ACUTE LEUKEMIAS 1 Flashcards by KWANELE MTHEMBU

All pluripotent cells in the bone marrow proliferate into what 2 cells?

Myeloid and Lymphoid

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Proliferate into their mature end cells within the bone marrow

Myeloid cells

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Migrate to the lymphoid organs to complete maturation

Lymphoid precusors (T cells)

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An uncontrolled proliferation of myeloid or lymphoid blasts

Acute leukemia

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What is the mechanism that ensures that the cells remain proliferative and never mature so cancer progresses?

Cells are blocked at an early stage of differentiation and
have a proliferative advantage

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Do acute leukemias metastisize and invade tissues and organs outside of the marrow?

Yes,
They can invade BM, blood and extramedullary sites

*They often replace normal haematopoietic cells in the BM, which causes life threatening cytopenias

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Arise from multiple genetic mutations, both
unchecked proliferation and abnormal or no maturation

Acute leukemias

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Most common type of acute leukaemia in adults, with the median age at presentation of 65 years

Acute Myeloid Leukemia

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Patients are often younger

Acute promyelocyte anaemia

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Common in children, with peak incidence between ages of 2
and 5 years.

Acute Lymphoid Leukemia

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Name the cell that is not of myeloid origin
A. Erythroblast
B. Basophil
C. Natural killer cell
D. Neutrophil

Natural killer

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The pathogenic genomic abnormalities in haematopoietic
stem and progenitor cells include:

structural cytogenetic abnormalities
mutations
leading to abnormal proliferative advantage.

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Acute leukemia Risk factors

Chromosomal abnormalities (e.g., Fanconi anaemia, Down
syndrome etc.)
Germline predisposition
Drugs (i.e. chemotherapy) or benzene
Radiation
Other myeloid malignancies

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List the symptoms of bone marrow failure

Anaemia; dyspnoea, palpitations, fatigue, headache etc.
Thrombocytopenia; mucocutaneous bleeding (easy bruising, petechiae, epistaxis, bleeding gums, menorrhagia etc.)
Neutropenia; infections
Tissue infiltration – gingival
hyperplasia, lymphadenopathy,
hepatomegaly, splenomegaly,
CNS, scrotum etc.
Joint and bone pain (paediatric
population) - limping or
refusing to walk

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Death within 30 days of
diagnosis

Acute Promyelocytic leukemia

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What is the cause of sudden death following Acute Promyelocytic Leukemia (APL)?

Production of pro-coagulant granules by the (APL)»trigger the DIC»Leads to coagulation and clots forming throughout the microvasculature»>Platelets and clotting factors depleted»>Hermorhage and bleeding

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The translocation unique to APL

t(15,17)

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Describe how the t(15,17) mutation is derived

Involves the PML gene (promyelocytic leukaemia) on chr 15 and the RARa gene (retinoic acid receptor-alpha) on chr 17

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What is a maturation block?

myeloid precursors unable to mature beyond the promyelocyte stage

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A common finding in Acute Myeloid lukemia, which leads to increased blood viscosity

Hyperviscosity

*Seen with WBC counts >100 x 109/L

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Describe the impact of high, immature leukemic myeloids in the blood

Intravascular accumulation of these quickly proliferating cells»increased viscosity of blood»thrombotic complications

helpful in making a hyperviscosity diagnosis

Fundoscopic examination

The PML-RARA fusion gene is the same as which
translocation?
A. t(15;17)
B. t(8;21)
C. t(9;22)
D. t(12;21)

Can occur in all ages but has its peak incidence in the 7th
decade (70 yrs)

Acute myeloid leukemia

Survival expectations remain age-dependent, with a 62% estimated 5-year survival in patients diagnosed under the age of 50 years, 37% in 50–64 years, and only 9·4% in ≥ 65 years

AML

An acute leukemia classified according to morphology

AML

primarily a disease of childhood, ~75% of cases in children <10 years

ALL

An acute leukemia presenting with good prognosis in children, >90% survive without disease in the long term. However, the outcome of older adults (≥40 years) and patients with relapsed or refractory disease remains poor.

ALL

Which of the 2 lymphoblastic leukemias is more common? The B or T cell lymphoblastic leukemia?

