ACUTE LEUKEMIAS 1 Flashcards
All pluripotent cells in the bone marrow proliferate into what 2 cells?
Myeloid and Lymphoid
Proliferate into their mature end cells within the bone marrow
Myeloid cells
Migrate to the lymphoid organs to complete maturation
Lymphoid precusors (T cells)
An uncontrolled proliferation of myeloid or lymphoid blasts
Acute leukemia
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
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
Arise from multiple genetic mutations, both
unchecked proliferation and abnormal or no maturation
Acute leukemias
Most common type of acute leukaemia in adults, with the median age at presentation of 65 years
Acute Myeloid Leukemia
Patients are often younger
Acute promyelocyte anaemia
Common in children, with peak incidence between ages of 2
and 5 years.
Acute Lymphoid Leukemia
Name the cell that is not of myeloid origin
A. Erythroblast
B. Basophil
C. Natural killer cell
D. Neutrophil
Natural killer
The pathogenic genomic abnormalities in haematopoietic
stem and progenitor cells include:
- structural cytogenetic abnormalities
- mutations
leading to abnormal proliferative advantage.
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
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
Death within 30 days of
diagnosis
Acute Promyelocytic leukemia
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
The translocation unique to APL
t(15,17)
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
What is a maturation block?
myeloid precursors unable to mature beyond the promyelocyte stage
A common finding in Acute Myeloid lukemia, which leads to increased blood viscosity
Hyperviscosity
*Seen with WBC counts >100 x 109/L
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)
A
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»_space;>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
B
Which type of abnormality cannot be detected on
karyotype?
A. Mutation
B. Trisomy
C. Monosomy
D. Translocation
A
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»_space;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.
