Oncology Flashcards
1
Q
Abnormality in CML
A
t(9;22)(q34q11)
Bcr-abl1
2
Q
How many cml patients have the t(9;22)
A
95%
5% cryptic or complex
3
Q
Findings in CLL
A
13q14 miRNA good 11q22-23 ATM intermediate \+12 Low Del 6q21 low Del 17p13 high risk Complex
4
Q
What does CLL transform to
A
DD MCL
DLBCL
HL
5
Q
Genetics of plasma cell myeloma
A
Hyperdiploid (odd numbers)- 3,5,7,11,15,19,21
Non hyperdiploid - IGH
6
Q
3 B-cell neoplasms
A
CLL
MM
LYMPHOMA
7
Q
Location of IGH
A
14q32
8
Q
Near haploid?
A
Less than 30
9
Q
Low hypodiploid
A
30-39
10
Q
High hypodiploid
A
44-44
11
Q
Near Triploid
A
60-78
12
Q
High hyperdiploid
A
51-65
13
Q
Genetics in Childhool ALL
A
T(4;11)(q21-q23) KMT2a-AFF1
T(12;21)(p14;q22) ETV6-RUnx1
14
Q
MDS CLASSIFICATIONS
A
Good - normal, del5q, del 12p, del 20q
Int - del 7q, + 8, +19, i(17q)
Poor - -7, inv(3), t(3), -7/del7 double, complex (3)
Very poor - more than 3 abn
15
Q
3 good prognosis AML
A
T(8;21)(q22;q22) runx1/runxt1
T(16;16)(p13;q22) or inv(16;16) CBFB/myh11
T(15;17)(q24;q21) PML-Rara
16
Q
If increased granulocytes and immature myoblasts what is indicated?
A
CML
17
Q
What is CML?
A
Chronic myeloid leukaemia - MPN originating in pluripotent bone marrow stem cells
Clonal myeloproliferative disorder of haematopoietic stem cells
18
Q
How is blast crisis defined in CML?
A
> 20% blasts
19
Q
What is a tyrosine kinase?
A
Enzyme that can transfer a phosphate group from ATP to a protein in the cell. On off switch in many cellular functions. Phosphorylation of proteins is an important mechanism in cell signalling and regulating cellular activity e.g. proliferation.
Phosphorylation of tyrosine amino acids.
Leads to conformational change
20
Q
What proportion of CML is ph negative but BCR-ABL positive?
A
2%
21
Q
New proportions CML
Classic 9-22
Variant 9,22,Z
Cryptic ins (22;9)
A
87%
10%
3%
22
Q
How does deletion of der(9) affect CML?
A
It doesn’t with imatinib
It used to with interpheron treatment
Fish - 1 red, 1 green, 1 fusion
23
Q
Fish patterns in CML?
A
Classic - 1 red, 1 green, 1 fusion
Der(9) del would be 1R1G1F (use aqua (9q34)
Aqua: 1RAQ(normal 9), 1G(normal 22), 1Faq (shows 9q intact therefore colocalisation)
1RAQ 1G 1F
24
Q
Common secondary abnormalities associated with advanced CML?
A
\+8 (33%) \+Ph (30%) ISO 17q (20%) \+19 (12%) Loss y \+21 -7
Usually evolve later but sometimes present
25
Clinal abnormalities in ph- cells following treatment
```
+8
-7
-y
Del 20q
Del 7p
+y
+marker
```
8-10% incidence
26
What’s the international scale for Barcelona-abl1?
Conversion factor for each lab.
Previously administered by European reference lab but now locally in Uk / Salisbury/Southampton
With aid of WHO standards and soon to be commercially available “Lyon panel” dilutions of K562 in HL60 (freeze dried cell line)- UKNEQAS
```
Improve comparison
IS expresses detectable disease as %
MMR - 0.1%
Apply lab specific conversion factors - sample exchange with reference lab
Had to convert all graphs
```
27
What causes tki resistance?
Mutations in TKD
Depending on location - different resistance
Compound mutations are worse
Polyclonal (2 clones with different mutations) or compound
P-loop mutations poorer prognosis
28
What is ELN?
European leukemiaNet
CML guidelines
29
What is considered prolonged remission and what is monitoring strategy?