B cell

An acute lymphoblastic leukemia resulting to mediastinal mass

T cell

organ involvement quiet seen with this kind of leukemia– splenomegaly, hepatomegaly, LAD, testicular swelling, CNS etc

ALL

Techniques or methods to carry out ALL diagnoses

- Clinical history and examination * FBC, differential count and peripheral smear * CXR - lymphadenopathy or an enlarged thymus. * CEU, LFT’s, PT, PTT, LDH, Uric acid etc

EXAMPLES OF IMPORTANT GENETIC FEATURES IN ALL

Good prognosis * Hyperdiploidy-> 50 < 66 chromosomes * t(12;21) Bad prognosis * t(9;22) * KMT2A gene rearrangement –11q23

The full blood count for an AML

- White cell count – low, high or normal * Haemoglobin – usually low (anaemia) * Platelets – usually low (thrombocytopenia)  typically severe decrease in counts Need to request a differential count, to check WBC composition & neutrophils >>>pancytopenia = neutropenia, anaemia and thrombocytopenia. * Peripheral smear – increase in BLASTS. * Acute leukaemia ≥20% blasts in the blood or BM but......... * Some acute leukaemia with specific genetic abnormalities can be diagnosed with <20% blasts. - Auer rod - AML

Specific AML Investigation methods or techniques

- Bone marrow aspirate and trephine biopsy * Flow cytometry * Conventional cytogenetics * FISH analysis * NGS

This AML investigation method Uses antibodies directed against surface and cytoplasmic antigens

Flow cytometry

An AML investigation method that detects large chromosomal abnormalities. Analysis of the number and structure of chromosomes

CONVENTIONAL CYTOGENETICS

Allows analysis of chromosome structure at a molecular level

FISH

- Able to detect multiple genetic abnormalities in a single test: * Mutations and translocations. * Diagnostic and prognostic significance.

NXT GENERATION SEQUENCING

An Auer rod is seen in which type of acute leukaemia? A. T lymphoblastic leukaemia B. Acute myeloid leukaemia C. B lymphoblastic leukaemia D. Chronic lymphocytic leukaemia

Which type of abnormality cannot be detected on karyotype? A. Mutation B. Trisomy C. Monosomy D. Translocation

FACTORS WHICH AFFECT AML PROGNOSIS ON VARIOUS PATIENTS

- Age * Cytogenetic abnormalities * Additional mutations * Response to initial chemotherapy * CNS disease in ALL * Performance status

EXAMPLES OF IMPORTANT GENETIC FEATURES IN AML

Good prognosis * t(8;21) * Inversion 16 Bad prognosis * Complex karyotype

MANAGEMENT OF THE ACUTE LEUKEMIAS

- Supportive therapy - should be initiated to correct haematologic, metabolic and infectious complications. - transfusions, antibiotics, fluids etc. * Specific therapy * Chemotherapy – systemic and CNS * Allogeneic haemopoietic stem cell transplantation

Discuss chemotherapy

- Work by impairing mitosis >>targeting rapidly dividing cells. * They prevent mitosis by various mechanisms including damaging DNA. * Familiarity with the agents used is required to prevent or anticipate and treat toxicities timeously. * Many side effects are due to damage to normal cells that divide rapidly e.g. BM, digestive tract and hair follicles.

Name the side effects of chemotherapy

- Short term; hair loss, immunosuppression, cytopenias, nausea and vomiting, skin rash, mucositis etc. Long term: - Infertility – consider fertility preservation prior to chemotherapy. - Secondary malignancies

Basic Principles of Treatment

the goal is to completely eradicate blast cells through intensive chemotherapy (induction phase) Patient on chemo are at risk of infections and chemotherapy side effects Consolidation phase – for patients in complete remission (CR) to eliminate residual leukaemic blasts and prevent relapse. - better tolerated than induction therapy Maintenance – to maintain remission, for up to 2 to 3 years. CNS directed therapy – in ALL, to prevent and treat CNS disease. -given at all the phases of therapy.

To see with response to chemotherapy

- Complete remission – absence of extra-medullary disease (no LAD, hepatomegaly, splenomegaly etc.) - absolute neutrophil count > 1 x 109/L - platelet count >100 x 109 /L - <5% blasts in the bone marrow

APL management

- ATRA (All Trans Retinoic Acid) is required. * Helps with maturation of promyelocytes to granulocytes  reverses the coagulopathy associated with APL. * Should be given ASAP if any suspicion of APL – this is a medical emergency.