Childhood Leukaemias Flashcards
CHILDHOOD LEUKAEMIAS
Definition: The leukaemias represent a ____________ and ____________ at a specific stage of normal ____________ or ____________ haematopoiesis.
Clonal expansion
arrest
myeloid
lymphoid
Traditionally, leukaemias have been classified morphologically by the predominant cell line involved into:
List 4 of them
Lymphocytic
Monocytic
Myelocytic
Undifferentiated
LEUKAEMIAS
Are also classified temporarily by the survival time and morphologic maturation of the untreated patient, as:
Acute – which runs a __________ course and characterized by a predominantly _________ (_________) cells.
Chronic – which runs a _________ course and characterized by predominantly _________ cells.
rapidly fatal course
primitive (blast)
protracted
mature
Approx 95 % of childhood leukaemias are of the (acute or chronic?) variant and consists of the following types:
_________________ – 75%
_________________ also known as _________________ – 20%
_________________- <0.5%
_________________
acute
Acute lymphoblastic laeukaemia (ALL)
Acute myeloblastic leukaemia (AML)
acute non-lymphocytic leukaemia (ANLL)
Acute undifferentiated leukaemia (AUL)
Acute mixed – lineage leukaemia (AMLL)
Chronic myeloid leukaemias is unusual in the very young children and constitute about _____% of all childhood leukaemias consisting of:
__________________ (Ph1-positive) myeloid leukaemia-about 1-3% of all childhood leukaemias
______________________ (JMML) very rare- usually occurs before 2 years of age.
_______________ leukaemia occurs extremely rarely, if ever, in children.
3%
Philadelphia chromosome-positive (Ph1-positive)
Juvenile myelomonocytic leukaemia (JMML)
Chronic lymphocytic leukaemia
EPIDEMIOLOGY of childhood leukemias :
Age
This differs greatly from one type of leukaemia to another.
In the Caucasian population ______ shows a peak in the ______ year age group, accounting for 25-30% of all childhood cancers.
In Africans on the other hand, the peak is between ___ and ____ years.
_________ and its variants on the other hand show no childhood peak (about 500 new cases reported in USA yearly).
ALL; 2-5
5 and 14 years.
AML
EPIDEMIOLOGY of childhood leukemias CONT
Sex
More (boys or girls?) suffer from acute leukaemia than (boys or girls?). Approximately 2/3 of patients are (boys or girls?).
Race
Incidence of leukaemia is twice as high in (white or black?) than in (white or black?) children (4.2/100,000 white children vs 2.4/100,000 black children in USA).
Clustering
There is no evidence that childhood leukaemia occurs in clusters or in epidemic proportion in the population.
Familial Incidence of Leukaemia
This is not significant.
boys ; girls
boys.
white ; black
EPIDEMIOLOGY CONT
Patients with Very High Risk:
Some individuals are at unusual high risk of developing leukaemia. These include:
______________ of children with acute leukaemia (risk 1 in 5)
Children with congenital disorders characterized by chromosomal anomalies:
________ syndrome
______________
________ syndrome
Patients receiving therapeutic _________ for ankylosing spondylitis and polycythemia vera, and
____________ survivors.
Identical twins
Bloom’s syndrome
Fanconi’s anaemia
Down’s syndrome
irradiation
Atomic bomb survivors.
AETIOLOGY of childhood leukemias :
Aetiology is unknown
Factors that have been implicated in pathogenesis are:
____________ , exposure to X-ray in the ________ trimester in-utero
Chemical carcinogens – e.g. exposure to _______ (AML)
Drugs (e.g., use of ________ agents either alone or in combination with __________ (AML)
Infectious agents especially ________. Genetic considerations:
Identical twins- if one twin develops leukaemia during the first 5 years of life, the risk for the 2nd twin is 20%
Siblings of leukaemia patients has four times greater risk than general population
Chromosomal abnormalities
Ionizing irradiation ; first
benzene ; alkylating
radiotherapy ; viral
CHILDHOOD LEUKAEMIAS-CLINICAL FEATURES:
Most children with acute leukaemia come to the attention of the physician because of the consequences of _________________ or evidence of ______________________ by leukaemic cells.