Greater 2 years
Every4-6 weeks in first 12 months
If stable every 3 months
Same for post BMT
30
Some other genes might influence CML - progression after tki
DNMT3A and ASXL1
Branford Et al 2018
WES and RNA SEQ
variants found at presentation in 15/27 (56%) with subsequent blast
ASXL1, runx1, ikzf1 and new in SETD1B - 3 patients
If very high cases upfront could consider SCT?
31
Chance of maintaining remission if come off tki
40-60%
Requires even closer monitoring to rescue early relapse
32
Most common myeloproliferative disease?
CML
| 15-20% of all leukaemias
33
Risk factor in CML?
Ionising radiation - increase after atomic bombs on Hiroshima and Nagasaki
Radiation therapy treatment
More common men than women
Median age 60
34
Clinical features CML
Leukocytosis
More immature cells
Splenomegaly
High platelets but not erythrocytes
Weight loss, fever, bone pain, weaknes, joint pain, fatigue, loss appetite
35
Advantage of fish over g-band
- quick, expertises, sun microscopic, no need for dividing cells
Drawback - only specific question
36
CML DRUGS
```
Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib
```
Don’t cure
Treatment tki greatly improved survival 85% expected to have normal life span
37
Define complete haematological response
Normalisation of blood count
Resolution of splenomegaly
As many as 10^10 leukaemia cells may still be present sensitivity 5%
38
Define complete cytogenetic response
No ph metaphase amongs 20 marrow cells (5%sensitivity)
But-abl ratio 1% or less (fish sesnsitivity 1%)
39
Define major molecular response
Bcr-abl ration 0.1% or less
40
Complete molecular response
Bcr abl ratio of 0
41
What proportion of people will fail imatinib by 24 months?
49%
42
Second generation tki
Dasatanib
- 300 gold greater potency than imatinib
Effective against lots tkd mutations except T315I
Binds both inactive and active firms bcr-abl1
Actually believed to be superior
Nilotinib
- as above ok for most must except T315I
Better fit to protein
43
Future aims CML
Identifying those at diagnosis who will progress to blast e.g. level CIP2A- patients with high CIP2A DEFINITELY progress to blast- don’t progress if get second generation TKI
Identifying those to stop treatment
- side effects - nausea, diarrhoea, headaches, muscle cramps, fluid retention. Predicted to save NHS 1 million
Novel targets to eliminate residual stem cells
44
What is destiny trial?
DeEscalation and Stopping Treatment of Imatinib Nilotinib or srYcel
Given half dose for 12 months then stopped
45
Drug that is resistant to T315I?
Ponatinib
46
Why are second generation tki not front line?
Although increased potency and gets cyto and mol response quicker, not translated into better long-term outcomes
Also tolerance, safety and cost - more early and late toxicities, imatinib off patent since 2016
Patients fail frontline move to secondary - might be skewing survival data
High sokal score - should go second generation up front
47
DMR
Deep molecular response
48
Alternatives to ELN
National cancer comprehensive network - 2018 USA
Difference - at 6 months 7% usual monitoring but would be ELN warning
49
ELN warnings
Additional abnormalities
50
Probability of developing blast crisis?
5% in tki era
Note most chromosome abnormalities decrease but-7 and 3q26 seem to increase now
51
What is STIM1 study?
French stop imatinib 1
Prospective trial 100 CML with undetectable disease 5 log reduction over 2 years
Relapse - two positive samples 1 month apart
Rise of log 1
At 77 months 60% relapsed but retreated and fine - no AKD and no blast
Most relapsed in first 7 months, none occurred after 2 year mark
Findings confirmed 7 other trials
EURO- SKI - biggest 750 patients - saving 28 million estimated
52
Who might be good for discontinuing treatment?
Non high Sokal risk
Typical transcript type
Optimal response over 8 years
In MR4.5 for 2 years
Exclude - prior advanced failure, In failure, less than 3 years treatment, not in mr4.5, deep molecular response less than a year
Hughes and Ross 2016 guidelines
53
Falling disease post continuation imatinib?
Highly sensitive genomic pcr to monitor depth
Reduction mr5-mr6.1
Gradual extinction of long lived lineage commited cells that lack self renewal
Depletion of slow proliferating cml precursors
Do we need this?
54
MAJOR MOLECULAR RESPONSE?
3 log reduction from baseline
55
Definition ELN warning
Characteristic of disease that adversely affect patient response to imatinib - more monitoring
56
What does CML transform to?
AML, ALL especially if del 5, -7 or inv16
Progression - EV1 on 3q26
Myeloid progression - +8 +12
57
Most common bcr-abl1 fusions?
