Chronic Leukemia Flashcards
CHRONIC LEUKAEMIAS
(Rapidly or Slowly?) progressing malignancy that starts in blood- forming tissue and causes the production and accumulation of abnormal blood cells.
Slowly
CHRONIC LEUKAEMIAS
Accumulated blood cells are ________ cells . cells in (early or late?) stages of myeloid or lymphoid cell production
matured white
Late
CHRONIC LEUKAEMIAS
There are two main types: _________ and ________ , both of which primarily affect (children or adults?) .
chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML)
Adults
CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
____clonal disorder characterized by a progressive accumulation of __________ lymphocytes
- Characterized by chronic persistent lympho_____.
Mono
functionally incompetent
cytosis
CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
In the case of CLL, B-cell CLL derives from the _____________ B cell.
They express CD___, CD__ and CD___ and have (elevated or reduced ?) levels of membrane immunoglobulins (IgM, IgD), CD79b & FMC7.
antigen- experienced
19; 5; 23
Reduced
CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
CLL cells are monoclonal because they _____________________
express only one form of light chain (lambda or kappa) on their cell surface.
In CLL
All normal stages of lymphoid development are postulated to have a malignant counterpart.
T/F
T
CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
B cell CLL is characterized by a progressive accumulation within the marrow and blood of long-lived mature leukaemic lymphocytes due to:
stimulation of ______ by ______
due to reduced ______
not because of _______
growth by external signals
apoptosis
rapid production
CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)
B cell CLL is characterized by a progressive accumulation within the marrow and blood of long-lived mature leukaemic lymphocytes due to:
•stimulation of growth by external signals e.g _____,_____ and ligands binding to ________, and
•due to reduced apoptosis felt to be largely mediated by overexpression of ___, a protein known to inhibit cellular apoptosis.
cytokines, chemokines; B cell receptors
bcl-2
T-CLL is a common disease.
T/F
F
T-CLL is a rare disease, therefore Much less is known about
_____ is the most common form of leukaemia in the western hemisphere
It makes up ___-__% of all leukaemias.
B-CLL
25-30
The peak incidence of CLL is in the ___ decade of life.
The overall incidence is 20 per 100,000 in persons >___ years of age.
6th
70
The male to female ratio of CLL is __:___
2:1.
95% of CLL is of ___ cell origin.
___-CLL is a rare disease.
B
T
CLL - Epidemiology
Overall median survival of patients is about ___-___ years.
10 to 20
CLL - Epidemiology
Individual prognosis can be quite variable – _____ in some patients and life expectancy is not shortened, _____ in others and can progress rapidly and survival from diagnosis may be __-__ years.
indolent
aggressive
2-3
CLL - Epidemiology
Mortality often due to:
•overwhelming _____ with marked ____ and ——-
•Overwhelming ______
•_______
•transformation to an aggressive ______, so called a _______
tumour burden; adenopathy and splenomegaly
infection
bleeding
Lymphoma; Richter’s transformation.
CLL – Clinical features
Incidental finding on _____, where there is isolated _____ and the patient is asymptomatic.
If complaints are present, they are usually:____,_______, night sweats, fever and ________
CBC; lymphocytosis
weakness, easy fatigue
weight loss.
CLL – Clinical features
• There may be frequent bacterial and viral infections because of ________.
•Patients with CLL may report ________ to _________ or _______
hypogammaglobulinemia
an exaggerated response
mosquito or other insect bites.
CLL – Clinical features
On physical examination, (symmetrical or asymmetrical?) peripheral ______ is most frequent abnormal finding involving the neck, axillae and inguinal regions.
