Haematological Malignancies Flashcards
1
Q
What is the definition of leukaemia?
A
- Circulating leukaemia cells in the peripheral blood
- Leukaemia cells in the bone marrow
2
Q
Myelodysplasia
A
- Insufficient production of mature blood cells
- +/- leukaemia cells in the peripheral blood/bone marrow
3
Q
Myeloproliferative disorders
A
Excessive production of mature blood cells
4
Q
Lymphomas
A
Lymphoid cancers in lymphoid containing tissues
5
Q
Plasma cell dyscrasias
A
- Increased plasma cells in BM
- Paraprotein (monoclonal immunoglobulin - M band)
- +/- end organ damage
6
Q
Haematological malignancies associated with EBV infection:
A
- Hodgkin lymphoma
- Burkitt lymphoma
- Post-transplant lymphoproliferative disorder
7
Q
Haematological malignancies associated with HTLV-1 infection:
A
- Acute t-lymphoblastic leukaemia/lymphoma
8
Q
Haematological malignancies associated with HIV infection:
A
- Cerebral DLCBL
- Hodgkin lymphoma
- Diffuse large B-cell lymphoma
9
Q
Haematological malignancies associated with HHV-6 infection:
A
Primary effusion lymphoma
10
Q
Environmental exposures assoc with increased risk of haematopoietic malignancies?
A
Chemotherapy:
- Secondary/treatment related AML/MDS
- etoposide
- anthracyclines (doxorubicin etc.)
- autologous SCT
Radiation:
- Secondary acute leukaemia/CML/myelodysplasia
Petrochemical/benzene
- multiple myeloma
Hair Dye
- follicular lymphoma
11
Q
Familial haematological malignancies?
A
Cancer syndromes
- Li fraumeni syndrome (p53)
- Bloom syndrome (BLM gene, DNA helicase)
Identified mutations:
- Acute leukaemia (RUNX1)
- Myelodysplasia (GATA2)
12
Q
What morphological, cytochemical and immunophenotyping characteristics are seen in AML?
A
Morphology:
- acute leukaemia >20% blasts in blood or BM
- blasts with auer rods - Myeloid leukaemia
- Cytochemistry - myeloperoxidase positive
Immunophenotyping:
- myeloid antigens i.e. CD13, CD33
13
Q
What is the strongest prognostic factor in AML?
A
Age >60 is the strongest adverse prognostic factor
14
Q
What are the cytogenetic/molecular prognostic factors of AML?
A
Cytogenetics:
Good - t(15;17), inv(16), t(8;21)
Intermediate - normal, Y-
Poor - del7, del5q, inv(3), t(3;3), t(6;9), t(9:22), 11q23 abn, complex (>= 3 abnormalities)
Molecular (w. normal karyotype)
- NPM1 - good
- FLT3 - poor
15
Q
What chemo is used in AML, and how many cycles?
A
Cytarabine, anthracycline (doxorubicin)
1x induction course, with 2x consolidation courses
16
Q
How does age influence therapeutic strategy in AML?
A
Age > 60 - choose Rx based upon functional status. regardless, chemotherapy has not been shown to improve survival.
17
Q
How does FLT3-ITD influence treatment in AML?
A
Consider allo BMT in 1st remission, if appropriate donor and patient.
18
Q
What is the treatment strategy in relapsed AML?
A
Consider allo BMT - only curative therapy.
If appropriate donor, if appropriate patient
19
Q
What are the options in treatment refractory AML?
A
Unclear if there is failure to reach CR2, or in relapses within 6 months of completing therapy.
20
Q
How is the diagnosis of Acute lymphoblastic leukaemia made?
A
Morphology - >20% blasts on film with NO auer rods
Immunophenotyping:
- lymphoid antigens:
- either CD10 TdT
- B-cell CD19/20
- T-cell CD2/3/4/8
21
Q
What are prognostic factors in ALL in Adults?