E13a2 e14a2 210kda protein
E1a2 190kDa protein
E19a2 230kda protein
Use RNA as breakpoints spread out
58
What are MPN?
Group of related clonal haematological disorder
Predominantly over 60
Accumulation of 1 or more myeloid cell lineage
Tendency to transform AML
59
7 forms of MPN (WHO)
CML
Classic - polycythaemia vera, essential thrombocythaemia, primary myelofibrosis
Atypical
Chronic neutrophilic leukaemia, chronic eaosinophilic leukaemia, MPN Unclassified
60
What is polycythaemia Vera?
Increased RBC
Fatigue, headache, dizzi, sweating, ruddy complexion, mild splenomegaly
95% have JAK2 p.V617F
Raised Hb, viscous blood, increased red cell mass, low erythropoietin
61
What is essential thrombocythaemia
Increased platelets
Large mature megakaryocytes IN BM
Exclude bcr-abl, cml, pv,pmf, mds,
Presence jak2, calr or mpl mutation
Symptoms - headache, dizziness, syncope,visual disturbance
Progress to MF AND AML
LAB: elevated platelets, leukocytosis, 85% have mutation in jak2, CALR or MPL
62
3 genes for ET
JAK2, mpl, CALR
63
What is primary myelofibrosis?
Proliferation megakaryocytes and granulocytes in BM
DEPOSITION of fibrous connective tissue in BM, worsening pancytopaenia and extramedullary harmatopoesis
Anaemia and associated features - tired, splenomegaly
Lab - uncleared rbc, year drop rbc, large platelets, and increased cd34+ blasts
10-20% risk to AML
93% have JAK2, calr, mpl
64
Role of JAK2
No receptor tyrosine kinase involves haematopoesis
Direct activation through V617F and done PV IN exon 12
Indirect systemisation through CALR and mpl
65
What is common JAK2 mutation?
V617F
also exon 12 in some PV
66
What are 2 common CALR mutations?
52bp del
5bp ins
67
Common mpl mutation?
W515L
Also W515K, W515A AND W515R
68
Treatment for PV
Prevent thrombocytic event - low dose aspirin and venesection
Cytoreductive chemo
Hydroxyurea - reduces blood cells but can get resistant
Interferon - suppresses erythrocytosis but unpleasant side effects
Ruxolitinub - JAK2 inhibitor
69
JAK2 inhibitor
Ruxolitinib
70
Treatment ET
Reduce thromboembolic events - aspirin but not if high platelets as can increase bleeding risk
Cytoreductive chemo
Hydroxyurea - reduces platelets and risk bleed
Anagrelide - blocks megakaryocyte differentiation and proliferation
Interferon alpha - bad side effect
71
Treatment for MF
ISK stratify first
Young - allogenic sct
Lower risk solve anaemia - transfusion, erythronium stimulator, steroids, androgens, thalidomide
Splenomegaly - hydroxyurea interferon alpha, JAK2 inhibitor, splenectomy
72
MPN?
Myeloproliferative neoplasm
Clonal harmatopoiesis and chronic excessive production of mature differentiated blood cells
73
3 classic MPN
PV
ET
PF
74
What cell line has V617F
Exclusive to myeloid malignancies
75
Where is JAK2?
9p24
Jak2 deficient cells fail to respond to growth factors - erythropoietin resulting in lack of myeloid cell proliferation and differentiation V617F IS GOF
76
How can single v617f cause 3 disease?
1. One hit - sufficient to induce MPN BY EITHER - different cell type, background of patient, intensity of jak2 signalling
2. Secondary event where primary hit varies
Nb - homozygosity due to LOH AT JAK2 locus actually due to UPD
77
MDS?
Myelodysplastic syndromes - group haematological malignancies characterised by clonal expansionof bone marrow myeloid cells with impaired differentiation
Peripheral cytopenias due to ineffective harmatopoesis and dysplasia in 1 or more myeloid lines
Increased risk AML
78
Dysplasia?
Abnormal development of cells
79
CHIP
Clonal haematopoesis of indeterminate potential
Acquisition of somatic mutations that drive clonal expansion but not cytopaenias or dysplastic haematopoesis
Clonalmutations but not cytopaemias
Age related phenomenon - HSC OR other progenitors contribute to formation of genetically distinct subtype cells - globally derived,
Recent studies show 10-20% population over 70 show clonal haematopoesis
80
ICUS
Idiopathic cytopaenias undertermibed significance
Signs MDS But no muts and normal karyotype - monitor as may get MDS/AML
81
Somatic mutations in MDS?