Nodes are usually (painful or painless?) .
symmetrical; lymphadenopathy
Painless
CLL – Clinical features
_________ and ______ are variably present.
__________ and __________ are associated with CLL and can result in severe anaemia and thrombocytopenia.
Splenomegaly and hepatomegaly
Autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP)
CLL – Clinical features
_____ occurs 10-25% of the time, while ___ is seen in 2% of patients.
AIHA; ITP
CLL – Clinical features
________,______,_______, and _______ result from the immune dysregulation which occurs in CLL.
AIHA, ITP, hypogammaglobulinemia and an exaggerated response to mosquito bites
Which occurs more in CLL patients
AIHA or ITP
AIHA
Lymph gland involvement in CLL
•may be _____ or ____, but generally it is ____________
•________ or ______ but not ______
subtle or spectacular ; only within nodes
unsightly or uncomfortable; invasive
CLL – Laboratory findings
Lymphocytosis: diagnosis of CLL requires evidence of lymphocytosis, at least ____ × 109/L, and lymphocytic infiltration in the ______ of at least ___%.
10
bone marrow
40
CLL – Laboratory findings
With immunological methods, particularly the detection of monoclonal B-cell populations by _______, it is possible to diagnose the disease with lymphocyte counts below this threshold. (Absolute clonal B cell lymphocyte count >___ × 109/L)
light-chain restriction
5
CLL – Laboratory findings
30% of CLL patients have _______ or _______ secondary to an immune process or marrow infiltration.
anaemia or thrombocytopenia
CLL – Laboratory findings
Morphologically, the lymphocytes in blood films are (small or large?) and show scanty cytoplasm and a characteristic pattern of ________, nucleolus is ______
Small
nuclear chromatin clumping
inconspicuous
Azurophil granules are seen on all normal T cells
T/F
F
Azurophil granules are seen only in a minority of normal T cells.
CLL – Laboratory findings
The presence of ____/____ cells, literally _____, destroyed cells on a regular blood smear, is consistently seen with CLL
smudge/smear
flattened
CLL cells morphologicallu indistinguishable from normal lymphocytes.
T/F
T
CLL – Laboratory findings
•Peripheral film usually shows ____cytic _____chromic anaemia in (early or later?) stages.
•If AIHA is present, _____ and _____ can be seen on the blood smear.
•Bone marrow: cellularity is ___eased and 30-99% of nucleated cells are (mature or immature?) lymphocytes.
normo; normo; later
spherocytes and polychromasia
incr; mature
CLL in blood counts of 50x109/l (or more) are often with symptoms
T/F
F
As cells are small, non-functional and largely “inert”, CLL in blood counts of 50x109/l (or more) are often without symptoms
CLL – Laboratory findings
Immunophenotyping: CLL cells co-express CD___ and CD__.
19 ; 5
CLL – Laboratory findings
CD19 is a __ cell marker, and CD5 is a __-cell marker.
B
T
The expression of a T cell marker on a B cell is an example of _______
lineage infidelity
lineage infidelity is seen in only CLL
T/F
F
lineage infidelity that is seen not only in CLL but in AML and ALL as well.
CLL – Laboratory findings Immunophenotyping:
CLL cells are also positive for CD___, negative for CD____ (or dim+), are either ________ or _______ restricted and have a dim level of expression of the immunoglobulin heavy chains IgM and IgD.
23
79b
kappa or lambda light chain
Which is more normally, Bcell or Tcell
Tcell
The normal T-cell/B-cell ratio is reversed in CLL.
T/F
T
Normally, T lymphocytes constitute approximately ____% of the total lymphoid population and B lymphocytes, ____% of the lymphoid cells.
80
20
In B-cell CLL, B cells account for nearly ____% of all lymphocytes.
90
Cytogenetics and molecular diagnostics are needed to make the diagnosis of CLL.
T/F
F
They are not
CLL – Laboratory findings
Cytogenetics and molecular diagnostics are useful in _____________.
determining the survival of patients
CLL – Laboratory findings
Cytogenetics and molecular diagnostics:
In particular,___________, corresponding to a mutation in the _____ gene, is associated with a very short survival, as are ___________.
17p deletions; p53
11q deletions
CLL – Laboratory findings
Cytogenetics and molecular diagnostics:
Other markers of poor prognosis include the presence of the ____ mutation (with or without chromosome deletions), and an _________ gene.
p53
unmutated Vh
Vh corresponds to the _____ portion of the immunoglobulin _____ chain.
variable
heavy
CLL – Diagnostic criteria
•>__ x 109/L absolute blood lymphocytosis and cells morphologically _____ in appearance, sustained over at least a _____ period.
