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What is leukemia?
‡ Cancer of the white blood cells
‡ Acute or Chronic
‡ Affects ability to produce normal blood cells
‡ Bone marrow makes abnormally large number
of immature white blood cells called blasts
 !istory
‡ Means ³white blood´ in Greek
‡ Discovered by Dr. Alfred Velpeau in France,
1827
‡ Named by pathologist Rudolf Virchow in
Germany, 1845
 Main Types
‡ Acute Lymphocytic Leukemia (ALL)
‡ Acute Mylogenous Leukemia (AML)
‡ Chronic Lymphocytic Leukemia (CLL)
‡ Chronic Mylogenous Leukemia (CML)
 Acute lymphoblastic
leukemia (ALL)
-most common malignancy diagnosed in children
-, one third of all pediatric cancers.
-a peak incidence in children Y

Y .
-Although a few cases are associated with
inherited genetic syndromes,
the cause of ALL remains largely unknown„
 


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‡ - a fast-growing cancer of the white blood cells.
- In ALL, the bone marrow makes lots of
unformed cells called blasts that normally would
develop into lymphocytes
„„„„„„„„„ -!owever, the blasts are abnormal. They
do not develop and cannot fight infections.
‡ The number of abnormal cells (or leukemia
cells) grows quickly.
‡ They crowd out the normal red blood cells,
white blood cells and platelets the body needs
 Development of Leukemia in the
Bloodstream

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White Cell 6„ 
Red Cell
Platelet 6„ 


Blast
Germ Sources from v


 Y, by D. Newton and D. Siegel
6„   
‡ Possible risk factors for ALL include the
following£
!aving a brother or sister with leukemia„
Being white„„
Being exposed to x-rays before birth„
Being exposed to radiation„
Past treatment with chemotherapy
or other drugs that
weaken the immune system„
!aving certain genetic disorders, such as Down syndrome„
 Clinical picture
Appears 2-6weeks before diagnosis
Variable &nonspecific:

1-Generalised weakness and fatigue

2 -anemia
3-Frequent or unexplained fever and infections
4-Weight loss and/or loss of appetite
5-Excessive and unexplained bruising
6- bone pain,joint pain (caused by the spread of "blast" cells
to the surface of the bone or into the joint from the marrow
cavity)
7-breathlessness
8-Enlarged lymph nodes,liver&or spleen
Less commonly :
Vomiting
!eadache
Respiratory distress
rash
 Physical examination
Fever
Tachycardia
Irritability
Pallor
Ecchymosis
Periorbital edema
Papilledema
Epistaxis
!epatomegaly
Splenomegaly
Testicular enlargement
Bone pressure on pressure
Cranial nerve palsy
Skin lesions uncommon
(leukemia cutis)
Discrete
Cover face trunk &eventually all body
Individual lesions slightly nodular erythematous
& purpuric eventually necrotic
-nly 4 % present with CNS manifestations
5-10% with testicular affection
 ÔcÔ

‡ Mathe & colleagues were among the first to

propose amorphological classifications of ALL
‡ Drawbacks: subjective as it depends on
morphological features (cell size cytoblasmic
basophilia««.
 FAb classification
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‡ Depending on cell size ,nuclear chromatin
pattern ,shape ,prominence of nucleoli,
cytoblasmic characterestics,amount of
basophilia& vacuolization
‡ Labs agreed that fab was prognostic
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 W!- classification
‡ 1- Acute lymphoblastic leukemia/lymphoma
Synonyms:Former Fab L1/L2
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± t(12;21)(p12,q22) TEL/AML-1
± t(1;19)(q23;p13) PBX/E2A
± t(9;22)(q34;q11) ABL/BCR
± T(V,11)(V;q23) V/MLL
‡ ii. Precursor T acute lymphoblastic
leukemia/lymphoma
‡ 2- Burkitt's leukemia/lymphoma Synonyms:Former
FAB L3
‡ 3- Biphenotypic acute leukemia
‡ It depends on immunophenotyping
‡ using monoclonal antibodies against surface&
cytoplasmic differentiation antigens
   
 

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remains the most important predictor of the patient's
prognosis.
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u Various metabolic abnormalities
u may include increased serum levels of uric acid,
potassium, phosphorus, and calcium, and lactate
dehydrogenase (LD!).
u The degree of abnormality reflects the leukemic
cell burden and destruction (lysis). Although not
universally performed, coagulation studies can be
helpful, including tests of the prothrombin time
(PT), activated partial thromboplastin time (aPTT),
fibrinogen level, and D-dimer level to assess for
disseminated intravascular coagulation; these
studies are particularly important in a child who is
acutely toxic.
 Immunophenotyping

