17. Acute Myeloid Leukaemia Flashcards
leukaemie
1845: Rudolf Virchow and John Hughes Bennett, independently observed abnormal increase in white blood cells in patients.
For a while it was thought that these cells were fighting the cancer
1847: Virchow correctly identified the condition as blood disease, and named it leukämie (leukaemia)
myeloid cells
Granulocytes
Monocytic, erythroid and megakaryocytic cells lineages
Anything derived from the myeloid cell line can be affected in this type of malignancy
look at myeloid cell line
Lot more myeloid malignancies than lymphoid malignancies
Depending on where the mutation is within the line of differentiation will indicate the number of cells affected , how far back in the production of the myeloid cells does the mutation occur and what effect that might have so whether or not we have lots of a particular type of premature cell present and being produced erroneously due the malignancy and due to the mutation
Eg buildup of progenitor cells or mature cells depends on what mutation and what effect it will have
Lots of variabilities
what is acute myeloid leukaemia
Acute myeloid leukaemias: due to the presence of myeloblasts.
Blast cells are greater than 20%. (WHO classification system)
The malignant cells can accumulate in the bone marrow, blood and infiltrate other organs.
Acute – happens quite quickly , accumulation happens quite quickly
Chronic slower, but outcome is the same
Bone marrow count, blasts present in bone marrow
Myeloblasts Accumulate in bone marrow blood and organs, depends on number . As bone marrow doesn’t expand a lot so into blood then infiltrates organs
incidence of acute myeloid leukaemia AML
Affects all ages, but is most common in later life, 65yr+
Approx. 2000 people diagnosed with AML every year in UK
About 25% of cases occur in people under the age of 25
more cases in older people
AML is not just one disease
Can be caused by lots of different genetic mutations in stem cell or myeloid precursor cell
- Translocations between chromosome 8 and 21 [t(8;21)]
- Translocations between chromosome 15 and 17 [t(15;17)]
Prior myelodysplastic syndrome or myeloproliferative disease (MPD) that transforms into AML: - elderly / poor prognosis
Could affect red cells platelets and lead you with risk of developing aml
Could transform into aml, tends to be once transformed the outcome is not good not many treatment option
However prior syndromes have more treatments which allow patients to remain stable
AML classification
Classified into 8 sub-categories (M0-M7) using the French-American and British (FAB) scheme.
The subtypes are associated with different cytochemical stains, immunophenotype and molecular genetics.
M0 Undifferentiated blasts M1 Lightly granulated blasts M2 Granulated blasts often with Auer rods M3 Promyelocytic leukaemia M4 Myelomonocytic leukaemia M5 Monocytic leukaemia M6 Erythroleukaemia M7 Megakaryocytic leukaemia
May use this while waiting for other tests
Tells us what mutations are present so we can target treatment
Auer rods – issue with granules within the fell, they arent maturing, mutation means granules clump together, form projections
M7 platelets
Can see at which level is affected
Eg myelomonocyte is precursor of monocytes
Can see how mature of immature the cell is in that malignancy
molecular genetics of AML (1)
FAB class M3 acute promyelocytic leukaemia (APML)
- Promyelocytic leukaemia gene (PML) on chromosome 15 fuses with
- Retinoic acid receptor a gene (RARα) on chromosome 17
- PML-RARα fusion product (t15;17), blocks differentiation of cells
- 98% of cases of M3!
FAB class M3 acute promyelocytic leukaemia
normal is pluripotent bone marrow stem cell to hematoblast to promyelocyte to myelocyte to poly
but in this case we get translocation in promyelocyte so doesn’t progress any further and we see an accumulation
treatment of AML- M3 APML
Treated with all-transretinoic acid (ATRA)
Degrades the fusion product…
Induces differentiation of the leukaemic cells (t15;17)
molecular genetics (2)
M2 AML: granulated blasts with Auer rods
-t(8;21)
-Brings together RUNX1 (a transcription factor) with RUNA1T1 (a co-repressor)
-New fused gene generates products: blocks differentiation
-Build-up of blasts characteristic of the disease (often promyelocytes and myelocytes)
Different translocation with slightly different effect
Extra readin p53 regulation within leukemic cells
clinical features of AML
Dominated by bone marrow failure - infiltration of the bone marrow by myeloblasts
Anaemia, thrombocytopenia, infections
Skin infiltration and CNS disease
Clinical features are varied.
Rbc not produced effective so anaemia – tired run down
Thrombocytopenia (easy bruising) as platelets cant be produced as bone marrow is overwhelmed by non functioning wbc so increased risk of infction . Patient may have repeated infections
laboratory findings of AML
Diagnosis based on; Full blood count (FBC) Morphology Blood film - blasts Bone marrow smear - >20% blasts
- Immunophenotyping : immunological markers by flow cytometry (uses monoclonal antibodies to identify cell antigens which define lineage and maturity: CD13, CD33, CD117)
- Cytogenetics & molecular genetics: chromosomal abnormalities
treatment of AML
Supportive and specific
Treatment of bone marrow failure
Episodes of fever
Chemotherapy divided into:
induction (remission-reduction) and
consolidation (post induction) phases.
Induction therapy aims to achieve a complete remission (<5% blasts in bone marrow, normal blood counts, clinical status).
Consolidation therapy is to eliminate any residual cells present.
no leukaemic cells present, sensitive technique, treatment is to eliminate
cytotoxic drugs
-All AML are given induction chemotherapy with cytarabine and an anthracycline (daunorubicin). (normally 2 cycles and 2 drugs)
-The M3 subtype – promyelocytic leukaemia - is treated with ATRA in combination with standard chemotherapy.
characterized by a chromosomal translocation [t(15;17)] involving retinoic acid receptor alpha (RARα or RARA)
Treatment with ATRA causes differentiation of the immature leukaemic promyelocytes into mature granulocytes.
-Consolidation therapy is based on prognostic factors. Favourable prognostic factors will get shorter courses while those with poor prognostic factors will have longer consolidation.
can affect all cells, not just leukaemic cells so might stimulate bone marrow failure, need a blanace
ATRA however is targeted, doesn’t affect healthy cells
