AML Flashcards
which syndromes are associated with AML
trisomy 21, monosomy 7 chromosome instability (FA, DC, Bloom) SCAN SDS DBA, CAMT NF-1, JMML PNH, SAA GATA2, CEBPA, RUNX1
What is the WHO classification for AML
1) BM myeloid blasts > 20%
OR
2) Recurrent cytogenetic abnormalities (no min blast count)
-t(8;21)(q22;q22), RUNX1-RUNX1T1 (CBFA2-AML1-ETO).
-inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), CBFB-MYH11.
-APL with t(15;17)(q24;q21), PML-RARA.
-t(9;11)(p22;q23), MLLT3(AF9)-MLL.
-t(6;9)(p23;q34), DEK-NUP214.
-inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), RPN1-EVI1.
-t(1;22)(p13;q13), RBM15-MKL1.
-mutated NPM1.
-mutated CEBPA.
3) MDS-related
4) Therapy-related
5) Trisomy 21-related
6) Myeloid sarcoma
7) AML NOS - divide by FAB classification
AML High risk
therapy-related AML MDS-related AML Monosomy 5, monosomy 7,del5q FLT3/ITD with allelic ratio > 0.4 Induction failure MRD>0.1% at end Ind#1 (without low-risk cytogenetics)
AML Favourable risk
Down syndrome Inv 16 t(8;21) NPM or CEBPalpha mutation t(15;17) APL MRD negative at end induction 1 (1;11) - MLL-KMT2A *Note fav. genetics with MRD+ are still fav. risk
AML prognostic factors
Unfavorable:
- poor cytogenetics
- MRD positive
- high WBC count
UK AML Trials
MRC 10: ADE similar to DAT but more toxicity with thioguanine
MRC 12: MAE vs ADE. Mitox reduced relapse rate but no difference in EFS or OS. 4 courses = 5.
MRC 15: GO improves survival for patients with favourable cytogenetics
Adding Etop to AD does not change outcomes (adults)
BFM trials
BFM 93: ADE equals AIE - trend towards Ida
BFM98: HR-AML No difference in chemo vs alloHSCT
BFM 2004: L-dauno eq Idarubicin but higher dose of L-dauno. Less toxicity with L-dauno
North American trials
AAML 0531 - GO improves EFS for low-risk cyto, int-risk who got SCT from MSD and high-risk who got SCT. Intensity of CD33 expression key.
AML1031: Bortezomib in low-risk and sorafebib in FLT3-ITD
Immunophenotype
Pan myeloid: CD 13, 33, MPO (except M7) Monocytic: 11b, 14 Erythroid: Glycophorin A (235a) Megakaryocytic: 41a, 42, 61, absent MPO AP: autoflorence, bright CD33, HLA-dR neg, CD 43 neg t(8;21): often coexpress CD19
Prognostic factors in relapse
- Length of remission: 40% OS >1 yr vs 10%
- Molecular alterations at relapse: WT1 or FLT3-ITD
- No HSCT in CR1
- Response to therapy
What is the M2 FAB subtype associated with?
called AML with differentiation
t(8;21)
Can commonly present with chloromas
What is the M5 FAB subtype associated with?
called acute monocytic leukemia
Commonly presents with CNS involvement, gingival hyperplasia, chloromas and leukemia cutis
Commonly associated with MLL rearrangement
What are the 2 types of therapy related AML?
1) Alkylating agents and radiation:
•Long latency (5-7 years) from exposure, common preceding MDS
•Cytogenetics: -7, del(7q), -5, del(5q); complex cytogenetics
2) Topoisomerase II inhibitors (etoposide > anthracyclines)
•Short latency (1-2 years) from exposure, rare preceding MDS
•Cytogenetics: 11q23 rearrangements most common, but t(8;21), t(15;17), t(9;22) and inv(16) can also occur
What is differentiation syndrome?
Clinically will see: Fever, edema, pulm infiltrates, hypoxia, resp distress, hypotension, renal/hepatic dysfunction, effusions, rash
–Risk correlates with high WBC; can occur in absence of ATRA
–Rx: Prompt recognition and use of dexamethasone, hold ATRA until resolving
inv (16) and t(16;16) creates which chimeric protein
CBFB-MYH11 chimeric protein which is assoicated with a high rate of long-term remission
t(15;17) results in the PML-RARA fusion gene
What is RARA
Its a transcription factor that binds retinoids and interacts directly with DNA
What does FLT3-ITD stand for and what does it represent?
FMS-like tyrosine kinase mutations internal tandem duplications. The ITD’s result in ligand independen activation of the kinase and uncontrolled proliferation of the leukemic blasts
Associated with higher WBC at diagnosis and are cytogenetically normal. These patients have a poorer prognosis
What immunophenotype characterizes M3 or APML?
HLA-DR negative Bright CD33 CD15+ Usually CD34 negative cells autofluoresce
what immunophenotype characterizes M6?
Glycophorin A+
Then standard AML markers: HLA-DR+, CD33+, CD34+, CD13+
what immunopheotype characterizes M7?
CD41+, CD42+, CD61+
Then standard AML markers: HLA-DR+, CD13+, CD33+, CD34+
What immunophenotype characterizes M4/M5?
CD11b+, CD14+
Then positive for the standard AML markers: HLA-DR+, CD13+, CD33+, CD34+
For AML what is considered an early and late relapse?
early relapse is <12 months from diagnosis; 5yr survival is 13%
late relapse is >12 months from diagnosis; 5yr survival is 36%
What treatment is used for remission induction in relapsed AML?
FLAG-idarubicin is a commonly used protocol
What is gemtuzumab?
recombinant humanized anti-CD33 monoclonal antibody conjugated to calicheamicin; an anti-tumour antibiotic.
Was withdrawn from the market in 2010 due to concerns of increased induction mortality and lack of efficacy. Was used upfront in COG trial in induction1 and intensification 2, EFS improved but not OS, due to TRM
Can obtain the drug by compassionate release
How does arsenic work in APML therapy?
Arsenic binds to the PML part of PML-RARA, leading to its degradation and resulting in partial differentiation and induction of apoptosis of leukemic promyelocytes
What is the suspected reasons for the development of differentiation syndrome?
SIRS
endothelial damage with capillary leak syndrome
occlusion of microcirculation
tissue infiltration
What % of patients with Down Syndrome AML will have been diagnosed with TMD
4-10%
When does TMD usually spontaneously remit?
What percentage of these patients will develop AML?
around 4-10 weeks of age
20% will develop AML
Why do patients with down syndrome AML have a very good outcome?
Most have a mutation in GATA1-a hematopoietic transcription factor, which causes the myeloblasts to be very sensitive to cytarabine
What mutation is commonly found in MPAL (mixed phenotype acute leukemias)?
MLL rearrangement
What are the two main categories of MPAL?
Biphenotypic: have both lineages on all of the cells
Bilineage: have a mixed population of lymphoid and myeloid blasts
The other 2 are:
1-undifferentiated: express no lineage specific markers
2-Leukemia that switches lineage during therapy