A
Adult ALL
- Poor t(9;22), with molecular Bcr-Abl also poor
(pediatric age group remains the strongest good prognostic factor)
22
Q
What are treatment options in Acute Lymphoblastic Leukaemia?
A
Induction Chemotherapy:
No single therapy directly compared in trials.
Example = Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) alt with high dose MTX and cytarabine.
If Ph+ve, must use TKI (imatinib/dasatinib)
Maintenance chemotherapy:
- consolidation as above
- maintenance, no consensus
High risk disease - should consider Allo BMT - i.e. Ph+ALL in CR1 or in relapse.
23
Q
What effect does minimal residual disease have upon prognosis?
A
In patients who achieve Molecular CR 4 months post Rx, vs those who do not, survival is significantly higher in those who are Ph- and did not undergo SCT post Cr1.
24
Q
What AEs are associated with myeloablative chemo?
A
Gastro - mucositis, diarrhoea.
BM suppression - anaemia, thrombocytopenia, neutropenia
Hair loss
25
```
What toxicity is associated with:
cytarabine
anthracycline
asparagine
vincristine
```
cytarabine - neurotoxicity
antrhacycline - cardiomyopathy
asparagine - liver toxicity
vincristine - neurotoxicity
26
What is the most effective therapy for acute adult leukaemia?
Allogeneic transplant
27
What is the mortality rate in allo SC transplant?
provides graft versus leukaemia effect.
up to 30% in MUD
10% in MRD
infection - bacterial, fungal/aspergillus, PCP, CMV, RSV
Acute GVHD - mortality >50%
Chornic GVHD
28
What is a complement mediated therapy in ALL?
rituximab - CD20+vs ALL - causes complement mediated lysis of CD20 B-cells.
29
What are T-cell mediated therapies in ALL?
1) blinotumomab - Bispecific T-cell engaging (BiTE) antibodies (CD19/CD3) - indicated in refractory/relapsed B-ALL
2) Chimeric antigen receptor 19-28z - modified T-cell infusions.
30
What are the two chronic leukaemias?
Chronic lymphocytic leukaemia - lymphoproliferative disorer
Chronic myeloid leukaemia - myleoproliferative disorder
31
What is the commonest haematologic malignancy and lymphoproliferative disorder?
Chronic lymphocytic leukaemia
32
What is the characteristic finding on a peripheral film in CLL?
Smear Cells
33
In what disease are smear cells seen?
chronic lymphocytic leukaemia
34
What is the characteristic immunophenotype seen on peripheral blood in CLL?
CD5+ CD19+ b-cells, displaying clonality
| - lymphocytes kappa OR lambda light chain restricted
35
What clinical findings are associated in CLL?
lymphadenopathy
immune haemolysis (spherocytes)
thrombocytopenia
bone marrow failure
36
What are the prognostic factors (broadly) in CLL?
clinical stage
immunophenotypic
cytogenic
molecular
37
What are the clinical stages of CLL?
Stage I - lyphocytosis only
Stage II - lymphadenopathy
III - cytopenias (non-immune i.e. BM replacement more significant)
38
What are the cytogenetic prognostic factors in CLL?
>90% have abnormal FISH
11q and 17p deletion - poor prognosis - rapid, therapy resistant
13q deletion - good prognosis
39
What is a poor molecular feature in CLL?
unmutated IgVH genes - assoc with advanced stage, adverse cytogenetics, therapy resistant
40
What is the significance of ZAP-70 in CLL?
Surrogate marker for IgH mutational status. Higher CD38+ ZAP-70 expression is associated with IgH unmutated.
- earlier requirement for therapy
- decreased response, PFS, OS to fludarabine based therapy
41
What resistance to therapy is a poor prognostic marker in CLL?
Fludarabine
42
What treatment is indicated in Asymptomatic CLL patients?