The chief complaints are:
_______ and lassitude from anaemia.
_______ due to infection occasioned by granulocytopenia
Haematologic manifestations – ________, ________, _____________ due to thrombocytopenia
_________ pain or limp
Headache, vomiting, and nerve palsies are results of __________ spread.
The duration of symptoms may vary from days to months: the median duration being between _____-_______
bone marrow suppression
extramedullary infiltration
Pallor
Fever
petechiae ; epistaxis
rectal bleeding
Bone pain or limp
meningeal spread.
1-3 months
FAB classification of ALL
Morphologic and immunologic evaluation has demonstrated that the acute lymphocytic and myelocytic leukaemias of childhood are not _______genous entities.
homogenous
Acute lymphoblastic leukaemia can be sub-classified according to the _____________________ (FAB) classification as _____, ___ and _____ morphologic subtypes.
This has been largely abandoned as no longer clinically relevant, although the ______ morphology is consistently associated with ____________ ALL (_______ leukemia).
French-American-British (FAB)
L1, L2 and L3
L3 ; mature B-cell ALL
Burkitt’s leukemia
Immunophenotypic Classification of Acute Leukemias
Diagnosis of acute leukaemias is now largely based on ____________ of ______________ expressed on blast surface.
This has improved diagnostic accuracy and management outcome.
immunophenotyping of antigens expressed on blast surface.
Lymphoid markers include:
CD___, CD___, CD____, and CD___ (pre-B or B cells) and CD___, CD___, CD___, CD__, and CD____ (T cells).
These has been used to subdivide ALL into 3 broad groups:
___________,___________, and ____________
CD10
CD19
CD20
CD22
CD2, CD3, CD4, CD5, and CD8 (T cells).
precursor B-cell, mature B-cell, and T-cell ALL
Immunophenotypic Classification of Acute Leukemias-AML
Myeloid antigens markers include:
CD___, CD___, c-___, CD___ and CD___ (monocytic markers), _________________ (erythroid marker), and
CD____ (megakaryocytic marker).
CD13, CD33, c-kit, CD14 and CD64
Glycophorin A
CD41
The blasts of undifferentiated Leukaemias are peroxidase- and butyrate-_________ and express none of the myeloid or lymphoid antigens.
They are treated like _______
negative
AML
Aims of therapy
The aims of therapy in acute leukaemia are cure and include the following:
•To induce a ________ and ________ remission
•To maintain remission by systematic ____________ and prophylactic ___________
•To treat the ____________ of therapy and of the disease.
clinical and haematologic remission
chemotherapy and prophylactic CNS therapy
complications
TREATMENT OF LEUKEMIA
Definitive treatment encompasses 3 distinct phases and 4 components:
__________ of complete remission using ___________________,
___________ therapy may surpass the doses used during induction
___________ of therapy is usually administered at doses approaching those used during induction
__________________________ during the __________ and __________ phases.
Induction ; combination chemotherapy,
Intensification
Consolidation
Central nervous system prophylaxis
induction ; consolidation phases.
TREATMENT
Maintenance therapy is usually defined as therapy that is less ___________ than therapy used to produce ______________, for a fixed period of time
For successful treatment patient must be prepared by, Counselling patient/parents
Do pre-chemotherapy laboratory investigations
Give supportive therapy.
myelosuppressive
remission
Supportive therapy given
___________,_____________ and _________________ . These are required before and during therapy to treat temporary bone marrow failure
________ therapy when infection occurs/is suspected
___________- To prevent or treat hyperuricaemic acidosis and uric acid nephropathy
_____________ for hyperleukocytosis (WBC >100,000/mm3)
Give Prophylactic antibiotic –______________ and antimalarial – ___________ .
