B14 - Chronic Leukaemia Flashcards
chronic leukaemia
Clonal defect may be early but cell still has capacity to generate end stage cells
‘acute’ means patients would die quickly without treatment, chronic means they can live with their disease - ‘acute’ is only in relation to having no treatment
Chronic cells look like end stage blood cells, very few of them are curable
Acute is better defined as an ealry progenitor
Chronic - cells can differentiate and look like end stage blood cells
types of chronic lymphoid leukaemia
- malignant proliferation of what looks like mature myeloid or mature lymphoid cells even though the defect may have occurred early in cell development
- Types
○ Chronic myeloid leukaemia
○ chronic lymphocytic leukaemia - Subtypes
○ Myeloproliferative neoplasms
○ Hairy cell leukaemia B
○ B-prolymphocytic leukaemia
○ T-prolymphocytic leukaemia
Chronic lymphocytic leukaemia (CLL)
- 7/100 000 (commonest blood cancer in the western world)
- Uncommon in Asian communities
- Disease of the elderly >60 years (3% population)
- Some blood donors have sub clinical chronic lymphocytic leukaemia, can be detected but the patient has no symptoms
- 1400 new cases per annum in Australia
- Slight male predominance
- Neoplastic proliferation of mature B lymphocytic cells
CLL presentation
- Presentation
○ Lymphadenopathy (enlarged lymph nodes, because lymphocytes are made in bone marrow and will circulate in the blood - lymph nodes are primary lymphoid tissue)
○ Lymph node involvement
○ Recurrent infections due to supressed immune system, low immunoglobulin and reduced cellular immunity
CLL typical age
- Age: adults, elderly
CLL B cell levels
- > 5x10^9 monoclonal B cells in PB
○ Diagnosed when total count of B cells with particular phenotyping of CLL characteristics exceed these values
○ Normal B-lymphocyte count is 1x10^9
○ Diagnosed when there is 5x upper end of the reference range
CLL morphology
○ Small, mature lymphocytosis with smear cells (broken in the process of making the blood film)
○ Minimal cytoplasm
○ Nucleus has condensed clumped darkly stained chromatin
CLL clinical features
○ Symptoms
§ Anaemia, neutropenia, thrombocytopenia, lymphocytosis, lethargy
§ Infections, fevers, bleeding, bruising, fevers, night sweats, weight loss (bone marrow compromise)
§ May be asymptomatic
○ Signs
§ Enlarged liver and spleen (hepatomegaly and splenomegaly)
§ Enlarged lymph nodes (lymphadenopathy)
§ May affect tonsils, salivary glands
CLL blood count
○ >5x10^9/L cells for at least 3 months
○ Majority of patients have had a blood count for some other reason and it happens to be detected
CLL morphology
○ Small, mature lymphocytosis with smear cells
○ Minimal cytoplasm: condensed chromatin
CLL - B-cell phenotype/antigenic profile:
○ CD19 (B cell marker)
○ CD23 (most B cells do not express, but CLL are generally CD23 positive)
○ CD79a (B cell marker)
○ CD5 (T-cell associated antigen that is expressed in malignant b cells in chronic lymphocytic leukaemia for some reason)
○ kappa or lambda light chain restriction (light chains of immunoglobulin molecule - because they are clonal, they will express one or the other - either all kappa or all lambda) - can be determined to be leukaemic if they all have the same one
CLL - Flow cytometry/immunophenotyping
○ B-lymphocytes: CD19, CD20w (b cell antigen), CD23, CD79a, CD200 (b cell associated marker), kappa or lambda light chain
○ Aberrant expression of CD5 (a t cell antigen)
§ CD5 and CD23 is leukaemic
CLL - Cytogenetic studies
○ Good prognosis: trisomy 12, del 13q
○ Poor prognosis: del(11q), del(17p)
○ FISH: spots of chromosome 12
- FISH for +12 in CLL
○ Using probes for chromosomal regions and looking at them within the nucleous of cells
○ Immuno-flowFISH: WA invention to detect chromosome abnormalities in immunophenotyped CLL cells using flow cytometry
