‫بسم هللا الرحمن الرحيم‬

Leukemia &
Aplastic Anemia
Hala Assem,
MBBCh, ECFMG, MS, M.D
Professor of Pediatrics
Alexandria University, BAU,
Fellow, LSU
OBJECTIVES
 Identify normal hematopoiesis
 Define and classify causes of anemia
 Identify etiology, pathogenesis, how to
examine, diagnose and manage a child with
leukemia and differentiate it from other
diseases
 Identify etiology, pathogenesis, how to
examine, and diagnose aplastic anemia
 Interpret hematological values and
laboratory investigations of anemia
Normal CBC
Bone Marrow
Hematopoiesis
 Normal RBC
Hematologic Value Cord 3m 6m-6y 7-12 y
Hb (g/dl) 17 11.5 12.5 13
Ht % 55 35 37 39
RBCs 5.3 4.3 4.7 5
Nucleated RBCs % 6 0 0 0
Reticulocytes % 5 1 1 1
ANEMIAS
Definition:
Anemia is defined as a reduction of the red
cell volume (hematocrit) or hemoglobin
concentration below the range of normal
values for age.

CLASSIFICATION OF ANEMIAS
1. Anemia from inadequate erythropoiesis.
2. Anemia of blood loss (post-hemorrhagic).
3. Anemia due to  destruction (hemolytic).
I. Anemia resulting from inadequate erythropoiesis
1. Inadequate precursor cells in BM (BM failure):
(a)- Single cell line: (Pure red cell anemia)
Congenital pure red cell aplasia, TEC
(b)- All cell lines (Pancytopenia)
Hereditary (Fanconi’s anemia)
Acquired: idiopathic or 2nd to infection (parvovirus), irradiation, toxin,
drugs (antimetabolites, anti-inflammatory).
lnfiltration by leukemia, lymphomas, neuroblastoma.

2.Inadequate erythropoiesis despite normal precursors:

Anemia of infection (acute and chronic).
Anemia of chronic inflammation.
Anemia of chronic renal failure.

3. Inadequate erythropoiesis due to deficiency of specific

nutrient factors:
Iron , folate, B12, B6, E, PEM, cretinism.
 II. Anemia from blood loss ( post-hemorrhagic):
Acute post-hemorrhagic anemia after overt bleeding
Chronic post-hemorrhagic anemia (occult bleeding-iron
deficiency). e.g. due to Ancylostoma or cow's milk allergy.
III. Anemia due to increased destruction (Hemolytic):
(a)- Corpuscular causes:
1. RBC membrane: hereditary spherocytosis, elliptocytosis, etc.
2. RBC enzymes: G6PD deficiency, pyruvate kinase deficiency.
3. Hemoglobin: - Qualitative: sickle cell disease, Hb C, D, etc
Quantitative: thalassemias
(b)- Extra-corpuscular causes:
1-Immune:
- Iso-immune: Rh and ABO incompatibility
- Auto-immune: idiopathic or 2ry (e.g. SLE)
2- Non immune: - March hemoglobinuria
- Paroxysmal nocturnal hemoglobinuria
- Infections (malaria, toxoplasmosis, septicemia)
- Toxic: snake venom, industrial toxins
- Mechanical: burns, prosthetic cardiac valve
3- Hypersplenism
Childhood cancer
1- Acute leukemia is the most common malignancy 
in childhood (1/3 of cases)
2- CNS tumors: the second most common. (20%) 
3- lymphoma: the 3rd most common. (12%) 
4- Neuroblastoma: the most common extracranial 
solid tumor in infancy. (8-10%)
5- Wilms’ tumor: the 4th most common childhood 
malignancy and the 2nd most common malignant
retroperitoneal tumor.
6- Others: soft tissue sarcoma, retinoblastoma, 
bone tumors, …
Definition

leukemia is a heterogeneous group of

malignant disorders resulting from a
clonal expansion and arrest at a
specific stage of maturation in normal
myeloid or lymphoid hematopoiesis
leading to the appearance of blast cs
in peripheral blood.
Classification of childhood
leukemias
LEUKEMIAS

ACUTE CHRONIC
(97%) (3%)

ALL (75%)
AML (20%) Ph1+ve myeloid leukemia
AUL (<0.5%) JMML
AMLL
ACUTE LYMPHOBLASTIC
LEUKEMIA
Pathogenesis:

 ALL rasults from the interaction

between multiple
Genetic and
Environmental risk factors:
 Ionizing radiation

 Chemicals e.g. benzene

 Drugs e.g. alkylating agents

Pathogenesis (cont.)
Genetic considerations:
↑ incidence in:
1- Identical twins
2- Siblings of leukemia patients
3- Chromosomal abnormalities (Down,
Bloom, Fanconi anemia)
4- Genetic disorders:
*agammaglobulinemia *ataxia
telangectasia *Schwachman-Diamond
*Diamond- Blackfan *Kostmann disease
*neurofibromatosis
Molecular events in
leukemogenesis
Two general mechanisms for leukemia
induction:
1- Activation of proto-oncogene/ creation of a
fusion gene with oncogenic properties.
2- Loss or inactivation of tumor suppressor
genes.