Watchful observation
43
What oral therapy is available to CLL patients?
chlorambucil
44
What are standard IV regimens in the treatment of CLL?
fludarabine/cyclophosphamide regimens
| fludarabine/cyclophosphamide/rituximab (gold std)
45
What therapy can be used in CLL with p53 mutation?
alemtuzumab - anti CD52
| SEs - neutropenia, CMV, PJP
46
What is the target of alemtuzumab? SEs?
alemtuzumab - anti CD52 - present on mature lymphocytes, but not on stem cells.
neutropenia, CMV, PJP
47
Indications for alemtuzumab?
CLL
Cutaneous t-cell lymphoma
t-cell lymphoma
48
In what instances is a allo SCT indicated in CLL?
poor prognosis, in a patient who is suitable and has an appropriate donor
49
What are the clinical features of myelodysplasia?
Bone marrow failure
- anaemia
- neutropenia
- thrombocytopenia
+/- blasts in peripheral blood/BM
50
What are the types of myelodysplasia? (7)
1) Refractory anaemia
2) Refractory anaemia w ringed sideroblasts
3) refractory anaemia with multilineage dysplasia
4) refractory anaemia with excess blasts 1 and 2 (1 peripheral blood monocytes
51
What is the significance of 5q mutation in MDS
5q del syndrome
- females
- better prognosis
- good response to lenalinomide
52
What are prognostic factors in MDS?
Cytogenetics - poor if complex
Cytopenia - trilineage cytopenia with low plt count - poor
Bone marrow blasts >10% - poor
Transfusion requirements
Two prog systems - IPSS, WPSS
IPSS - cytogenetics, cytopenia, blast %
WPSS - type of MDS, chromosomal changes, transfusion requirements
53
What are the treatment options in MDS?
Supportive care - transfusion (+ iron chelation with >20 units of RBCs)
Epigenetic therapy (clinical trials)
- azacytadine
- decitadine
- lenolinamide
Chemotherapy
- Hi dose cheme as per AML
Allogeneic SCT
- if poor prog (high risk IPSS, v. high risk WPSS)
- suitable donor and recipient
54
What are indolent non-hodkin lymphomas?
```
CLL/SLL
Marginal zone lymphoma
- MALT, nodal, splenic
Follicular Lymphoma
Mycosis fungoides
```
55
What are aggressive NHL?
```
Diffuse large B-cell lymphoma
Burkitt lymphoma
Precursor T-lymphoblastic
B-lymphoblastic
Mantle cell
```
56
What is the rationale behind treatment of aggressive/non-aggressive NHL?
Always treat aggressive NHL.
| Treat indolent NHL only if symptomatic or bulky, regardless of extent of disease.
57
How is Lymphoma Diagnosed/staged?
Require tissue in all cases - Bx of Ln or Mass, BMAT
Staging is comprised of:
- Ex
- Biochem ?Inc LDH
- Imaging - CT NCAP
- PET scan (Hodgkin, DLBCL)
- Bone marrow Bx
- +/- LP
58
What is the lymphoma staging system?
Ann Arbor:
- stage I - single nodal group
- stage II - >= nodal groups on same side of diaphragm
- stage III - nodal groups on both sides of the diaphragm
- stage IV - bone marrow/extranodal involvement
B - symptoms - poor prognosis, signify high disease burden
59
What are the characteristic cells seen in Hodkin lymphoma?
reed sternberg cells
60
What is the treatment of early stage disease in HL?
Stage I-II, non bulky, nil B Sx
are treated with abbreviated ABVD therapy - doxorubicin, bleomycin, vincristine, dacarbazine + involved field radiotherapy.
can achieve >80-90% DFS
61
What is the treatment of extensive stage disease in HL?
Stage IIB, bulky, stage III-IV, B Sx
ABVD chemotherapy +/- involved field radiotherapy
Can use escalated dose BEACOPP: Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone
62
What is the treatment of relapsed or primary refractory disease in HL?
Autologous SCT
Brentuximab - anti CD30
Allo SCT
PD-1 checkpoint inhibitor in trials.
63
What is the prognostic index used for Extensive Stage HL?