•___% lymphocytes in a _________ bone marrow.
•A monoclonal B-cell phenotype simultaneously showing CD__ positivity (dual positivity CD__, CD__-__ and CD___).
5; mature; 4 week
30; normocellular or hypercellular
5; 5; 19-20; 23
CLL – Differential Diagnosis
_______
_______
_______
_______
________
________
B-PLL B cell prolymphocytic leukaemia
T-PLL/CLL
Hairy cell leukaemia (HCL)
Non-Hodgkin’s lymphoma Mononucleosis and other viral infections
Acute lymphoblastic leukaemias
CLL – Differential Diagnosis
B-PLL – B cell prolymphocytic leukaemia:
clonal disorder of B cells where 55% or more of cells have a _____ when examined morphologically. (More or less?) aggressive leukaemia.
nucleolus
More
CLL – Differential Diagnosis
T-PLL/CLL
– may be indistinguishable from ____ or ____ morphologically.
-_____distinguishes the T cell origin of this malignancy from its B cell counterpart.
-(More or less?) aggressive leukaemia.
B-CLL or B-PLL
Immunophenotyping
More
CLL – Differential Diagnosis
Hairy cell leukaemia (HCL)
– also produces a clonal lymphocytosis but the lymphocytes have ________ .
-Usually associated with more profound _______, and with marked ________.
hair-like projections
pancytopenia
splenomegaly
CLL – Differential Diagnosis
Non-Hodgkin’s lymphoma with circulating lymphoma cells:
-In ______ lymphoma and _____ lymphoma there may be circulating malignant lymphocytes.
-____lymphoma with ___ lymphocytes (SLVL) (or splenic marginal zone lymphoma) may also present with a clonal lymphocytosis.
follicular; mantle cell
Splenic; villous
CLL – Differential Diagnosis
Mononucleosis and other viral infections:
-Mononucleosis can cause ____,_____, and ______.
- Usually it is an illness of ______, in whom CLL is quite (common or rare?) .
-Unlike CLL, mononucleosis and other viral infections are _____ and the lymphocytosis _____________
lymphocytosis, splenomegaly and adenopathy
younger adults;rare
self-limited ; resolves spontaneously.
CLL – Differential Diagnosis
Acute lymphoblastic leukaemias are usually very (difficultly or easily?) distinguished from CLL by their presentation and by the morphology of the _______.
easily
blasts
Also, lymphocytes in mononucleosis are usually atypical.
They are irregularly shaped, _______ size , and sometimes resemble ______.
medium to large
monocytes
CLL – Staging (Rai)
0-_______: >___ x 10^9 in blood and >__% in bone marrow
1-stage 0 with ______
2- stage 1 with _______
3- stage 2 with _____
4- stage 3 with ________
lymphocytosis; 15; 40
enlarge lymph node
hepatomegaly, splenomegaly, or both
Anaemia
thrombocytopenia
CLL – Staging (Binet)
Binet Staging classifies CLL according to the ____________ as well as presence of ________ or _______
number of lymphoid tissues that are involved
low red blood cell count (anaemia) or low number of platelets (thrombocytopenia):
CLL – Staging (Binet)
Binet Stage A patients have _______ areas of enlarged lymphoid tissue and _______ anaemia or thrombocytopenia.
Binet Stage B patients have _______ areas of enlarged lymphoid tissue and ________ anaemia or thrombocytopenia.
Binet Stage C patients _______ anaemia and/or thrombocytopenia
fewer than three ; do not have
three or more ; do not have
have
CLL –
Secondary causes of anaemia eg iron def.,or AIHA or ITP must be treated after staging.
T/F
F
Before
CLL – Treatment and outcome
The Rai staging system, developed in the 1980s, predicts ______ from the time of diagnosis and reflects the ____ of disease.
median survival
burden
The Rai staging system aids in determining who should be treated.
T/F
T
CLL – Treatment and outcome
Indications for treatment: Unlike AML and ALL which are uniformly fatal shortly after diagnosis, CLL may have an indolent course. Thus, not all patients ______________.
