Acute Leukaemia Flashcards
Acute Leukaemia
Lymphoid or Myeloid
-Often aggressive diseases assoviated with immature blast cells and marrow failure
- can progress rapidly and fatally without treatment
- Arise from malignant transformation of a haemapoietic stem cell/ progenitor cell
- Defined by presence of > 20% blasts in blood or bone marrow
- Diagnosis of actue leukaemia is given if there is less than 20% but specific cytogenetic/molecular abnormalities
AML (Acute Myeloid Leukemia ) or ALL (Acute Lymphoblastic/lymphoid leukemia) - differential diagnosis
- Blood count and morphology from initial diagnostic procedure; ALL often shows no differential , AML may show differentiation e.g promyelocytes, monocytes and Auer rods: diagnostic.
- Definitive diagnosis made from immunophenotyping and molecular
- Cytochemistry e.g myeloperoxidase, sudan black, non-specific esterases.
Immunophenotyping AML
Stem Cells: HLA- DR, CD34
TdT::: T-ALL: cCD3, CD7, CD2 and Precursor B-ALL: cCD22, CD19, CD10
AML: CD13, CD33, CD117
Classification systems
French American British (FAB)
World Health Organisation (WHO)
WHO Classification
Takes into account: Genetic, immunophenotypic, biological and clinical features
-Subcategories have predictable clinical outcome
- 20% blasts
Acute Lymphoblastic Leukaemia - Clinical Characteristics/ incidence
- Characterised by proliferation of lymphoblasts in the bone marrow
- Most common childhood Leukaemias: Incidence peaks about 3-7 years then declines and rises again after 40 years.
- Precursor B-ALL (CD10) is the most common
- Various pathogenic mechanisms implicated: may be in utero or postnatal initiating event followed by secondary trigger e.g infection
Pathogenesis of ALL
- Genetic lesions are central to development.
- Dysregulation of genes encoding transcription factors and thus regulation of haemopoiesis play a role.
Examples: - Germline polymorphisms in a group of genes involved in B cell development e.g. IKZF1 are more frequent in B-ALL.
- BCR-ABL1 and tyrosine kinase dysregulation.
- Mutations in tyrosine kinase receptors for growth factors e.g. FLT3.
-Activating mutations of NOTCH1 , a gene encoding a transmembrane receptor that regulates normal T-cell development. - Most common abnormality in childhood ALL is t(12; 21)(p13; q22) ETV6‐RUNX1 translocation. RUNX1 protein involved with transcriptional control of haemopoiesis - repressed by the ETV6-RNX1 fusion protein.
Clinical Features of ALL
- Caused by marrow failure and organ infiltration
Bone marrow failure causes: - Anaemia
- Infections - Bruising, purpura, bleeding e.g gums, menorrhagia
Organ infiltration causes:
Splenomegaly/hepatomegaly/Lymphadenopathy - B cells still go where they normally would to mature and accumulate there
Bone tenderness
Meningeal syndrome (vomiting, blurred vision, headaches etc.)
Fever
Testicular swelling
Lab Investigations ALL
FBC:
- N/N anaemia
- Thrombocytopenia
- WBC = low/normal/high
Morphology: Blast cells in blood film
Bone marrow: Hypercellular with > 20% blast cells
- Immunoglobulin/ T-cell receptor (TCR) gene rearrangement.
- CSF
- Biochemistry: Raised LDH, uric acid
- Immunophenotyping and cytogenetics
ALL- Immunophenotyping
- Example of T cell markers: cCD3, CD7 and CD2
- Example of B cell markers: cCD22, CD19, CD10, cytoplasmic/membrane immunoglobulin.
- Can be used to separate subtypes:Pro-B ALL, Common ALL, Pre-B ALL, B cell ALL
AND
Early T-ALL, Cortical T-ALL, Mature T-ALL - Common ALL (c-ALL) is the most frequent (CD10 positive).
WHO Classification of Lymphoid Malignancies
-Classified according to if its T or B cell origin and underlying genetic defect.
-Subtype is important for treatment and prognosis.
-Specific genetic abnormalities.
