Leuks Flashcards
(120 cards)
1
Q
whats the incidence of adult AML
A
Adults: 2.5/100,000/yr; 65yrs; 25% acute leuks; 55% abn karyotype
2
Q
Symptoms of AML
A
fatigue, shortness of breath, brusing, bleeding gums, recurrent infections, splenomegaly, tender bones
3
Q
what inherited disorders have a predisposition to AML
A
Fanconi, Neurofibromatosis, familial platelet disorder, Down Syndrome
4
Q
How does core binding factor work
A
RUNX1-CBFB form heterodimer (CBF) that binds target genes via RUNX1 transcriptional domain and regulate differentiation and cell survial.
fusion proteins allow CBF to bind to genes but transcriptional activation is lost (dominant negative inhibition) leading to differentiation arrest and inhibition of TP53 causing cell survival.
5
Q
whats DIC
A
Disseminated intravascular coagulation. widespread activation of clotting cascade causing formation of clots in capillaries causing organ damage. The APL cells also release an enzyme that simultaneously breaksdown the clots causing excessive bleeding (can be fatal if not controlled/stopped)
6
Q
whats RA (retinoic Acid syndrome)
A
occurs in patients treated with ATRA: caused by the differentiation of the APL cells
potentially serious consequence by fliud accumulation and retention in tissues. occurs during remission induction.
steriods given as a precaution.
7
Q
what are the rearrangement for GATA2,EVI1 in AML
A
inv(3)(q21q26.2) or t(3;3)
2nd abns: -7, -5, complex
poor
8
Q
discuss myeloid proliferation’s in DS
A
theres a 150 fold increase in AML incidence in DS less than 5yrs.
50% cases have M7: Acute megakaryoblastic leuk
all have GATA1 mutation
1) Transient abnormal myelopoesis TAM(10% DS newborns) 70-80% resolve in 3mths (20-30% devp AML 1-3 yrs later)
2) AML ass. DS. Devp in first 5yrs favourable outcome compared to children without DS
9
Q
whats a monosomal karyotype
A
2 or more monosomies or 1 monosomy in addition to a structural abn
10
Q
what are the favourable AML abns
A
Child hood: t(8;21) and inv (16)
adult: t(8;21) and inv (16) and t(15;17)
Mutated NPM1 & wt FLT3 or FLT3 low
Biallelic mutated CEBPA
11
Q
what are the poor childhood AML abns (under 16yrs)
A
5q abns, -7, t(6;9), t(9;22), 12p abns
12
Q
what are the poor adult AML abns (16-59)
A
abn 3q (excluding t(3;5)(q21~25;q31~35)), inv(3)(q21q26), add5q/del5q/-5, -7/add7q/del7q, t(6;11), t(10;11), MLL rearr. t(9;22). -17/del17p. complex (4 or more abns) Monosomal karyotype Mutated RUNX1, ASXL1, TP53
13
Q
discuss FLT3 in AML
A
13q12. 1/3 AML, receptor tyrosine kinase.
ITD: internal tandem duplication: exon 14 and 15 in frame dup juxtamembrane domain (75-80%AML, 30-40% CN-AML). autophosphorylation of receptor and activation of FLT3. Poor prognosis (survival 20-25% at 4yrs)
TKD: tyrosine kinase domain: codon Asp835 and Ile836 (5-10%AML, 20-35% CN-AML). Unclear prognosis.
14
Q
what chr abns are FLT3-ITD most often seen with
A
t(15;17), t(6;9), CN-AML
15
Q
discuss CEBPA in AML
A
CCAAT/enhancer binding protein alpha. 19q13.3. 10% AML (90% CEBPA mut: CN-AML)
seen with FLT3-ITD (22-33%)
biallelic muts: favourable outcome (can be 1x germline and 1x somatic)
16
Q
discuss NPM1 in AML
A
Nucleophosmin. 5q35.1 (53-60% CN-AML) generally mutually exclusive from rearrangements
exon 12: 4bp insertion: frameshift
lower relapse rate, better survival, improved treatment response.
seen with FLT3-ITD (40%)
17
Q
discuss MLL-PTD
A
Partial tandem duplication (5-10% CN-AML, 90% +11)
spans exons 2-6 or 6-8.
