18.06.14 AML Flashcards
What is AML?
heterogeneous disease resulting from the clonal expansion of myeloid blasts in the peripheral blood (PB), bone marrow (BM) or other tissue.
What is the incidence and mean age of onset of adult AML?
Median age 65 at diagnosis, 2.5/100,000/yr, slight male predominance, AML accounts for 25% of acute leukaemias, ~55% cytogenetically abnormal
What is the incidence and mean age of onset of paediatric AML?
<15 years, 0.7/100,000/yr, AML accounts for 15~20% of all acute leukaemias, with peak incidence in first year decreasing to 4 years (median 2 years), ~
What proportion of adult and paediatric AML is cytogenetically abnormal?
Adult - 55% cases abnormal cyto
Paed - 78% cases abnormal cyto
What are the symptoms of AML?
What is the incidence and mean age of onset of adult AML?
What are the recurrent abnormalities seen in AML?
- t(8;21)(q22;q22); (RUNX1T1-RUNX1)
- inv(16)(p13.1q22) or t(16;16)(p13.1q22); CBFB (16q22)-MYH11 (16p13)
- t(9;11)(p22;q23); MLLT3-MLL (now known as KMT2A by HUGO)
- t(15;17)(q24;q21)
- t(6;9)(p23;q34)
- inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1 (3q21)-EVI1 (3q26)
What rearrangement is seen in acute promyelocytic leukaemia?
t(15;17)(q24;q21); PML-RARA
Describe features of t(8;21)(q22;q22).
(RUNX1T1-RUNX1) Good prognosis when treated with high dose cytrabine FAB M5 Auer rods Predominantly in younger pateints Secondary chromsomes (>70%) cases -X, -Y, del(9q) Mutations of KRAS and NRAS seen in 30% KIT mutations in 20-25%
Describe features with inv(16)(p13.1q22)
(CBFB)
Found in 5-8% of AML
Good prognosis when treated with high dose cytrabine
Fab class M4
Occurs in all age groups, predominantly younger patients
Easy to miss on karyotype
FISH and RT-PCR may be required
Secondary findings in 40%: +22 (10-15%), +8, del(7q), +21
KIT mutations in 30%
Mutations of KRAS or NRAS seen in 30%
What is the core binding factor?
RUNX1-CBFB proteins heterodimerise to create CBF that binds target genes via the RUNX1 transcriptional activation domain, which regulates normal blood cell differentiation, and cell survival.
The fusion proteins produced by the above rearrangements allow the CBF to bind to the target genes, but the transcriptional activation is lost via a dominant negative inhibition leading to arrest of differentiation and TP53 induction being inhibited resulting to increased cell survival.
Describe APL
t(15;17)(q24;q21) (PML-RARA) Good prognosis 5-8% of AML FAB M3 Predominates in mid-life Small number have cryptic rearrangements required RT-PCR Sensitive to ATRA
Describe the aetiology and treatment of APL
- Expression of PML- RARα is associated with inhibition of differentiation and increased cell self-renewal.
- The PML-RARα protein (a dominant negative form of RARα) binds to DNA and represses transcription of retinoic acid target genes, like the normal RARα protein. However, PML-RARα doesn’t respond to the transcriptional signal induction of the genes, so the genes remain repressed.
- Additionally, the function of the PML protein is disrupted: PML blocks cell growth and proliferation and induces apoptosis. However, PML-RARα does not block proliferation or induce apoptosis.
As a result, excess promyelocytes accumulate in the bone marrow and normal white blood cells cannot form, leading to APL
- A symptom of APL is DIC (disseminated intravascular coagulation): widespread activation of the clotting cascade resulting in the formation of blood clots in the small blood vessels throughout the body that organ damage. It also consumes the clotting factors resulting in severe bleeding can occur from various sites.
- All-trans-retinoic acid (ATRA), a ligand for RARα, is effective therapy for APL especially when given in combination with conventional chemotherapy.
- ATRA binds the fusion protein with resultant dissociation of co-repressor complexes, engagement of co-activation complexes by the chimerical receptor and subsequent degradation of the fusion protein. Promyelocytes can then undergo normal hematopoietic differentiation and apoptose naturally with a minimum release of the clotting factors therefore reducing the risk of haemorrhage.
Describe AML with t(9;11)(p22;q23)
9-12% of paed cases, 2% of adult cases
FAB M%
<20% blasts requrie close monitoring for more definitive evidence of AML
t(9;11) most common MLL
Secondary abn +8 (20%)
Prognosis Intermediate (better than other MLL translocations)
Describe AML with t(6;9)(p23;q34); DEK-NUP21
Found in 0.7-1.8% of AML. Occurs in both adults and children.
FAB class: all except M3, M7
Sole abnormality in most cases
Secondary abns: FLT3-ITD mutations occur in 69% of paediatric cases and 78% of adult cases, some cases have a complex karyotype.
FLT3-TKD mutations are uncommon in this subgroup.
Cases with <20% blasts must be monitored for more definite evidence of AML.
Generally a poor prognosis.
Describe AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1 (3q21)-EVI1 (3q26)
Found in 1-2% of AML. Mostly in adults. Associated with tri-lineage dysplasia.
- A variety of abnormalities of 3q occur in myeloid malignancies, with the two named above, the most common & a distinct entity.
- RPN1: enhancer of EVI1 expression increased cell proliferation/ impaired differientiation
- Secondary chromosome abns (common): -7 most frequent (50%), -5q, complex karyotype. They may precede the development of the 3q26.2 abnormality.
Prognosis:
- Associated with aggressive disease and short survival.
Describe AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL
Found in <1% of cases. FAB class: M7. It most commonly occurs in infants without Down syndrome, mainly in the first six months of life.
- Sole karyotypic abnormality in 75% cases
Secondary abns: high hyperdiploidy/ hypotriploid (chr 51-61)
Prognosis:
- Intermediate: Early reports suggested a poor prognosis, but more recent reports have found the patients respond well to intensive AML chemotherapy with long disease-free survival.
What is AML with myelodysplasia-related changes?
- An acute leukaemia with 20% or more blasts in BM or PB with morphological features of MDS or a prior history of MDS or MDS/MPN, or MDS-related cytogenetic abnormalities.
- 24-35% of all AML. Occurs mainly in the elderly, is rare in children.
- Chromosome abnormalities are similar to those found in MDS and often include gains/losses, most common: complex karyotypes, -5/del(5q) and -7,del(7q)
- Complex karyotype is defined as three or more unrelated abnormalities, none of which are included in the ‘AML with recurrent genetic abnormalities’ subgroup.
What are therapy-related myeloid neoplasms?
- Accounts for 10-20% of AML.
- Most patients have received alkylating agents and/or radiation as well as topoisomerase II inhibitors, so a division according to the type of therapy is usually not practical and is no longer recommended.
- 90% of patients with therapy-related neoplasms have cytogenetic abns identical to those observed in ‘AML with myelodysplasia-related features’ or in ‘AML with recurrent cytogenetic abnormalities’
- patients with therapy-related myeloid neoplasms have a significantly worse outcome than do their de novo counterparts with the same genetic abnormalities, suggesting that there are biologic di
What are the common abnormalities seen in myeloid sarcoma?
Also known as granulocytic sarcoma. A tumour mass consisting of myeloid blasts occurring at a site other than the bone marrow. Genetic abnormalities detected in ~55% cases include: -7, +8, MLL-rearrangements, t(8;21), inv(16) and many others. Clinical behaviour and response not affected by cytogenetics. Improved outcome with allogeneic or autologous BM transplantation.
