Leukemia in children.
Haemolytic Uraemic
Syndrome (HUS).
Sakharova Inna. Ye., MD,
Univ. assistant
Leukemia
Acute
lymphoblastic leukemia
(ALL)
Acute
nonlymphocytic leukemia
(ANLL) or
acute myeloblastic leukemia (AML)
Chronic
myelocytic leukemia
(CML)
Acute lymphoblastic leukaemia
(ALL) is a malignant
transformation of a clone of
cells from the bone marrow
where early lymphoid
precursors proliferate and
replace the normal cells of the
bone marrow.
Risk factors for the development
of childhood leukemia
 Heredity (presence of inherited
genetic syndromes, for example
Down syndrome or ataxia
telangiectasia, presence of
cytogenetic abnormalities )
 Environmental factors (ionizing
radiation and electromagnetic
fields, parental use of alcohol and
tobacco)
The conclusion of the USA National Radiological Protection
Board is: Laboratory experiments have provided no good
evidence that extremely low frequency electromagnetic
fields are capable of producing cancer, nor do human
epidemiological studies suggest that they cause cancer in
general. There is, however, some epidemiological evidence
that prolonged exposure to higher levels of power
frequency magnetic fields is associated with a small risk
of leukaemia in children. In practice, such levels of
exposure are seldom encountered by the general public in
the UK. In the absence of clear evidence of a carcinogenic
effect in adults, or of a plausible explanation from
experiments on animals or isolated cells, the
epidemiological evidence is currently not strong enough
to justify a firm conclusion that such fields cause
leukaemia in children.
According to the French-American-British
(FAB) classification, leukemic lymphoblasts
in ALL subdivide into three categories:
 L1 lymphoblasts are small cells with
homogeneous chromatin, regular nuclear
shape, small or absent nucleolus, and
scanty cytoplasm. This subtype is the most
common in children with ALL.
 L2 lymphoblasts are large and
heterogeneous cells, heterogeneous
chromatin, irregular nuclear shape, and
nucleolus often large. They are much less
common than L1 cells and are sometimes
mistaken for myeloblasts.
 L3
lymphoblasts
are
large
and
homogeneous cells and cytoplasmic
vacuolisation that often overlies the
nucleus as the most prominent feature.
This is just 1 to 2% of cases.
Immunological classification (on
the basis of immunophenotype):
• Non-T, non-B cell ALL accounts for
80 % of all cases;
• Malignancy of B cell precursors;
• B-cell ALL;
• T-cell ALL.
Shown here is bone marrow aspirate from a
child with B-precursor acute lymphoblastic
leukemia. Note that the marrow is replaced
primarily with small, immature lymphoblasts
that show open chromatin, scant cytoplasm,
and a high nuclear-cytoplasmic ratio.
Shown here is bone marrow aspirate from
a child with T-cell acute lymphoblastic
leukemia. The marrow is replaced with
lymphoblasts of varying size. No myeloid
or erythroid precursors are seen.
Megakaryocytes also are absent.
Shown here is bone marrow aspirate from
a child with B-cell acute lymphoblastic
leukemia. The lymphoblasts are large and
have basophilic cytoplasm with
prominent vacuoles.
The first symptoms of acute
leukemia are:
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Tiredness, irritability
Intermittent fever
Failure to thrive (poor growth)
Bleeding from gums/nose
Easy bruising
Bone pain
Headache
Nausea/vomiting with CNS
involvement
The signs of acute leukemia during
examination are:
 Skin pallor, tachycardia and a flow murmur
may be obvious because of anemia
presence.
 Signs of infection can be non-specific like
fever or pneumonia may be present.
 Thrombocytopenia often causes petechiae
on
the
lower
limbs.
Disseminated
intravascular
coagulation
(DIC)
may
aggravate the situation and cause larger
ecchymoses. Petechiae are small dots,
purpura is larger and ecchymoses are
larger bruises.
 Hepatomegaly may be found.
 Lymphomatous
features:
massive
splenomegaly,
anterior
mediastinal
mass, massive lymphadenopathy.
 Leukaemia cutis is an uncommon
condition due to infiltration of the skin.
 Superior vena cava syndrome is caused
by mediastinal adenopathy compressing
the superior vena cava. A prominent
venous pattern develops over the upper
chest from collateral vein enlargement.
The face may appear plethoric and the
periorbital area may be edematous.
 Involvement of sanctuary sites: 1) CNS
involvement
manifests
as
diffuse
meningeal infiltration with signs of
increased intracranial pressure; 2)
testes, one or both of which may be
involved, with infiltration producing
enlargement that is out of proportion to
the child’s sexual development
Diagnostics of ALL:
 General blood count: normochromic
anaemia with a low reticulocyte index,
thrombocytopenia, neutropenia,
different WBC count (leucopenia or
hyperleucocytosis), presence of
lymphoblasts;
 Bone marrow aspiration and biopsy
(sternal puncture) are the definitive
diagnostic tests to confirm the
diagnosis: more than 25 % of
lymphoblasts prove the diagnosis of
ALL;
 Bone marrow samples should undergo
cytogenetics and flow cytometry for
identification of the type of leukemia;
 DIC may occur and this produces an
elevated prothrombin time, reduced
fibrinogen level and the presence of
fibrin degradation products in
coagulogram;
 Lactic dehydrogenase levels (LDL) are
usually raised and rapid cell turnover
may raise uric acid in biochemical blood
test;
 Lumbar
puncture
with
cytospin
morphologic analysis: This is performed
before
systemic
chemotherapy
is
administered to assess the presence of
CNS involvement and to administer
intrathecal chemotherapy.