associated with short remission
18
Q
Name a FLT3 inhibitor
A
Sunitinib. AC220
19
Q
name some candidate genes that are mutated in AML
A
TET2, DNMT3A,TP53, SF3B1, RUNX1, U2AF1, EZH2, WT1, IDH,
20
Q
What are the good risk cyto in MDS IPSS-R
A
normal. del(5q). del(12p). del(20q). double including del(5q)
21
Q
What are the intermediate risk cyto in MDS IPSS-R
A
del(7q). +8. +19. i(17q). any other single or double independent lones
22
Q
What are the poor risk cyto in MDS IPSS-R
A
-7. abn3q (inv(3),t(3q),del(3q)). double including -7/del(7q). complex 3 abns
23
Q
What are the very poor risk cyto in MDS IPSS-R
A
complex more then 3 abns
24
Q
What are the very good risk cyto in MDS IPSS-R
A
-Y, del(11q)
25
what are the categories of MDS
MDS-SLD (single lineage): 10-20% MDS: survival: 66mnth: progression 5% AML
MDS-MLD (multilineage): 30% MDS: 33mnths
MDS- RS: 10% MDS: 6 yrs: 1-2%
MDS-RS-SLD
MDS-RS-SLD
MDS-EB (40% MDS)
MDS-EB-1 (5-9% blasts in BM): 16mnths: 25% AML
MDS-EB-2 (10-19% blasts in BM): 9mnths: 33% AML
MDS with isolated del(5q31): 145mnths (lenalidomide)
26
What gene mutations are detected in MDS
Histone function: EZH2, ASXL1.
DNA methylation: DNMT3A, ISH1,2, TET2
27
why carry out an SNP array for MDS
20% cases: LOH
abnormalities detected in 80% cases
28
discuss Chronic neutrophilic leukaemia
blood neutrophilia. Rare. splenomegaly. survival 6mnth-20yrs
90% chr Normal.
+8, +9, del(20q), del(11q14), del(12p)
29
discuss Chronic eosinophilic leukaemia
eosinophilia in PB, BM and tisues. Rare. 5yr survival 80%.
Need to distinguish from idopathic hypereosinophilia and PDGFRA,B, FGFR1 rearr
+8, i(17q)
30
discuss Polycythemia Vera
increase in red blood cell popn. 2.6/100,000/yr. survival over 10yrs. 20% t to AML/MDS
JAK2: 98%
20% abns: +8, +9, del(20q), del(13q), del(9p) (progression)
31
discuss myelofibrosis
pancytopenia due to fibrous connective tissue in BM. 1.5/100,000/yr. survival mnths-decades.
JAK2: 63%
30% abns:del(13q), der(6)t(1;6) MF markers
+8, +9, del(20q), del77q)/-7
32
discuss essential thrombocythaemia
sustained thrombocytosis in PB. 2.5/100,000/yr. survival 10-15yrs. 5% t to AML/MDS.
JAK2: 63%
5-10% abns: 8, +9, del(20q),
33
what abns are associated with myeloid and lymphoid eosinophilia
PDGFRA (4q12): cryptic 800Kb del of CHIC2--> FIP1L1-PDGFRA. responds to Imatinib
PDGFRB (5q33): t(5;12)(q33;p13) PDGFRB-ETV6. responds to Imatinib
FGFR1 (8p11): t(8;13) FGFR1-ZNF198. NOTrespond to Imatinib
PCM1-JAK2: t(8;9)(p22;q24): ? JAK2 inhibitor
34
discuss CMML
survival 20-40mnths, t to AML 15-30%:
persistent monocytosis. presence of auer rods. CMML-1, CMML-2
abns (20-40%): +8, -7/del7q, abn12p, i17q.
RAS muts 30-40%
35
discuss JMML
profileration granulocytes and monocytes. 1.3/100,000. 0-14yrs
NF1: 200-500 fold increase risk of developing JMML
prognosis poor (w.out BMT less than 1yr, moct die of organ failure). progression to AML 15-20%
abns (30-40%): -7/del7q
36
what is CML
myeloproliferative neoplasm that originates in the pluripotent stem cell and is associated witha BCR-ABL1 fusion. neutrophilic leukocytosis
1-2/100,000/yr. 50-60yrs. 15-20% all leuks
37
what are the 3 phases of CML
Chronic phase: accumulation of myeloid precusors and mature cells in the BM, PB and extramedullary sites. less than 5% blasts in BM.
Accelerated phase: increase in disease burden and in the frequency of precusor cells rather than terminally differentiated cells. hypercellular BM (10-19% blasts). clonal evolution of Cyto is seen.
Blast phase: rapid expansion of a popn of myeloid or lymphoid immature blast cells. over 20% blast in PB ot BM. cells infiltrate tissues.
38
what lineage is seen in in CML BP
70% cases: meyloid.
20-30% cases: lymphoblasts
can get mixed phenotype cells in BP
39
discuss the BCR bkpt in CML
5'BCR-3'ABL1.
major bkpt (exons 12-16): p210 protein in majority of cases.
