Haem: Leukaemia Flashcards
Define Acute Leukaemia
Neoplastic process affecting blood precursor cells (blast cells)
“Acute”: progressing rapidly, resulting in excess immature blood cells, and fatal
Pathoneumonic sign of Acute leukaemia when analysing bone marrow
Immature blast cells >20% of bone marrow cells
2 types of acute leukaemia
Acute Lymphocytic Leukaemia
Mutations in lymphoblast cell
Acute Myeloid Leukaemia
Mutations in the pluripotent haematopoetic stem cell OR multipotent myeloid stem cell
Clinical features seen in all types of Acute leukaemia
Bone Marrow Failure
- Anaemia (signs/sx of anaemia)
- Infection (neutropenia)
- Bleeding (thrombocytopenia)
Organ Infiltration of blast cells
- Hepatosplenomegaly
- Lymphadenopathy (ALL>AML)
- Others: Bone (ALL>AML), CNS (ALL>AML), Skin, Gums
Aetiology of Acute Leukaemias
Most times it is unknown however chromosome aberrations are commonly implicated:
- Duplication → resulting in increased copies of proto-oncogenes
- Inversion/Translocation → resutling in fusion genes which are pro-oncogenic
- Chromosomal loss → loss of tumour suppressor genes
Other commonly implicated aetiological factors:
- Ionising radiation (leading to DNA mutations)
- Cytotoxic drugs (leading to DNA mutations)
- Down’s Syndrome (AML>ALL)
2 Types of DNA abnormalities required for leukaemogenesis
Type 1: Promote cell proliferation
Type 2: Block cell differentiation
How do you diagnose Acute leukaemia
- Morphology of cells: increased blast cells, Auer rodes (AML!!)
- Immunophenotyping: differentiates between AML and ALL through CD receptors as well as ALL B-cell or T-cell predominent
- Cytogenics: identify chromosomal translocations for specific targetted treatment (e.g. Philadelphia chromosome in ALL)
Differentiating between ALL and AML:
Epidemiology
Differentiating between ALL and AML:
Clinical Features
Differentiating between ALL and AML:
Investigations
Differentiating between ALL and AML:
Management
Chronic Myeloid Leukaemia
Define and outline which cell carries leukaemogenic mutation
Myeloproliferative disease - with mutations in haematopoetic stem cell. Haematopoetic stem cell mutations (commonly the philadelphia chromosome) steer it into going down the myeloid differentiation pathway.
Unlike acute leukaemia, in chronic leukaemia you have partial maturation.
Chronic Myeloid Leukaemia
Age of onset
Middle-aged → 40-60s
Chronic Myeloid Leukaemia
Clinical feature
CLASSIC CLINICAL VIGNETTE:
Present feeling unwell, weight loss, recurrent infections and easy bruising.
On examination → MASSIVE splenomegaly (EXAM BUZZWORD)
Bloods → neutrophilia!!
Chronic Myeloid Leukaemia
Investigations when suspecting CML
FBC:
- Massively elevated WBC (50-500x109)
- Neutrophilia
- Basophilia
Blood film:
- Neutrophilia
- Basophilia
- Myelocytes (if you see myeloblasts you are thinking more acute CML)
→ biphasic peak where there is increased myelocytes and basophils/neutrophils
Bone Marrow Biopsy
- hypercellular BM with myelocytes (NOT myeloblasts) and mature granulocytic cells.
- myelobasts at <5% (unless in acute crisis)
FISH
- Philadelphia chromosome +ve in 80% of cases (translocation 9;22)
RQ-PCR
- BCR-ABL fusion gene (arising from the philadelphia chromosome)
Chronic Myeloid Leukaemia
Explain how the philadelphia chromosome contributes to the pathogenesis of CML
The philadelphia chromosome arises from the translocation between chromosomes 9 and 22.
This translocation creates a fusion gene: BCR-ABL
- ABL codes for a tyrosine kinase. TK’s are crucial for cell growth and division and therefore are not always expressed.
- BCR is a housekeeping gene. It is always being expressed.
→ This fusion gene, where BCR is first results in the constant expression of ABL.
→ Therefore resulting in increased TK activity resulting in increased cellular proliferation = leukaemia.
It is also thought that BCR-ABL expression in haematopoetic stem cells, steers them towards the myeloid lineage.