In fact, _____ patients, in particular, may die of another illness before they have any complications related to their CLL.
require therapy at diagnosis
elderly
CLL – Treatment and outcome
Decision to treat is guided by ______, the presence of _______, and ______ activity.
clinical staging
symptoms
disease
CLL – Treatment and outcome
Evidence that treatment can improve outcome is only available for patients with Rai stage ________
III and IV
Patients in earlier stages of CLL (Rai 0-II, Binet A) are generally treated
T/F
F
Are generally not treated but monitored with a “watch and wait” strategy.
CLL – Treatment and outcome
In early stages, treatment is necessary only if _____________ occur
symptoms associated with the disease
CLL – Treatment and outcome
Some early stage patients will be treated if they have a lymphocyte doubling time of _______, which reflects (more or less ?) aggressive disease.
less than 6 months
More
Indications for therapy in CLL:
________
________
____-related symptoms
Markedly enlarged or ——— _____
Symptomatic ________
Blood lymphocyte count doubling time <________
_______ transformation
_______ transformation
Anaemia; Thrombocytopenia
Disease
painful spleen; lymphadenopathy
6 months; Prolymphocytic; Richter
CLL – Treatment and outcome
The main categories of treatment include:
____therapy
_____therapy
___________ transplantation
___________
Intravenous ________
Chemo
Immuno
Allogeneic stem cell
Glucocorticoids
gammaglobulin
CLL – Treatment and outcome
Chemotherapy: The ____ analog ,______ is the most active agent used to treat CLL.
Other agents that are used are the alkylating agents, ______ and _____
•These drugs are given ___ or in ____ with ______ and/or with the ______
purine; fludarabine
chlorambucil and cyclophosphamide.
alone; combination; one another
monoclonal antibodies
CLL – Treatment and outcome
• Immunotherapy:
_____, a monoclonal antibody targeting CD___, which has (weak or strong?) expression on CLL cells, has more recently been added to the treatment of CLL.
Alemtuzumab, a monoclonal antibody against CD___, which is expressed on ___ lymphocytes, is also effective in CLL.
Rituximab
20; weak
53; all
CLL – Treatment and outcome
Allogeneic stem cell transplantation: This intensive therapy is reserved for (younger or older ?) patients with aggressive disease that may be ______ or may have _____ after treatment with _____.
It may cure up to ____% of patients but is associated with about a ____% chance of treatment related mortality, and a significant risk of ———— disease.
Younger
resistant; relapsed; fludarabine
30-40; 20
graft versus host
CLL – Treatment and outcome
Glucocorticoids (Prednisone) are used to treat ______ and _____
AIHA and ITP.
CLL – Treatment and outcome
Intravenous gammaglobulin (pooled, multi-donor immunoglobulins) are used to reduce the rate of _____ in patients with _________ and __________.
infections
hypogammaglobulinemia
recurrent infections.
Allogeneic stem cell transplantation in CLL
It offers the potential of the immune-mediated ____________ effect (adoptive immunotherapy).
graft-versus leukaemia
CLL – Late complications
Richter Syndrome:___ % of patients with CLL will transform to an aggressive ___________, which is often (easy or difficult?) to treat.
1-10
large B cell lymphoma
Difficult
CLL – Late complications
Prolymphocytic transformation: may occur _______ in approximately _____% of patients with CLL.
terminally
10
CLL – Late complications
Solid Tumour: CLL patients have a higher incidence of developing __________ (ie: GI, lung or any other organ) and also have a high risk of development of ____ cancers.
a second malignancy
skin
Bacterial, viral and fungal infections are the 3rd most important cause of morbidity and mortality in CLL.
T/F
F
Thee most!
CHRONIC MYELOID LEUKAEMIA
CML is a clonal disorder of _________________ cell.
a pluripotent stem
CHRONIC MYELOID LEUKAEMIA
It is characterized by:
______
Extreme blood ______ and granulocytic _____
_____philia
Thrombo_____
_____megaly
Anaemia
granulocytosis; immaturity
Baso
cytosis; Spleno
CML
Malignancy of the ________ cells with excessive proliferation of the _____ lineage (especially _______)
hematopoietic stem
myeloid
granulocytes
CML
The diagnosis of CML is usually based on detection of the _______ chromosome, or ______ t(__;__), which is present in ___% of patients.