(u-BCR (exon 17-20): p230- very raraely ocurs)
micor bkpt (exon 1-2): p190: seen in ALL (occasionally in CL- monocytosis- ?CMML.
40
what are the secondary abns in CML
+8 (50%)- seen transiently.
i(17q) (35%).
+Ph (30%)- seen transiently.
+19 (15%)
+21; -Y
41
which CML secondary abn is a reliable indicator of transformation
+19, i(17q), inv(3): reliable indicator
t(3;21)(q26;q22) EVI1-RUNX1: True transformation marker
42
what percenatges are cytogenetic CML response (BPG- Baccarani et al 2009)
No response: 96-100%
Minimal: 66-95%
Minor: 36-65% (to be reached by 3mnths)
Partial response: 35-1% Ph cells (to be reached by 6mnths)
Complete response: 0% Ph cells (to be reached by 1yr)
43
what s CML major molecular response
3-log reduction relative to baseline in 2 consecutive samples (to be reached by 18mnths)
now looking down to 4-log reduction
completer MR: no transcripts detected
44
what are the CML TKI
Imatinib. nilotinib. dasatinib. ponatinib. Bosutinib
45
whats the ABL1 mutation only Ponatinib is resistant to
T315I. (AKD: BCR-ABL1 kinase domain)
46
what is CLL
chronic mature B cell neoplasm: mature yet dysfunctional small round lymphocytes proliferate and accumulate in the PB, BM, spleen, liver.
most common leuk in adults: 2-6/100,00/yr. 72yrs.
5-10% transform into DLBCL (ricters)
47
what percentage of genetic abns are detected by FISH in CLL. what are the abns
over 80% detection rate Vs 40-50% by K.
del13q (50%). +12 (15%). delATM (15-20%). delTP53 (5-10%). del(6q26) POOR
48
discuss CLL del11q
11q22-q23.
up to 20Mb, can include BIRC3- may be ass w Fludarabine-refractory pats.
large lymphadenopathies--> progressive disease
49
discus del TP53 in CL
most frequently acquired abn after treatment. SHows shortest survival. doesn't respond well to standard therapy:
alemtuzumab FDA approved treatment for Tp53 del
50
discuss IGh rearr in CLL
in 20% CLL. ass w poor prognosis.
t(11;14). t(14;16). t(14;18). t(8;14)
51
what treatment for CLL
incurable so watch and wait for onset of disease/ progression. then...
FR: fludarabine (purine analogue) and rutiximab (anit-CD20)
52
what is MM
plasma cell neoplasm.
clonal expansion of a immunoglobin secreting, heavychain class-switched, terminally differentiated B cell that typically secretes a monoclonal immunoglobulin (paraprotein of M-protein).
Bone disease, impaired renal function, Anaemia
53
what chromosomes are gained in hyperdiploid MM
3,5,7,9,11,15,19,21
54
what treatment is given to MM
chemo, steriods, thalidomide, SCT
lenolidamide, bortezomib: promising signs
55
whats the incidence of childhood ALL
3-4/100,000. (75% occur under 6yrs).
25% pediatric leuks
85%B-ALL, 15% T-ALL
15-20% children relapse
56
whats the incidence of adult ALL
0. 9-1.6/100,000 over 60yrs.
0. 4-0.6/100,000 over 25-50yrs
6% adult leuks **ACGS guidelines >25yrs. many studies class adolescents (15-25 yr as adults)
75%B-ALL, 25% T-ALL
57
clinical features of ALL
brusing, bleeding, pallor, fatigue, infection, spleno-, hepto-megaly
58
discuss 9;22 ALL
24-4% childhood
25-30% adults
secondary abns: +Ph, del9p, HeH
Poor prognosis (often IKZF1 dels)
59
discuss MLL ALL
60-80% infant. 38% childhood. 10% adult.
secondary abns:+8, +X, i(7q)
poor prognosis
60
what are the chromosomes gained in ALL hyperdiploidy
4,6,10,14,17,18,21,X
25-30% childhood. 7% adults
(childrens COG: +4,7,10: low risk relapse)
61
discuss hypodiploidy ALL
near haploidy: 23-29
low hypodiploidy: 30-39 (unique ass. Of this and TP53 mut- often constitutional)
high hypodiplody; 40-44
1, 11, 17 usually retained- so 4 copies if doubled up
62
whats the prognosis of dic(9;20) in ALL
intermediate
63
whats the prognosis of dic(9;12) in ALL
intermediate in childhood (moorman 2010).
good in adults.