‡ Complete morphologic, immunologic, and

genetic examination of the bone marrow is
necessary to establish the diagnosis of ALL
Approximately 80% of childhood ALLs involve
lymphoblasts with phenotypes that correspond
to those of B-cell progenitor

T-cell ALL is identified by the expression of T-

cell±associated surface antigens, of which
cytoplasmic CD3 is specific
 Cytogenetic and molecular
diagnosis
‡ In more than 90% of ALLs, specific genetic
alterations can be found in the leukemic blasts.
‡ These alterations include changes in
chromosome number (ploidy) and structure;
about half of all childhood ALLs involve
recurrent translocations.
‡
 molecular techniques
, including fluorescence in situ hybridization
(FIS!), reverse transcriptase-polymerase chain
reaction (RT-PCR), and Southern blot analysis
help improve diagnostic accuracy.
 ^

 
ahest radiographyc
   
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Testicular ultrasonography   Ô
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Renal ultrasonography  Ôc
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Echocardiography and Ea 

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 : The results
confirm the diagnosis of ALL. In addition, special
stains (immunohistochemistry), immunophenotyping,
cytogenetic analysis, and molecular analysis help in
classifying each case.
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c: These tests are performed before systemic
chemotherapy is administered to assess for CNS
involvement and to administer intrathecal
chemotherapy
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Although it is not correlated with the immunophenotypic and

cytogenetic classification information, the FAB system is
generally well accepted and used. According to this system,
ALL is classified into 3 groups based on morphology.
L1: Cells are usually small, with scant cytoplasm and
inconspicuous nucleoli. L1 accounts for 85% of all cases of
childhood ALL.
L2: Cells are larger, than in L1. The cells demonstrate considerable
heterogeneity in size, with prominent nucleoli, and abundant
cytoplasm. L2 accounts for 14% of all childhood ALLs.
L3: Cells are large and notable for their deep cytoplasmic
basophilia. They frequently have prominent cytoplasmic
vacuolation and are morphologically identical to Burkitt
lymphoma cells. L3 accounts for 1% of childhood ALLs
 treatment

‡ Chemotherapy:
‡ 3 chemotherapy phases: induction,
consolidation or intensification, and
maintenance
‡ The earlier acute lymphocytic leukemia is
detected, the more effective the treatment„ „
Treatment of Recurrent ALL„
‡ Much of the treatment strategy depends on how
soon the leukemia returns after the first
treatment. The shorter the time interval, the
greater will be the need for newer and more
aggressive chemotherapy„
‡ The most commonly used chemotherapy drugs are
vincristine, L-asparaginase, anthracyclines
(doxorubicin, daunorubicin), cyclophosphamide,
cytarabine (ara-C), and epipodophyllotoxins
(etoposide, teniposide). Your child will also receive a
steroid (prednisone or dexamethasone) and vincristine
unless he or she is known to be resistant to these
medications. Intrathecal chemotherapy will also be
given„
‡ Cure Rates for ALL
‡ The chance of being cured of low-risk ALL is
about 85% to 95%, standard-risk is about 65%
to 85%, and high-risk ALL is about 60% to
65%„
phase Discription Agents
induction„ to rapidly kill most tumor Combination of„
cells„ Prednisolone„or„
This is defined as the dexamethasone„in
presence of less than 5% children„
leukemic blasts in the vincristine„
bone marrow, normal asparaginase„and„
blood cells and absence of daunorubicin„
tumor cells from blood, used in Adult
and absence of other signs ALL) is used to
and symptoms of the induce remission„
disease„
Intensification„ high doses of intravenous Typical
multidrug chemotherapy to intensification
further reduce tumor protocols use
burden„ vincristine„
most protocols include cyclophosphami
delivery of chemotherapy de„cytarabine„
into the CNS fluid„ daunorubicin„
multiple lumbar punctures„ etoposide„
thioguanine„or„
-mmaya reservoir„ mercaptopurine„
given as blocks
in different
combinations„
The aim of maintenance
therapy is to kill any
residual cell that was not
killed by remission
induction, and
intensification regimens.
Although such cells are
few, they will cause relapse
if not eradicated„
daily oral mercaptopurine,
once weekly oral
methotrexate, once monthly
5-day course of intravenous
vincristine and oral
corticosteroids are usually
used. The length of
maintenance therapy is 3
years for boys, 2 years for
girls and adults.
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‡ Central nervous system relapse is treated with
intrathecal administration of„hydrocortisone„
methotrexate, and cytarabine
 Treatment of Residual
Disease„
‡ All these treatment plans may change if the
leukemia hasn't completely disappeared
‡ treatment may be intensified or prolonged„„
‡ Bone marrow or cord blood transplant (also
called a BMT) ² a transplant (discussed further
below) offers some patients the best chance for
a long-term remission of their disease. Because
transplants can have serious risks, this treatment
is used for patients who are less likely to reach a
long-term remission with chemotherapy alone„
  