Philadelphia(Ph)
translocation ; 9;22
95
CML
Another 5% of patients with CML have complex or variant translocations involving ______ that have (different or the same?) end result, which is ___________________________________
additional chromosomes
The same
fusion of the BCR gene on chromosome 22 to the ABL gene on chromosome 9.
BCR -___________ gene on chromosome __
ABL- ________________ gene on chromosome __
breakpoint cluster region; 22
Abelson leukaemia virus; 9
CML
The Philadelphia chromosome is found in cells from the _____,______,______,________ lineages, indicating that CML is a disease of the ______________________ -cell.
myeloid, erythroid, megakaryocytic, and B lymphoid
pluripotent hematopoietic stem
Role of Ph. chromosome in pathogenesis of CML
Genetic sequence on Chromsome _______ (__) are fused with sequences translocated from Chromosome __(__)
22 (bcr)
9 (abl)
Role of Ph. chromosome in pathogenesis of CML
This fusion gene (___-___) codes for an abnormal protein with _____ activity ( ____ ).
Which is involved in signal transduction and activates pathways within the affected cells leading to ________
BCR-ABL
Tyrosine Kinase ; p210
malignant transformation.
Tyrosine kinases work by transferring a ___ group from ____ to intracellular proteins that regulate _______
phosphate
ATP
cell division.
The incidence of CML appears to be constant worldwide.
T/F
.
T
CML Epidemiology
CML is rare below the age of _____ years
But occurs at ____ decades of life, with a median age of onset of ___-___ years.
20
all
50–60
CML Epidemiology
The incidence is slightly higher in (males or females?) than in (males or females?) .
Males
Females
CML Epidemiology
The risk of developing CML is slightly but significantly increased by exposure to ___________, as occurred in survivors of the _______ exploded in Japan in 1945, and in patients irradiated for ________ but, in general, almost all cases must be regarded as ‘ ______ ’ and no predisposing factors are identifiable.
high doses of irradiation
atomic bombs
ankylosing spondylitis
sporadic
CML Epidemiology
there is familial predisposition and definite association with HLA genotypes
T/F
F
In particular, there is no familial predisposition and no definite association with HLA genotypes has been recognized.
CML -clinical features
The typical symptoms at presentation are: fatigue, anorexia, bleeding and weight loss.
Signs are _______,_______(2%), _____ (16%), ______ (1% of males)
About 20 - 40% of patients are ____ptomatic, and in these patients, the diagnosis is based solely on _________
splenomegaly, hepatomegaly
purpura; priapism
asym; an abnormal blood count.
CML -clinical features
The most common abnormality on physical examination is _______, which is present in up to _____ of patients.
splenomegaly
half
CML – Clinical features Natural Evolution of CML – CML Phases
_______ phase
_______ phase
______ phase
Chronic
Accelerated
Blastic
CML – Clinical features Natural Evolution of CML – CML Phases
Chronic phase: usually presents in this phase, with progressive ______ and ________. The disease is (responsive or resistant ?) to cytotoxic therapy.
leukocytosis and splenomegaly
responsive
CML – Clinical features Natural Evolution of CML – CML Phases
Accelerated phase: Symptoms are (better or worse?) , with night ____, ____ pain, splenomegaly is (more or less?) responsive to therapy.
Peripheral blood shows increasing numbers of _____,_____, and _______.
Disease is (easy or difficult?) to control. ____-___% blasts
Worse
Night sweats, bone pain
Less
basophils, blasts and promyelocytes
Difficult; 10-19
CML – Clinical features Natural Evolution of CML – CML Phases
Blastic phase:
symptoms progress, _______ deposits (_______) appear
> ____% blasts in blood or bone marrow.
Blast transformation may be lymphoid (___%) or myeloid (___%)
extramedullary; chloromas
20
15;85
CML – Laboratory findings Hematologic findings and Morphology:
The white cell count is (elevated or depressed?) and the differential shows ______ neutrophils, bands, metamyelocytes, promyelocytes and myelocytes (precursors of the neutrophils).