NB: Avoid ______ vaccines because of __________
Packed red cells, platelet transfusion and recombinant granulocyte colony-stimulating factor (G-CSF)
Antibiotic; Allopurinol
Partial EBT; Co-trimoxazole; proguanil
Live; immunodeficiency
INDUCTION OF REMISSION IN ALL
Drug used in Induction of Remission in ALL are:
___________ , ___________, ___________,
Doxorubicin, ___________/___________,
Consolidation of remission - similar to induction of remission
Delayed intensification- therapy similar to above
Maintenance of remission
For ALL , ___________ and ___________
Vincristine, Cyclophosphamide, L-asparaginase
Prednisolone/Dexamethasone,
6-mercaptopurine ; methotrexat
Definition of Complete Remission
A complete remission is defined as:
No symptoms attributable to the disease (e.g., fever, bone pain)
No hepatosplenomegaly, lymphadenopathy, or other clinical evidence of residual leukaemic tissue infiltration, normal CSF examination (including cytocentrifugation)
A normal blood picture, with minimal levels of _____/mm3 granulocytes,_______/mm3 of platelets, and ____g/dl HGB with no blast cells seen on blood smear
A moderately cellular bone marrow with moderate number of normal granulocytic and erythroid precursors, with adequate megakaryocytes and less than 5% blast cells, none possessing frankly leukaemic features
500
75,000
12
Definition of Relapse
•The appearance of any of the following:
> _____% __________ in a single bone marrow aspirate
•Progressive repopulation of lymphoblasts in excess of ____% culminating in > ____% in ___ or more bone marrow samples separated by one week or more
•>____% lymphoblasts in the bone marrow and ____% or more circulating lymphoblasts
•Leukaemic cell infiltration in ______________ organs, e.g., CNS or gonads (biopsy proven) (for the diagnosis of isolated extramedullary relapse, the bone marrow should contain <____% blasts)
•Lymphoblasts in the _______ with a cell count >__WBC/mm3
50% ; lymphoblasts in
5% ; 25% ; 2
25% ; 2%
extramedullary organs ; 5%
CSF ; 5WBC/mm3
PHYSICAL EXAMINATION of Childhood Leukemia :
This may reveal:
Pallor
Fever
_________ and _________
_________ and/or _________ Lymphadenopathy, _________ swelling, _________ swelling, ______ tenderness ______ stiffness are the results of leukaemic infiltration.
Petechiae ; purpura
Hepatomegaly ; splenomegaly
parotid gland ; testicular
bone ; neck stiffness
PLEASE NOTE THAT ________ IS NEVER GIVEN INTRATHECAL AS SUCH IS UNIFORMLY LETHAL
VINCRISTINE
Central nervous system therapy
Prophylactic age adjusted intrathecal therapy (IT) with ___________ ± ____________ or _________ _________ is given throughout the phases of therapy.
methotrexate ± hydrocortisone or cytosine arabinoside
Central nervous system therapy
Where there is evidence of CNS disease,
IT ___________, +
IT ____________ +
IT __________________ ± ___________________ are given.
methotrexate
hydrocortisone
cytosine arabinoside
Cranial radiotherapy
Chemotherapy for AML
AML is treated with intensive shortened chemotherapy therapy often containing such drugs as:
____________ ,
____________ ____________,
6-thioguanine,
____________ and
daunorubicin, given in about ____________ cycles.
Dexamethasone
Cytosine arabinoside
Etoposide
four cycles.
Chemotherapy for AML
Bone marrow transplant:
Except for _____ subtype (where ___________________ offers a possibility of cure) all children with AML who have an HLA-compatible related stem cells donor should be considered for stem cell transplant after the initial induction of remission.
M3
All trans-retinoic acid-ATRA
Acute promyelocytic leukemia (APL)
Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML), accounting for 5% - 15% of cases and is potentially curable.
APL results from _________ between the ________________ locus on chromosome ______ and the “________________” gene locus on chromosome _____ (t[15;17] translocation).
retinoic acid α ; 17
“promyelocytic leukemia”
15
APL presents mainly with ____________ resulting both from plasmin-dependent ___________ and __________________.
Addition of _____________________ to chemotherapy (idarubicin or daunorubicin + cytarabine) increase complete remission (CR) rates from 40% to between 70% & 90%
bleeding diathesis
primary fibrinolysis
disseminated intravascular coagulation.
all-trans retinoic acid (ATRA)
Acute leukemia prognosis
Overall cure rate for childhood ALL is estimated to be about _____%. The single most important prognostic factor is appropriate risk-directed ___________.
The initial wbc count has a consistent __________ linear relationship to the likelihood of cure. Other factors are listed in the table below.
treatment.
inverse
Acute leukemia prognosis
For reasons that are not understood, children with _____________ and AML have a particularly good cure rate (> 80%) with chemotherapy alone.