- Examples: ALL with t(12;21), ALL with t(9;22), Hyperdiploidy (> 50 chromosomes), Hypodiploidy (< 50 chromosomes)
ALL prognosis
Girls with a low WBC count and hyperdiploid or normal cytogenetics has a better prognosis than a boy with low WBC and hypodiploid cytogenetics.
ALL Treatment
-Supportive e.g. transfusions, infection management etc.
Chemotherapy/steroids: protocols differ with adults/children and prognosis e.g. dexamethasone, vincristine and asparaginase.
Remission induction: <5% blasts in bone marrow, normal count and no symptoms, Achieved in about 90% of children and 80-90% adults.
Intensification (consolidation) : high dose drug combinations aimed at eliminating residual leukaemia.
Maintenance therapy : intermittent treatment.
Specific treatment required for CNS disease e.g. intrathecal methotrexate
Allogeneic Stem Cell Transplant, especially if Ph positive.
CAR-T cell therapy.
>80% of children cured but much less in adults
Minimal Residual Disease
ALL can appear eradicated but specialised flow cytometry or molecular techniques e.g PCR may detect a small number of malignant cells (minimal residual disease)
Acute Myeloid Leukaemia (AML)- Primary and Secondary classifictions, incidence, definition
-Malignant clonal disorder of immature cells.
- Most common form of acute leukaemia in adults, rising to 15 per 100,000 in the elderly.
- Rarer than ALL in children (10-15% of leukaemias).
Primary AML – de novo.
Secondary AML – occurs following chemotherapy or other haematological diseases e.g. myelodysplasia.
-Each has different genetic markers and prognosis.
AML Pathogenesis
- Malignant transformation sometimes occurs at the stem cell stage or sometimes at a slightly later stage when the cell is committed to lineage differentiation.
- Results in the proliferation of a clone of cells that fail to differentiate and undergo apoptosis, causing marrow failure.
- Numerous molecular abnormalities. Most common:
Mutations in FLT-3 receptor result in activation of the receptor by phosphorylation, leading to proliferation and resistance to apoptosis.
Chromosomal translocations - inv(16) and t(8; 21) generate fusion proteins involving the core binding factor (CBF) genes.
Mutations in the nucleophosmin (NPM) gene.
Clinical Features AML
-Anaemia
-Bleeding/ bruising
-Tumour infiltration of tissues
- CNS involvement – especially M4 and M5 subtypes
- DIC – characteristic of Promyelocytic Leukaemia (APML/M3)
AML Prognosis
FLT3 mutations are the most frequent in AML. It is a major prognostic factor for predicting remission and relapse.
Hence the reason for development of TK inhibitors against FTL3.
NPM1 mutation (found in about 50%) associated with favourable outcome.
AML - Diagnosis & Classification (Immunotyping notes)
Based on FAB or WHO Classifications.
FAB: provides useful ‘vocabulary’ but little predictive value.
WHO: 20% blasts are present in the blood or bone marrow. Genetic markers, immunophenotyping and cytochemistry provide additional diagnostic and prognostic information.
Typical myeloid immunophenotype is CDI3+, CD33+ and TdT negative. Additional antibodies are required to help diagnose M0, M6 and M7.
WHO Classification of Myeloid Malignancies
- AML with recurrent genetic abnormalities: Specific mutations recognised. Good prognosis.
-AML with myelodysplasia-related changes: Dysplasia in at least 50% of cells in at least 2 lineages. Prognosis not as good as above.
-Therapy related myeloid neoplasms (t-AML): AML with previous exposure to drugs e.g. alkylating agents. Poor prognosis.
-AML, not otherwise specified: No cytogenetic abnormalities but mutations in FLT3 and NPM gene commonly seen.
-Myeloid sarcoma: Rare disorder resembling solid tumour of myeloblasts.
-Myeloid proliferation related to Down’s syndrome
-Blastic plasmacytoid dendritic cell neoplasm: Rare and aggressive, derived from precursor of plasmacytoid dendritic cells.
-Acute leukaemia of ambiguous origin: e.g. acute undifferentiated leukaemia and mixed phenotype acute leukaemia
AML Treatment
- Depends on risk group.
