erythroid, platelet, basophil lineages etc.)
What are acute leukaemias? (3)
Undifferentiated leukaemias
Characterised by immature WBCs (blast cells)
e.g. AML, ALL
What are chronic leukaemias? (2)
Differentiated leukaemias
Characterised by mature WBCs
4 types of leukaemia (4)
Acute lymphoblastic leukaemia (ALL)
Chronic lymphocytic leukaemia (CLL)
Acute myeloblastic leukaemia
Chronic granulocytic leukaemia
What genes are linked to leukaemia? (4)
Oncogene activation
Tumour suppressor gene inactivation
Some are specific to leukaemias
May involve genes similar to other malignancies e.g. RAS, MYC, P53
Chromosomal translocations + leukaemia (3)
To generate novel hybrid oncogenes
BCR-ABL (CML)
PML-RARA in AML type M4
What numerical chromosome changes can you get? (2)
Monosomy
Trisomy
How is leukaemia a clonal disease? (1)
All malignant cells are derived from a single mutant SC
What are the risk factors of leukaemia? (6)
RADIATION
- acute radiation accidents
- atomic bomb survivors
CHEMICALS
- industrial exposure to benzene
CHEMO
- alkylating agens e.g. Busulphan generates future risk of leukaemia
VIRUSES
- HTLV-1 predisposes to adult T-cell leukaemia
GENETIC (rare - some cases of CLL run in families, Down’s syndrome + Fanconi’s anaemia may predispose to leukaemia)
AGE
(Most not associated with any identifiable precipitating cause)
How do we treat leukaemia? (3)
Chemo with cytotoxic drugs
SC + BM transplant
Disease specific agents e.g. oncogene targeted drugs
What is chemotherapy? (3)
Combo of drugs used to kill leukaemic cells
Optimised for type + subtype of leukaemia
Cytotoxic drugs mostly target dividing cells
Examples of chemo drugs (7)
Cytosine arabinoside - cytosine analogue - interferes with deoxynucleotide synthesis - prevents successful DNA replication
Vincristine
- binds to tubulin dimers -> inhibits microtubule formation
- so blocking mitotic spindle
Side effects of chemo (4)
Kills normally dividing cells GI epithelium - diarrhoea + nausea Hair follicles - hair loss Loss of fertility Bone marrow suppression
What is SCBMT? (4)
Stem cell + bone marrow transplant
Intense chemo + total body irradiation
Wipes out leukaemic cells + normal SCs
Reconstitute bone marrow by transplanted SCs
What problems are there with SCBMT? (2)
Shortage of HLA matched donors
High mortality of procedure for old/v sick patients
What are symptoms of acute leukaemias? (3)
Thrombocytopenia (purpura, epistaxis = nosebleed, bleeding from gums)
Neutopenia (recurrent infections e.g. oral thrush)
Anaemia (weakness, shortness of breath)
How do we diagnose acute leukaemia? (2)
Presence of blasts or cytopenia in peripheral blood
Bone marrow aspirate >30% blasts = diagnostic
Pathophysiology of acute leukaemia (3)
Maturation arrest - all immature, at exactly same stage
Auer rods
If cells are blocked from maturing the blast cell pool builds up
What sorts of genes are involved in many chr translocations in acute leukaemias? (2)
Genes for TFs
Which control cell differentiation
What can the type of chr abnormality help with acute leukaemia diagnosis? (2)
Determining prognosis + response to treatent
How are acute leukaemias classified? (5)
FAB classification
- based on stage of differentiation arrest
- predominant cell type
- also some rare ones that don’t fit main classifications
WHO
- acute leukaemias with specific chr translocations are classified separately
How do we treat acute leukaemia? (4)
Chemo
Combo of drugs
Optimised for each type + sub-type of acute leukaemia
ALL (add chemo/radiotherapy to CNS)
What are the two phases of chemo in acute leukaemia? (2)
1 = remission induction 2 = consolidation therapy (to kill residual leukaemic SCs)
What are the outcomes of ALL? (4)
Kids > 90% LT remission/cure Adults have poorer prognosis: - diff oncogens mutations - diff cells of origin - poorer tolerance to therapy
What are the outcomes of AML? (2)
> 80% LT remission in young adults with aggressive treatment
Elderly unable to tolerate aggressive chemo/SCBMT
What are CLLs called + why? (2)
Chronic lymphocytic leukaemia
As large number of mature (clonal) lymphocytes in BM/peripheral blood
Symptoms of CLL (5)
Recurrent infections (due to neutropenia + suppression of normal lymphocyte function) Anaemia Thrombocytopenia Lymph node enlargement Hepatosplenomegaly
How do we treat CLL? (1)
Controlled by regular chemo to reduce cell numbers
Prognosis of CLL? (2)
Some may die in
What are the symptoms of CML? (3)
Anaemia
Night fever/night sweats
Splenomegaly
(Infection is not symptoms as lots of neutrophils)
How do we diagnose CML? (4)
Neutrophilia (v high WBC count)
Left shit in blood + bone marrow
Presence of Philadelphia chr (95%)
BCR-ABL gene arrangment
How do we treat CML? (3)
Controlled but not cured by chemo
Not cytotoxic drugs/interferon alpha
But imatinib
Prognosis of CML? (3)
Survival on treatment usually measure in yrs
But eventually progresses to accelerated phase + then blast crisis (resembles acute leukaemia)
How do we treat CML? (3)
Allogenic BM or SC transplant is curative
Autologous transplant sometimes tried
Most patients are >50yrs + do not tolerate transplant
What is the Philadelphia chr?
come back to this
What drugs specifically inhibits BCR-ABL? ()
Imatinib
Specific tyrosine kinase inhibitor
Inhibits BCR-ABL but notn most other tyrosine kinases
Causes apoptosis of CML cells
How is Imatinib compared to previous treatments for CML? (4)
Induces remission in more patients
With greater durability
Less SEs
But some patients become drug resistant