 Liver
and
renal
function
(ultrasonography) must be checked
before initiating chemotherapy;
 CXR may show pneumonia or an
enlarged mediastinal mass;
 Multiple gated acquisition (MUGA)
scan is required because many
chemotherapeutic agents used in
treatment are cardiotoxic, ECG is
also necessary;
 Molecular
techniques,
including
reverse-transcriptase
polymerase
chain reaction (RT-PCR), Southern
blot analysis, and fluorescence in
situ hybridization (FISH).
Patients can be divided into 3
groups on the basis of risk (The
Children’s Cancer Group):
 Good prognosis (have 80 % or greater
chance of cure): age between 2 and 10
years, WBC  10 G/L, absence of L3 cells,
absence of
lymphomatous features,
platelet count greater 100 G/L.
 Poor prognosis (have less than 50 %
chance of cure): age less than 1 year old
or greater than 10 years old, WBC  50
G/L,
presence
of
chromosomes
translocations, B cell ALL with L3 cells,
blasts with T-cell phenotype.
 intermediate prognosis (have 50 % or
greater chance of cure).
Good prognosis for those who have
brisk initial response to therapy
 The Children’s Cancer Group found
an improved prognosis in patients
with less than 5 % blasts in the bone
marrow
after
seven
days
of
chemotherapy.
 The Berlin-Frankfurt-Münster group
found a similar prognosis in patients
who had less than 1000 blasts/ml in
the peripheral blood after seven days
of prednisone.
With the exception of B-cell ALL, the
treatment of childhood ALL may be
considered in three categories:
1. Induction of remission
2. Consolidation of remission
3. Maintenance of remission
and all stages involve treatment with
cytotoxic agents and steroids varying
in intensity. In some books
4. The treatment of subclinical CNS
leukemia
is divided into special category also.
Induction is by quadruple therapy with
vincristine, prednisolone, anthracycline,
and cyclophosphamide or Lasparaginase or a 5-drug regimen of
vincristine, prednisolone, anthracycline,
cyclophosphamide, and L-asparaginase.
Intrathecal metotrexate is used in
proper days also. It is given over the
course of 4 to 6 weeks. This type of
therapy induces complete remission in
more than 95% of patients.
The main sign of remission is less
than 5 % of blasts in bone marrow;
additionally it should be less than
50 % of lymphocytes in peripheral
blood.
This is usually followed by consolidation
therapy often in the form of
dexamethasone, vincristine, and
doxorubicin, followed by
cyclophosphamide, anthracycline, and
6-thioguanine beginning at week 20. In
this phase of therapy, the drugs are
used at higher doses than during
induction. Consolidation therapy, first
used successfully in the treatment of
patients with high-risk disease, also
appears to improve the long-term
survival of patients with standard-risk
disease.
Maintenance therapy often consists of
periodic
“reinduction”
pulses
of
prednisone and vincristin as well as:
1) Daily oral 6-merkaptopurine and
weekly oral methotrexate for low-risk
patients
2) More intensive multiagent therapy for
intermediate- and poor-risk patients.
Relapses still occur in 30-40 % of
patients. If relapse occurs in the CNS or
testes, many children can still be cured
with irradiation and additional
chemotherapy. If relapse occurs in the
marrow within 18 months of diagnosis,
the chance of cure with either
chemotherapy or stem cell
transplantation is less than 10 %.
Bone marrow transplantation is used
rather more in children than in adults. If
a first-degree relative with a HLA match
is not available it is possible to use
autologous (own) bone marrow rather
than allogeneic (donor) marrow.
However, the results of autologous are
inferior to sibling donors and a study
gave 3 years survival after remission
and bone marrow transplant of 26%
with autologous bone marrow compared
with 68% with donor marrow.
Primary features of tumor lysis
syndrome include hyperuricemia (due
to metabolism of purines),
hyperphosphatemia, hypocalcemia,
and hyperkalemia.
Haemolytic Uraemic Syndrome (HUS)
 a triad of microangiopathic
haemolytic anaemia (Coombs’ test
negative), thrombocytopenia and
acute renal failure.
HUS has been associated with E. coli
with somatic (O) antigen 157 and
flagella (H) antigen 7. It produces a
toxin called shiga and hence this
group is called Shiga-toxin-producing
Escherichia coli (STEC). An
alternative name is vero toxin-
producing Escherichia coli (VTEC).
HUS clinical features
 profuse diarrhoea that turns
bloody 1 to 3 days later and
rarely on the first day
 fever, abdominal pain and
vomiting
HUS diagnostic criteria include
• packed cell volume of less than 30%
• evidence of erythrocyte destruction
on peripheral blood smear
• platelet count less than 150 x 109/L
• serum creatinine above the upper
limit for age
• haemoglobinuria
Therapy of HUS
 Antibiotics confer no benefit, even
if given early
 Massive intravenous infusions
with potassium adding (under urine
volume control)