- Supportive e.g. transfusions and prevent tumour lysis syndrome.
- Induction: e.g. combination of chemotherapy commonly used e.g. combination of daunorubicin and cytarabine. Aim is to induce remission.
- All the AML subtypes are treated similarly except for the promyelocytic (M3) in which ATRA (differentiation agent) is also used: Most cases of APML involve a chromosome translocation between 15 & 17. This results in the PML-RAR fusion protein which prevents immature myeloid cells differentiating.
50-85% of patients achieve remission – diminishes with age though.
-Consolidation to prevent relapse.
-New drugs now available: FLT3 inhibitors, monoclonal immunoconjugates e.g. CD33/CD45.
-Autologous or allogeneic stem cell transplant.
AML: New and Future Development
Trend for increase use of molecular, genetic and clinical features as well as morphology for classification likely to continue.
Identification of subgroups based on gene expression signatures.
Targeted treatment e.g. through prognostic groups or immunoconjugates, inhibitors of tyrosine kinase FLT-3 etc.
CAR-T cell therapy
What is Acute Myeloid Leukaemia M5a
Is the abnormal proliferation of myeloid cells
Is defined by FAB by more than 80% of myeloblasts in the bone marrow aspirate
Incidences increase with age
Makes up only 2.5% of childhood Leukemia’s
Acute Myeloid Leukaemia M5a Symptoms
Symptoms are often vague and non-specific - Similar to those of influenza and other common illnesses
-Anemia
-Bruising ( petectiae)
Infections
-Weightloss/ loss of appetite
-Fever and fatigue
Treatment of Leukaemia
- Started on chemotherapy (AML 15 trial)
-Cytarabine:
Damages DNA when the cell cycle holds in the s phase (synthesis of DNA)
and Inhibits DNA and RNA polymerase and nucleotide reductase needed for DNA synthesis
-Etoposide:
binds to and inhibits topoisomerase II and its function in ligating cleaved DNA molecules
-Held off blood transfusion initially
Patients Provisional Diagnosis
Acute myeloid leukaemia (monocytic variant with marked tissue infiltration)
Acute renal failure
Additional Provisional Diagnosis:Disseminated intravascular coagulation (DIC)
What is Renal Failure? What causes it?
Due to Tumour Lysis Syndrome
-Caused by rapid cell turnover, monoblasts lysing spontaneously
-Release of intracellular contents into circulation: Purine is broken down into uric acid
-Resulting in high uric acid levels (Hyperuricemia)
-Uric acid crystals cause obstruction of renal tubules
Treatment of Renal Failure
Started on haemodialysis (CVVHDF)
Diuretics (furosemide):
-Increase the removal of salts and water from the blood to urine
-High doses used in kidney failure
Rasburicase (urate oxidase enzyme):
-Leads to rapid decline in Uric acid levels
-Acts as a catalyst in the oxidation of uric acid to allantion
What is DIC (Disseminated Intravascular Coagulation)? What causes it?
-Pathological activation of coagulation mechanisms cause by procoagulant activity of blast cells
-Pro-coagulants :Tissue factors, Membrane factor V receptor, Cancer procoagulant
-Leads to the consumption of clotting factors and platelets
-Results in bleeding
Treatment of DIC
Fresh Frozen Plasma (FFP): Replacement of clotting factors
Cryoprecipitate: Replacement of Fibrinogen
Vitamin K: Aid the production of clotting factors (liver factors)
Initial management of DIC ( symptomatic care)
IV fluids and antibiotics (ceftazidime and gentamycin)
Intubated and ventilated following insertion of a central line in theatre
Inotropes (adrenaline, nor-adrenaline, milrinone) – for management of heart failure ( increases heart rate and BP)
Potential Outcomes of DIC
Multi-organ failure: Renal failure, Liver failure, Cardiac failure
Can continue to deteriorate despite treatment
CT showed multiple haemorrhages
Pupils fixed and dilated
Unlikely to survive at this point or would be severely brain
damage.
Made decision to withdraw life support.