```
Hansen-Clever score:
Age >=45
Male Sex
HB 15
Lymph
```
64
What are the features on histology of Follicular Lymphoma?
B-cell lymphoma - follicles on histology.
| Note Grade III Dz is treated as DLBLC
65
What is the prognostic index for Follicular lymphoma?
FLIPI index
- nodal groups >4
- LDH
- Age >60
- Stage III/IV
- Hb
66
What is the treatment for Follicular Lymhpoma?
In symptomatic disease:
- no treatment
- Radiotherapy - stage IA disease, which is uncommon, possibility of cure
- Chemotherapy - fludarabine containing or R-CHOP
- Auto SCT
67
What is the maintenance thereapy for follicular lymphoma?
Rituximab up to 2 years post Rx of high risk FLIPI score follicular lymphoma.
68
What is the histological characteristic of Diffuse Large B-cell lymphoma on histology?
diffuse effacement of LN on histology
69
What is the prognostic scoring system for DLBCL?
International prognostic index
- Age
- ECOG 3-4
- LDH
- Extranodal sites
- Stage III/IV
70
What is the treatment of limited stage DLBCL?
6 cycles of R-CHOP = rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone +/- IF radiotherapy
71
What is the treatment of extensive stage DLBLC?
CHOP + Rituximab +/- IF radiotherapy - with 10-15% benefit
72
What is the treatment of relapsed/refractory stage DLBLC?
Salvage high dose chemotherapy or Auto SCT
73
What are the BCR-ABL positive myeloproliferative disorders?
Chronic Myeloid Leukaemia
74
What are the BCR-ABL negative myeloproliferative disorders? (3)
Polycythemia vera
Essential thrombocythemia
Myelofibrosis
75
What are 4 Myeloproliferative disorders?
Chronic myeloid leukaemia
Polycythemia
Essential thrombocytosis
Myelofibrosis
76
What are the cells/features of Chronic myeloid leukaemia?
- neutrophilia
- basophils
- immature myeloid cells
- splenomegaly
77
What are the cells/features of polycythemia
increased RBC + clots + headache + erythromelgia (painful peripheries)
(can be primary or secondary)
78
Essential thrombocytosis
elevated platelets + clot + vascular disease
79
Myelofibrosis
low blood counts
leukoerythroblastic film with tear drop red cells
splenomegaly, bone marrow failure
80
What is the characteristic genetic mutation associated with CML?
t(9;22) - the philadelphia chromosome, causing a Bcr-Abl fusion protein
81
What are the phases of CML? (3)
Chronic phase - 85%, best prognosis - 100
Accelerated phase - blasts 15-29%, blasts+PM >30%, basophils >20%, Plts 30% blasts, either myeloid or lyphoid
82
What is the prognostic index for CML?
```
SOKOL index:
Age
Spleen Size
Platelet count
Blast %
```
83
What mutation is associated with BCR-ABL treatment resistance and poor prognosis?
T315I
84
What is the target of therapy in CML, the names of the drugs used and the % of DFS achieved?
BCR-ABL
imatinib, dasatinib, nilotinib
>90% DFS
85
When is allo SCT indicated in CML?
BCR-ABL therapy resistant mutation, primary resistant disease
86
What gene mutations are associated with MPN signal transduction? (2)
JAK2 V617F and exon 12 mutations
- all PV, 60% ET, 65% PMF
MPLW515K/L in essential thrombocytopenia
87
What are non signal transduction mutations associated in MPN?
Ca2+ binding ER chaperone - Calreticulin in Jak2V617 ET and MF - relatively good prognosis.
```
Epigenetic mods -TET2 EZH2 ASXL1
Cell metab IDH1/2
Protein stability CBL
Gene transcription IKZF1
RNA splicing factor SRSF2
```
88
What is the primary cause of death in PV and ET?
morbidity and mortality is from thrombosis (AMI, stroke, PVD), and venous thrombosis in unusual sites - cerebral vv, budd chiari
89
What treatment is indicated in esssential thrombocytosis?