64
what percentage of childhood ALL have IGH rearrangemtns
8% (predom adolescents)
t(5;14) IL3-IGH
t(XorY;14) CRLF2-IGH: Poor prognosis
65
what are the common breakpoints for T-ALL
35% TCR rearrangements
TCR A/D 14q11
TCR B 7q35.
TCR G 7p14
(partners: TLX1 (10q24), LMO1 (11p15), LMO2 (11p13)
66
what cryptic rearrangement occur in T ALL
1p32 deletion: STIL-TAL1
t(5;14)(q35;q32 : TLX3-BCL11B
67
what mutation is seen in Hairy cell leukemia
BRAF V600E
responds well to purine analogs: pentostatin, cladaribine
68
What's the incidence and abnormality rate of pediatric AML
Pediatric: 0.7/100,000/yr; less than 15yrs (peak in 1st yr); 15-20% acute leuks; 78% abn karyotype
69
What percentage of CML at diagnosis have t(9;22)
90-95%
70
What percentage of CML at diagnosis have a variant translocation (t(9;22;?)) or a cryptic translocation detectable by FISH or rt-PCR
5-10%
71
Discuss the BCR-ABL1 gene product
Cytoplasmic protein with enhanced tyrosine kinase activity --> constitutive activation of several signal transduction pathways causing CML.
72
How many cells are analysed at CML diagnosis
Rapid FISH: 100 interphase
T(9;22) +ve: analyse 3; score 7
T(9;22) -ve: analyse 10; score 10
73
What's the likely outcome for CML with a variant translocation
Similar to classical t(9;22) when treated with imatinib or other TKI
74
What impact on prognosis does secondary abns at diagnosis in CML
At diagnosis don't necessarily have impact on pt outcome, but their presence is a warning according to ELN guidelines
75
What impact does deletions of ABL1, BCR or BCR-ABL1 on der(9)
Before imatinib: linked to adverts clinical outlook
Post imatinib: it nullifies the prognostic difference. Therefore it's not mandatory to report der(9) deletions (BPG).
76
How often follow up test CML
G-band marrow at 3 months and 6 months post treatment.
Every 6 months until CCgR achieved after which cyto shud not routinely be required (RTLas-PCR used instead)
77
In terms of secondary abns what considered treatment failure in CML
Presence of an abnormality in two consecutive samples- implies emergence of new clone
78
What abns are seen in Ph- cells in TKI treated CML
+8; abns of 7; sex chr abns
Pay particular attention to 5, 7, 8, 13, 20, X, Y
79
According to Grimwade et al 2010 (AML) what's meant by a single abnormality
Balanced translocation; trisomy; monosomy
80
According to Grimwade et al 2010 (AML) what's meant by 2 abnormalities
Gain of 2 chroms (including tetrasomy); gain of a derivative chromosome; unbalanced translocation leading to gain and loss of chrom material eg der(7)t(1;7)(q21;q22)
81
Adult AML: t(6;11)(q27;q23) genes and prognosis
Adverse
KMT2A/MLLT4
82
What are the breakpoints of t(6;11) in adult AML. And prognosis
T(6;11)(q27;q23)
Poor
83
Adult AML: genes and prognosis t(10;11)(p12;q23)
Adverse
MLLT10-KMT2A
84
What breakpoints for AML t(10;11)
T(10;11)(p12;q23)
Adverse
85
Therapy-related AML: alkylation agents or irradiation. Discuss
Arise 5-7 yrs after therapy
Abn 5q and/or 7q
86
Therapy-related AML: topoisomerase II inhibitors. Discuss
2-3 years after treatment.