For a patient with an _________________________________ , the cure rate for AML is about 70% using chemotherapy followed by bone marrow transplantation.
For those without a suitable donor, chemotherapy alone cures about 50%.
Children who have AML who relapse have _________________ prognosis.
Down’s syndrome
HLA- matched family donor,
an extremely poor prognosis.
PROGNOSTIC INDICES IN ALL
Features: bad Good
Age
Race
Initial wbc
<1,>10 ; 2-10
Black; White
>50,000; 10-20,000
PROGNOSTIC INDICES IN ALL
Features: bad Good
Sex
Chest X-ray
Cell marker
Morphology
Male ; Female
Mediastinal mass; No mediastinal mass
T or B ; CALLA Positive
L3, L2 ; L1
PROGNOSTIC INDICES IN ALL
Features: bad Good
Chromosomes
Translocations (18;14)(4;11) (9;22)
Hyperploidy (>50 chromosomes)
Physical examination of childhood leukemia
Acute myelocytic lekaemia may present with a mass lesion (_________) particularly in the _____ or ________, even when the peripheral blood appear normal.
______________ is seen predominantly in Acute monocytic or acute myelomonocyticleukaemia
_____________ lesions of the ________ region are also characteristic of leukaemia with monocytic features.
chloroma
orbit ; spine
Gingival hypertrophy
Ulceronecrotic ; perirectal
LABORATORY FINDINGS of childhood leukemias:
1. Full blood count with differentials:
_________ is almost always present;
Platelets count is often ___________/mm3.
WBC count may be ______ , _______ or __________. _________ cell may be found in peripheral film.
Anaemia
< 100,000/mm3.
high, low or normal.
Blast cell
LABORATORY FINDINGS of childhood leukemias:
_______________ and ___________ is diagnostic. Presence of greater than ____% _______ cells indicate leukaemia, typically a minimum of ____% leukaemic ______ cells in the bone marrow aspirate confirms the diagnosis
Bone marrow aspiration and cytology
5% blast cells
20% leukaemic blast cells
DIFFERENTIAL DIAGNOSIS of childhood leukemia :
Infectious ____________
Infectious ____________
Pertussis
____________ ____________ ____________
____________ anaemia
____________ disease
____________ reaction
Neuroblastoma
Infectious mononucleosis
Infectious lymphocytosis
Idiopathic thrombocytopenic purpura
Aplastic anaemia
Rheumatic disease
Leukaemoid reaction
ACUTE LEUKAEMIAS:
Morphologic Classification
The hallmark of the diagnosis of acute leukaemia is the “________” cell, a relatively ___________ cell with diffusely distributed nuclear chromatin, one or more nucleoli, and basophilic cytoplasm.
blast”
undifferentiated cell
ACUTE LEUKEMIA
Blast cells are also part of the normal maturation sequence of haemic and lymphoid elements, but under normal conditions constitute less than _____% of the nucleated cells of the bone marrow and are never seen in the _______________.
The presence of an increased number of these cells is the sine qua non for diagnosis of an acute leukaemia.
5%
peripheral blood
Presence of granules
Presence of Auer rods
Lymphoblasts or Myeloblasts
Myeloblasts
Myeloblasts
PAS-positive
MPO -Positive
Sudan black -positive
Acid phosphatase -positive
Lymphoblasts or Myeloblasts
Lymphoblasts
Myeloblasts
Myeloblasts
Only In T-ALL
_____________________ (M0)
__________________ (M7) subtypes.
minimally differentiated
acute megakaryocytic
Diagnosis of M0 and M7 leukaemias typically require ____________ using __________
immunophenotyping
flow cytometry
ACUTE LEUKAEMIAS – FREQUENCY
The relative frequency of the acute leukemia variants of childhood is as follows:
Acute ___________ leukaemia 60-70%
Acute ___________ leukaemia 0-10%
Acute _____________ leukaemia 20-30%
Careful morphologic and immunologic evaluation has demonstrated that the acute lymphocytic and myelocytic leukaemias of childhood are not homogenous entities.
lymphoblastic
undifferentiated
myelocytic