TP53, nras?kras, runx1, atrx, flt3,kit, NPM1 as move into AML
82
WHO DEFINITION MDS?
Blood cytopaenias, exclusion of non-haematopoesis cause, excess blasts greater 5%, >10% dysplastic cells in at least 1 myeloid line, >15% ring suderibladts, cytogenetic abnormality, (excludes plus 8, loss Y, del 20q
Mutation and flow only support MDS not definitive
-y loss older men
Plus 8 seen aplastic anaemia
Del20q cytopaenias but not MDs
+15 also lacks diagnostic significance
83
Mutations seen in CHIP?
DNMT3A, TET2, ASXL1, TP53, JAK2, SF3B1
Chip phenomenon precludes the current use of mutations in isolation to diagnose MDS
84
Other things that can cause dysplasia?
Alcohol, infection, cytotoxic agents,nutritional deficiencies
85
MDS VERY GOOD
-Y
| Del 11q
86
MDs good
```
Del 5q
Normal
Del 12p
Del 20q
Double inc 5q
```
87
MDs poor
-7, inches/t involving 3q, double including -7, del 7q
88
MDs very poor
Greater than 3 abnormalities
89
Blasts in MDS?
Less than 20%
90
D.E. novo causes MDS?
Viral, smoking, fanconi, benzene exposure
91
Secondary MDS?
Due to cytotoxic chemicals, alkylating agent
Secondary MDs rising cos improvements in cancer related treatment outcomes
92
Standard care for MDS?
Supportive therapy,transfusions, bone marrow stimulation or chemo
BMT limited role but only curative treatment
93
How common is UPD in MDS?
20%
94
MDS WITH EXCESS BLASTS?
Poor as likely progress
95
High risk MDS?
RAEB1 - cytopaenias, less 5% blasts, no auer rods
RAEB2 - cytopaenias 5-19% blasts, plus minus auer rods
MDS-EB excess blasts
96
Aplastic anaemia?
Autoimmune disease which destroys HCS leading to pancytopaenia
Challenge to distinguish from MDS with hypocellular bone marrow
AA- cytopaenia at least 2 lines and hypocellular BM - macrocytosis buy no megakaryocytes and no dysplasia
MDS - dysplastic features, clonal chromosome abnormalities,
97
EVI1 location?
MDs poor
| 3q36 - won’t detect on SNP ARRAY
98
MDS V AA
Prognosis of AA derived MDS less favourable
If normal karyotype - call AA
CN LOH of 6p - AA. HLA complex
99
Pseudoclonality
Clonal evolution may indicate pseudoclonality because of depletion of stem cell reserves and clonal defects represent intrinsically non- pathogenic defects which tend to disappear with restoration of normal haematopoetic function
100
Favourable AML?
3 chromosomes
2 molecular
```
T(8;21) runx1-runxt1
Inv16 cbfb-myh11
T(15;17) pml-rara
Npm1 mut and flt3 low
Biallelic mutation in. CEBPA
```
101
Intermediate AML
2 cyto 2 chrom
Mut npmi and flt-itd high
Wt npm1 flt3 low/none
T(9;11) mllt3-kmt2a
Other cyto
102
Adverse AML
| 5 chromosomes
```
T(3/inv(3 GATA2 EVI1
T(6;9)DEK NUP214
T(9;22) bcr-abl
-5 or 5q
-17 -17 abn p
Complex
Monosomsl
Wt npmi flt3 high
Mutated runx1, asxl and tp53
```
103
Which aml translocation associatedwith myeloid sarcoma?
Inv16 t(16) CBFB-Myh11
104
What do you use ATRA for?
All trans retinoic acid
Differentiating agent to treat t(15;17) pml-rara
105
Driver vs passenger?
Drive - confers a fitness advantage
Passenger - no effect on fitness/growth characteristics
But - drug resistance?
106
Class 1 and 2 AML mutations?
Class 1 - proliferation advantage
Class 2 - impair differentiation
107
WHO classes of b-cell ALL
```
Hyperdiploid
Hypodiploid
T(9;22) bcr-abl1
T(12;21) etv6-rubx1
T(11q23) MLL
IAMP21
Bcr-abl1 like
T(1;19) tcf3-pbx1
T(5;14) IL3-IGH
```
