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.