  

‡ Radiation therapy„or radiotherapy) is used on painful bony areas,

in high disease burdens, or as part of the preparations for a„bone
marrow transplant„total body irradiation). Radiation in the form
of whole brain radiation is also used for central nervous system
prophylaxis, to prevent recurrence of leukemia in the brain.
Whole brain prophylaxis radiation used to be a common method
in treatment of children¶s ALL. Recent studies showed that CNS
chemotherapy provided results as favorable but with less
developmental side effects. As a result, the use of whole brain
radiation has been more limited
‡ Recent data suggest that leukemia arises from
the stem cell that acquires features of
differentiated cells. Although this observation
may appear to be a subtle difference, it is
important because it implies the need to
eradicate the leukemic stem cell, and not just the
differentiated blasts, to achieve a cure„
      
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‡
Stem cell transplant is a method of giving chemotherapy and
replacing blood-forming cells destroyed by the cancer treatment.
Stem cells (immature blood cells) are removed from the blood or
bone marrow of a donor and are frozen and stored. After the
chemotherapy is completed, the stored stem cells are thawed and
given back to the patient through an infusion. These reinfused
stem cells grow into (and restore) the body's blood cells. A stem
cell transplant using stem cells from a donor who is not related
to the patient is being studied in clinical trials„
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‡ ' !arrison's Principles of Internal Medicine, 16th Edition,
Chapter 97. Malignancies of Lymphoid Cells. Clinical Features,
Treatment, and Prognosis of Specific Lymphoid Malignancies.
‡ ' Finding Cancer Statistics » Cancer Stat Fact Sheets »Chronic
Lymphocytic Leukemia National Cancer Institute
‡ ' Colvin GA, Elfenbein GJ (2003). "The latest treatment advances for acute
myelogenous leukemia". O

Y  (8): 243±6. PMID 14582219.
‡ ' Patients with Chronic Myelogenous Leukemia Continue to Do Well on
Imatinib at 5-Year Follow-Up Medscape Medical News 2006
‡ ' Updated Results of Tyrosine Kinase Inhibitors in CML ASC- 2006
Conference Summaries
‡Thank you
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A. Immune thrombocytopenias
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a. Idiopathic thrombocytopenic
Purpura
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There is a higher incidence than expected
of human leukocyte antigens (!LA) B8
and B12 in patients. Persone with this
specific phenotype run a higher risk of
devel-oping thedisease, if exposed to
precipitating factors.
 Clinical Features
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 Clinical approach to nonthrombocytopenic purpura
based on bleeding time
PetechiaePurpura
Ecchymoses

Normal Platelet Count

Bleeding Time
Normal Abnormal
!enich- Schonlein Fvlll activity
„„„„„„„„„„„„„„„„„„„„„„„„„„„„„„„„„„„
Purpura Fvlll antigen„„„„„„
Purpura factitia Vwf
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 Fvlll activity
Fvlll antigen
Vwf

Normal Abnormal

Platelet aggregation Von Willebrandµs

(ADP, epinephrine disease
Collagen, ristocetin

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Congenital vascular
Adhesion defects disorders hemorrhagic
Aggregation defects Telangiectasia
Defects in release Ehlers-danlos syndrome
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a- Always less than 100.000/mm3
b- -ften less than 200.000/mm3 in
patients with severe generalized
hemorrhagic
Glatelet Diseases Based on
Glatelet 6ize
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1- Rationale for high-dose intravenous gamma globulin

(IVGG) (Table10-6)
a. Reticuloendothelial fc-receptor blockade
b. Decrease in autoantibody synthesis
c. Protection of platelets and/ or megakaryocytes from
platelet antibody
d. Clearance of persistent viral infection by
Infusion of specific antibody
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a. Acute ITP: a total does of 2g/kg body weigh
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(1) 0.4g/kg IVGG per day for 5 days or

(2) 1g / kg per day for 2 days.

In infants less than 2 years old, 5-day protocol is
better tolerated
b. Chronic ITP
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A patient with the following clinical findings

should be treated with both steroids and high-
dosage IVGG until he or she is clinically
improved and is asymptomatic and the platelet
count is greater than 30.000/mm3 :

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