Translocations: KMT2A or RUNX1
87
What abnormalities are often seen in solid extra-medullary granulocytic sarcomas (w. Or w.out BM infiltration)
T(8;21)(q22;q22) or inv(16)(p13q22)
88
What rearrangement must be looked for in biphenotypic leukaemia or leukaemia in infants (under 12months)
KMT2A or t(9;22) if biphenotypic- acute leuk
89
If fanconi is confirmed or suspected what chromosomal abnormality should be looked for
-7/del7q or dup3q (MECOM probe)
90
What clonal aberrations are common in Shwachman-Diamond Syndrome
:i(7)(q10) and del(20q)
May be transient and don't neccessarily indicate MDS or imminent transformation to AML
91
If see double minutes in AML what are most likely to be
Amplification a of MYC or MLL
92
In paediatric AML who's risk stratification is used by BPG
Harrison et al 2010
93
In adult AML who's risk stratification does BPG use
Grimwade et al 2010. (Age 16-59yrs)
94
What's the prognosis of ALL 7p12 abnormality
Poor IKZF1
95
What the chr position of ALL IKZF1
7p12
96
ALL: what's classed as high hyperdiploidy
51-65 chroms
97
In ALL what's the definition of iAMP21
5 or more copies of RUNX1 signals corresponding to 3 or more star copies on a single abnormal chromosome 21
98
What's the new myeloid neoplasm: eosinophilia rearrangement in WHO2016
PCM1-JAK2
t(8;9)(p22;q24.1)
Responds to JAK2 inhibition
99
What percentage of MDS have clonal abns
40%
100
What therapy is used in cases of MDS with del(5q) as sole abnormality
Lenolidomide (50-75% cytogenetics response; 30-45% Complete CCy)
101
What therapy is used in cases of MDS with chromosome 7 abnormalities
Azacitidine
102
If apparently normal karyotype in AML when should inv(16) be considered
Haematologist reports bone marrow morphology consistent with inv(16)
Secondary abnormalities ass. With inv(16) seen: del(9q), +22
103
Discuss MDS isolated del5q and TP53 mutation
TP53 associated with aggressive disease in MDS.
Appears to predict poorer response to Lenalidomide in pts with del(5q).
In del(5q) pts: TP53 status should be investigated to ID adverse subgroup of del5q
104
What mutation is associated with MDS-RS
SF3B1. If have this favourable prognosis (if have low RS but this mut- still MDS-RS)
105
Name some recurrent abns diagnostic of MDS
-7/del7q; -5/del5q; i(17p)/t(17p); -13/del13; del11q; idic(Xq13)
Del(12p)/t(12p); del(9q); t(11;16)(q23;p13.3); t(3;21)(q26.2;q22.1); t(1;3)(p36.3;q21.1); inv(3)(q21q26.2); t(6;9)(p23;q34)
106
Why karyotype MPN
Not essential for diagnosis.
Abns are not usually specific. While normal karyotype=uninformative; chromosomal abns= diagnostically useful to confirm a clonal disorder. Evolution of karyotype strongly suggestive of transformation to MF or AML (abn 5q, 17p, 7)
107
What mutation is seen in systemic mastocytosis
KIT D816V
108
What defines a clone according to ISCN
2 or more with cells with same structural abn or gain
3 or more cells with same chromosome lost
109
What gene mutation is strongly associated with CNL
CSF3R. T618I
110
What gene mutation is associated with ring sideroblasts in MDS/MPN-RS-T and MDS-RS
SF3B1
In MDS/MPN-RS-T it is seen with JAK2, MPL or CALR
111
What percentage of MDS patients have gene mutations
80-90%
112
What's happens to the genes involved in AML inv(3)
GATA2 enhancer activates MECOM and simultaneously confers GATA2 haploinsufficiency.
113
Based on preliminary data: what secondary abns support t(9;22) in an acute leuk being dnAML instead of CML-BP
Deletion of IGH, TCR
Deletion of IKZF1 and/or CDKN2A
114
What percentage of children have iAMP21 and what's the prognosis
2% esp. In older children with low WBC counts. Uncommon in adults
Advers prognosis that's improving eith the use of intensive/aggressive therapy
115
What's ALL BCR-ABL1-like
B-ALL with translocations involving tyrosine kinase or cytokines receptors (CRLF2)
Association with an adverse prognosis, but repsonds to TKI
116
What are some of the tyrosine kinases involved in the translocations in ALL BCR-ABL1-like
ABL1 (other partner to BCR); ABL2; PDGFRB; NTRK3; TYK2; CSF1R; JAK2
There are over 30 different partner genes described
All respond to TKI
Deletion of IKZF1 and CDKN2A/B often seen
117
What gene mutations are seen in T-ALL: Early T-cell precursor lymphoblastic leukaemia
FLT3; NRAS/KRAS; DNMT3A; IDH1/2 (myeloid ass. Mutations)
NOTCH1; CDKN1/2 (typical T-ALL mutations)= INFREQUENT
118
What mutation has prognostic significance in CMML
ASXL1
119
What are the 9 functional categories of mutated genes in AML?
```
Transcription factor fusions
The NPM1 gene
Tumour suppressor genes
DNA methylation related genes
Signaling genes
Chromatin remodelling genes
Cohesion complex genes
Spliceosome complex genes
Myeloid transcription factor genes
```
120
If setting up a AML gene panel what would be the kin genes to screen, according to ELN 2017
NPM1, CEBPA, RUNX1 (define disease)
FLT3 ITD & TKD
TP53 & AXSL1 (consistently poor prognosis)