Hydroxyurea:
| - aim for plt
90
When is hydroxyurea indicated in the treatment of PV?
With splenomegaly, thrombocytosis and or intolerant of phlebotomy, >50yo
91
When is aspirin indicated in ET?
previous thrombotic event, age >60 - has 1/4 risk of recurrence
92
When is primary prophylaxis indicated in PV or ET?
if able to tolerate ASA in PV
| ET
93
What are the goals of venesection in PV?
aim for Hct
94
When is interferon alpha indicated in ET and PV?
ET - women of childbearing age
| PV -
95
What medication is used in the elderly with ET/PV?
chlorambucil
96
What are adverse prognostic findings in Myelofibrosis?
```
Age >65
BSx +ve
Hb 25
Blasts >1%
+/- cytogenetics
Thrombocytopenia
```
97
What constitutes supportive therapy in Myelofibrosis?
transfusion
palliative chemotherapy
+/- splenectomy/splenic irradiation
- allogeneic transplant may be considered in appropriate patients
98
What mutation is targeted in selective therapy for Myelofibrosis, and by what agent?
Jak2
Targeted by Jak1/2 inhibitor Ruxolitinib
improves splenomegaly/systemic symptoms, but no survival benefit over supportive Rx.
AEs: haematologic toxicity with anaemia and thrombocytopenia.
Does not eradicate the disease clone JAK2V617F
99
What are the high risk mutations in PMF? (4)
ASXL1
EZH2
SRSF2
IDH1/2
100
What is a low risk mutation in PMF?
CALR
101
What are Clinical prognostic factors in PMF?
IPPSs
DIPPS
DIPPS-plus
102
What are 3 significant plasma cell dyscrasias?
Monoclonal gammopathy of uncertain significance
Multiple myeloma
Amyloidosis
103
What are the diagnostic features of MM?
>10% malignant plasma cells on BMAT
Monoclonal Ig on serum/urine
- M band (suspicious if prot/albumin gap)
- IgG > IgA > IgM > IgD
- reduction in other immunoglobulins (immune paresis)
104
What organs are involved typically in MM?
CRAB!
Calcium elevated
Renal impairment/failure
Anaemia
Bones - lytic lesions, significant osteopenia, spinal cord compression
105
What is the prognostic index for MM?
International staging system
Stage I: B2 microglobulin =35
Stage II: not I or III
Stage III: B2 microglobulin >5.5
106
What are poor prognosis cytogenetics in MM?
```
complex karyotypes
del13
del17
t(4;14)
```
107
What is oral disease modifying therapy in MM?
melphalan
dexamethasone
thalidomide
108
What is IV disease modifying therapy in MM?
cyclophosphamide (esp if rapid response required/extensive disease)
109
What are immune mod agents used in MM?
thalidomide
| lenalinomide
110
What is a small molecule inhibitor used in MM, and it's target of action
Bortezomib
binds to 26S proteasome and inhibits.
30% have peripheral neuropathy.
also causes myelosupression and shingles
111
What is coupled with auto SCT in MM?
high dose melphalan therapy has a mortality benefit.
Can do tandem auto-allo transplant in high risk patients
allow for high dose chemo to be given
112
What is the pathology of primary systemic amyloidosis?
= MGUS with attitude
amyloidogenic monoclonal protein
(often very low level and undetectable on SPEP)
Serum free light chains elevated (kappa or lambda)
113
What organs are involved in systemic amyloidosis?
Kidney - nephrotic syndrome/failure
Heart - cardiac amyloid - diastolic dysfunction, septal thickening, cause of death
GIT - vasculopathy and bleeding risk
Skin - amyloid plaques
114
What is involved in the prognostic index for primary systemic amyloidosis?
Troponin
| pro-BNP
115
What is the therapy for Primary systemic amyloidosis?
po - melphalan, dexamethasone
immunomodulators - thalidomide, lenalinomide +/- auto SCT in select pats
Trials - anti-amyloid Ab