WBC >____ × 109/L
The platelets are usually (elevated or depressed?)
Elevated ;mature
50
elevated
CML – Laboratory findings Hematologic findings and Morphology:
Haemoglobin is often slightly (above or below?) normal.
There is also ___ease in the number of basophils and sometimes of _____ in the peripheral blood.
The bone marrow shows marked (myeloid or lymphoid?) hyperplasia.
Below
incr; eosinophils
myeloid
The biochemical changes seen in CML are specific
T/F
F
non-specific.
CML – Laboratory findings : Biochemical changes
chronic phase serum uric acid is _____ but frequently ____.
serum alkaline phosphatase is _____ or ____
LDH) is usually _____.
Serum K+ may be spuriously _____
The serum vitamin B12 and B12 binding capacity are greatly ____eased
slightly raised ; normal
normal or slightly raised.
raised
raised; incr
CML-biochemical changes
Serum K+ may be spuriously raised due to ____________ from _______ or, less commonly, from ______ after the blood is drawn.
The serum vitamin B12 and B12 binding capacity are greatly increased due to ______________.
leakage of intracellular potassium from platelets
leucocytes
raised levels of transcobalamin I
CML – Laboratory findings
Immunophenotyping Is needed to make the diagnosis of CML.
T/F
F
Immunophenotyping Is not needed to make the diagnosis
of CML.
CML
Cytogenetics: The presence of the _______ is the sine qua non of this disease.
Philadelphia chromosome
CML - Treatment Supportive treatment
•______ and ______ prior to starting cytotoxic therapy for prevention of ___ nephropathy (nucleic acid breakdown)
•_____for bone pain or splenic pain
•______________ may be used for palliation of massive splenomegaly
Hydration and allopurinol ; urate
Analgesics
Splenic irradiation
bone pain or splenic pain – these are more commonly seen in the _____________ phases of CML
accelerated and blast
CML - Treatment
Specific treatment
Choice of therapy depends on the ________,___________ and the availability of a matched bone marrow donor.
age of the patient, phase of disease
CML - Specific treatment
Chronic phase
•______(____)
•_____therapy
•_____ transplantation
Glivec (imatinib)
chemo
Stem cell
CML - Specific treatment
Chronic phase
Glivec (imatinib) inhibits the _______ of the ______. Produces clinical, haematological and cytogenetic remissions in a (low or high?) percentage of patients in the chronic phase.
tyrosine kinase activity
BCR-ABL fusion protein
High
First line drug in the management of chronic phase disease is ???
Imatinib
CML - specific Treatment
Chemotherapy:
Mention 5
Cytarabine
Hydroxyurea
Alpha- interferon
Busulfan -
α Homoharringtonine
Hydroxyurea :
May be used in pregnancy
carcinogenic
T/F
T
F( it’s not)
Alpha interferon will effectively ______
α Homoharringtonine Enhances ______ of CML cells.
lower the cell count.
apoptosis
Interferon can used if BMT is planned.
T/F
With reason
F
Interferon is not used if BMT is planned – worsens outcome.
CML- specific treatment
Stem cell transplantation: Allogeneic SCT is a proven treatment for CML but due to its risks is usually reserved for ________.
Although Better results are obtained in ____ than _______ or ____ phases.
imatinib failures
chronic
accelerated or acute
CML - Specific Treatment
Blast phase
Lymphoid: ____ and _____ will induce remissions in some patients ( back to ___ phase) ; remissions are of ___ duration
Myeloid:______ and _____ , remissions are (easier or harder?) to induce than in de-novo AML.
vincristine and prednisone ; chronic; short
cytosar and adriamycin; harder
CML - specific Treatment
Accelerated phase
Cytotoxic therapy used in _______, or ————
Combination of agents – add ——- to oral agent
higher doses; switch agents.
cytosar
Imatinib is valuable in management of blastic transformation
T/F
T
Imatinib is valuable in management of blastic transformation but resistance usually occurs within a few weeks