Chronic Myeloid Leukaemia
Outline the different stages of CML and how they are distinguished
Chronic Myeloid Leukaemia
How is CML treatment response monitored
Chronic Myeloid Leukaemia
Outline the treatment regime for CML (in chronic phase, Ph +ve)
TYROSINE KINASE INHIBITORS:
1. Imatinib
2. Rasatinib
3. Bosutinib
Failure of response in 12 months OR complete response but resistance acquired (escape mutations) you move to next generation of tyroskine kinase inhibitors. If all 3 fail consider allogenic stem cell transplant.
Chronic Myeloid Leukaemia
Outline the benefits of Tyrosine kinase inhibitor therapy
- Decreased in mortality (annual mortality 2%)
- 95% 5 year survival
Chronic Lymphocytic Leukaemia
Definition and which cell is targeted
Lymphoproliferative disease (similiar to lymphoma)
Arising from mutations in naive B cells or Post-germinal centre memory B cells where there is intereference of B cell receptors activating specific tyrosine kinases (e.g. Bruton’s TK preventing maturation, and BCL2 which prevent apoptosis)
Chronic Lymphocytic Leukaemia
Distinguish CLL and Small Lymphocytic Lymphoma (SLL)
Essentially same disease with slightly different presentations.
CLL is primarily seen in bone marrow while SLL is primarily seen in clusters of B-cell malignant cells in lymph nodes (thought to be the case in mature CLL)
Chronic Lymphocytic Leukaemia
Epidemiology
M>F
Elderly (median 65-70)
Chronic Lymphocytic Leukaemia
Clinical features
Often asymptomatic and incidental finding in blood result = lymphocytosis (commonest cause of lymphocytosis!!!!!)
May also present with
- Symmetrical painless lymphadenopathy
- BM failure: anaemia, thrombocytopaenia, recurrent infections (infections account for 50% of deaths in CLL)
- B-cell systemic symptoms: FLAWS
- Hepatosplenomegaly
Chronic Lymphocytic Leukaemia
A sudden deterioration in CLL can be explained by?
Richter’s transformation - whereby CLL transforms into a more aggressive large cell lymphoma (Diffuse large B-cell lymphoma).
This can be accounted for by subsequent mutation resulting in this transformation.
Chronic Lymphocytic Leukaemia
What syndrome is CLL associated with?
Evan’s Syndrome - associated with autoimmunity involving two or more cytopaenias (AIHA, ITP)
Chronic Lymphocytic Leukaemia
Investigation findings
FBC
- Elevated WBC count (high % of WBC composed of lymphocytes)
- Low serum immunoglobulin
Blood film
- Smear cells
Flow Cytometry
- CD5+ , CD19+ and CD23+ monoclonal B cell population
Chronic Lymphocytic Leukaemia
Differentiate the monoclonal population in a healthy patient and a patient with CLL
Healthy patients’ mature B-cells: CD19 +ve but CD5 -ve
Healthy patients’ mature T-cells: CD19 -ve but CD5 +ve
CLL patients monoloclonal population: CD19 +ve and CD5 +ve
Chronic Lymphocytic Leukaemia
Outline the staging used in CLL
Binet Staging: A,B,C
Stage A:
- High WBC
- <3 groups of enlarged lymph nodes
- Usually no treatment required - watchful waiting
Stage B:
- >3 groups of enlarged lymph nodes
Stage C:
Anaemia or thrombocytopaenia (bone marrow failure)
Chronic Lymphocytic Leukaemia
Prognostic factors used in CLL
Cytogenics - looking for a collection of common genetic abnormalities screened for that convey worse prognosis:
- 17p (TP53) deletion → worse prognosis as it is deletion of p53 tumour suppressor gene
Immunoglobulin gene mutation status:
- IgH unmutated → worse prognosis
Binet staging can be used for prognosis as well
Chronic Lymphocytic Leukaemia
Treatment
Asymptomatic, Slowly progressive disease, Elderly and frail:
1. Watchful waiting
1. Supportive treatment: vaccinations (not live), prophylaxis of antivirals or antibiotics
young patients can be cured with allogenic stem cell transplant
If any of the below → Indication for chemotherapy
- Progressive lymphocytosis (doubling <6months)
- Progressive BM failure
- Massive/progressive hepatosplenomeagly
- Systemic sx
TREATMENT:
1) chemotherapy - FCR
OR - increasingly more so:
1) Targeted therapy = BTK inhibitor (ibrutinib - inhibits B cell production) or BCL2 inhibitor (venetoclax - induces apoptotic pathway and good response in p53 mutated CLL patients)
Important complication of using venetoclax therapy in CLL
tumour lysis syndrome