○ ○ Left: trisomy 12 - three pink spots ○ Right: P53 (tumour suppressor gene) deletion in some cells on the short arm of chromosome 17 ○ Blue colour indicates the nucleus ○ Fluorescent In-Situ Hybridisation § Hybridise a probe bought from a manufacturer with the cells ○ Invention at UWA § Combining immunophenotyping of cells and fish test in one test § Analyse 100 000 cells instead of just 100 § Much more sensitive § Gives prognostic information - tells what treatment is needed
- CLL for del(17p)
○ TP53/del17p deletions or mutations and prognosis
○ A different disease
○ Short survival
○ Different treatment
○ FISH sensitivity: 5-7% del (17p)
§ 7% of the cells have to have the abnormality
○ Antigens: CD3, CD5 (marker of CLL), CD19, FISH: CEP17, 17p12
○ Need specialised therapy
CLL - Indications for treatment
○ Symptoms of CLL
○ Cytopenia(s): anaemia, thrombocytopenia
○ Treatment might not be needed at diagnosis ‘watch and wait’
○ ‘Doubling time’ - how many months/weeks it takes for the leukaemic cell count to double
○ If patient is symptomatic and doubling time is fast treatment is needed
CLL treatment
○ Determined by genetics eg. 17p treatment needs to be different
○ Multi-agent chemotherapy - similar to the acute leukaemias
○ Anti-CD20 antibody (eg. Rituximab antibody based therapy which latch onto CD20 molecule on the cell) - targeted treatment
○ Small molecules inhibitors (eg. Venetoclax - BCL2 inhibitor increasingly being used )
○ Treatment protocols based on patient fitness
chronic myeloid disorders
- Phases
○ Chronic phase - most patients present with this
○ Accelerated phase
○ Blast phase (transformation) - acute leukaemic phase
CML or CLL more common
CLL
CML affects
- Disease of middle age 30-60 years
- Slight male predominance
CML presentation
- Leucocytosis: neutrophilia and increased neutrophil precursors (normally seen in bone marrow
- Blast cells (<5%), eosinophils 7 basophils in blood - primary a neutrophilia with some precursors normally seen in the bone marrow present in the blood
- Too many basophils not working properly with abnormal granules
- Massive splenic enlargement - fullness in abdomen
- Incidental finding when patients have a blood count - usually symptomatic of anaemia, bleeding, recurrent infections
- Very high white cell count
Philidelphia chromosome
- T(9;22) Ph (shortened for Philadelphia)chromosome - generates a small defective 22 chromosome
BCR/ABL translocation
creates a fusion gene with abnormal function - can be targeted with therapies - functions as a tyrosine kinase - results in over-proliferation of granulocytic cells
phases of CML
- Chronic phase (1-10 yrs) <5% blast cells
- Accelerated phase - more aggressive
- ‘blast’ phase: acute leukaemic phase - acute leukaemia
symptoms of CML
- Asymptomatic - incidental on routine blood test
- leucocytosis, thrombocytosis, abdominal ‘fullness’, fatigue, malaise, bleeding, bruising, spleen enlarged
blood film of CML
- Neutrophilia
- Eosinophilia
- Monocytosis
- Basophilia (hypogranular)
- Myeloid cells at various maturation stage (L shift)
- Blast cells: number determines disease phase - more than 5% means patient is in the accelerated phase, blast phase if 20% or more
cytogenic studies of CML
- T(9,22) Philadelphia chromosome abbreviated to PH
○ Longer chromosome 9
○ Shorter chromosome 22 - Philadelphia chromosome
○ Fusion gene - functions as a tyrosine kinase
treatment of CML
- Treatment - tyrosine kinase inhibitors - targets abnormal fusion gene product
○ Imatinib
○ Dasatinib
○ Nilotinib
○ Ponatinib
llogenic stem cell transplant- Pre-TKI 5-year survival rate 45%
- Post-TKI 5-year survival rate 90%
- Treatment free remission - having treatment stopped
○ This may be sustained and life long, we do not know whether they are ‘cured’
○ Some patients present with acute leukaemia and then the philidelphia chromosome is found, showing they may have had CML and it has progressed to the acute phase