* Over expression of anti-apoptotic genes

(BCL2, BAX genes) can render leukemic cells
resistant to a wide variety of insults and
stimuli.
Classifications (cont.)

1- Immunophenotyping:

ALL

Precursor- B ALL T- lineage ALL

[ +ve CD19, CD22, CD24, CD79a] [+ve CD3,CD7,CD5,CD2]

Early pre-B 60%

Early- T
Pre-B 20%
Mid-thymic T 10-15%
Transitional pre-B 3%
Mature- T
Mature B 1-2%
 Classification of acute
leukemias
2- Morphologic classification (FAB)
Based on blast morphology (cell size, nuclear
shape, No and prominence of nucleoli, amount of
cytoplasm):
L1 → 80 – 88 %

L2 → 8 -18 %
L3 → 1 - 5 %
Classifications (cont.)
3- Cytochemical staining:
* Myeloperoxidase: +ve myeloblast
- ve lymphoblast
* Sudan black B: - ve lymphoblast 
* PAS : coarse granules or heavy blocks in 
lymphoblasts
* non-specific estrase and acid 
phosphatase: focal staining in paranuclear
or Golgi region→ T-ALL
* TdT: +ve in 90 % of ALL 
Classifications (cont)

4- Cytogenetic classification:
1- Changes in chromosomal no:
Hyperdiploid [51-65] → good prognosis 20-30%
Near tetraploid [82-94]→ poor prognosis rare
Hypodiploid [<46] → poor prognosis

2- structural abnormalities:[pseudodiploid]:
Translocations → poor prognosis 40%
Inversion
deletion
 Clinical picture of ALL
1-General systemic effects: fever, lassitude,
pallor, weight loss, anorexia.
2- BM invasion: anemia
 neutropenia
 Thrombocytopenia
 pancytopenia
3- Lymphoid system invasion:
 lymphadenopathy
 mediastinal mass
 hepatosplenomegaly
 PETECHIAE

Purpuric eruptions
Anemia + infection + purpura and
organomegaly
 Clinical picture [cont.]
Extramedullary invasion:

CNS: ↑ICP, meningeal, parenchymal

involvement,hypothlamic syndrome, DI, Hge.
*Genitourinary: testicular, ovarian, renal
infiltration, hematuria.
*Bone and joints: bony pains, arthritis.
*Skin: in neonatal leukemia and AML.
*Cardiopulmonary: asymptomatic, infiltration,
Hge
Investigations of ALL
1- Complete blood count and blood
smear.
2- BM exam., histochemistry, immunopheno-
typing, cytogenetic
3- Blood chemistry: electrolytes, Ca, K, P, uric
acid, renal & liver functions.
4- CSF for diagnosis of CNS leukemia, cytology
5- coagulation profile.[AML→↓I, V, IX,X]
6- Cardiac function: ECG, ECHO.
7- Infectious disease profile.8- chest X-ray,
skeletal survey
Acute Lymphoblastic Leukaemia

 Lab findings :-
 1-Anaemia , normocytic normochromic
,bleeding tendency .
 2- leucocytic count show 3 patterns
occasionally very high leucocytic count
>100.000 or slightly elevated . Some
times normal or decreased .
Normal bone marrow
Normal bone marrow
Bone Marrow Aspiration with
blasts > 25%
Prognostic criteria: Cure 80%
Determinant Favorable Unfavorable
1- WBC count <10,000/cmm >10,000/cmm
2- Hb < 7 gm/dl >10 gm/dl
3- platelets > 100,000/cmm <30,000/cmm
4- Age 3-7 years < 1, >10 years
5- sex Female Male
6- Race White Black
7-time of remission < 14 days >28 days
8- liver/spleen/LN Not enlarged ↑↑↑enlarged
Prognostic criteria [ccont.]
Determinant favorable unfavorable
9- mediastinal massAbsent Present
10-CNS leukemia Absent Present
11- FAB L1 L 2, L3
12-immunophenotype Early pre- B T- ALL
B-ALL
Mixed lineage

13- cytogenetic
Hyperdiploid Pseudodiploidy
6q- t(9;22) t(8;14)
t(4;11) t(14q+)
 Treatment: risk classification

Standard risk High risk

Eligible
Age 1- <10 yr Standard arm
Initial WBC count <50000/cmm
Age 1- <10 Augmented arm
FAB L1/ L2
+ WBC count > 50000 CNS leukemia
Not eligible
T-ALL Age>10/<21 yr BM day 14 M2/M3
FAB L3 T-ALL
CNS leukemia Overt testicular
Testicular leukemia leukemia
BM day14= M2/M3
translocations
 CNS leukemia
Leukemic cells are usually present in the meninges at
diagnosis even if they are not identifiable in CSF.
These cells survive systemic chemotherapy because of poor
drug penetration of BBB.
In absence of prophylactic treatment, CNS was the initial
site of relapse in >50% of patients.
Cranial irradiation prevents overt CNS leukemia but
produces late neuropsychological effects, particularly in
younger children.
Therefore, standard risk patients typically receive
intrathecal chemotherapy to prevent CNS involevment.
Still, the most important extramedullary sites of relapse are
the CNS and testes.
CNS leukemia

Clinical picture:
1- signs of ↑ ICP → DD chemical
meningitis.
2- convulsions, isolated cranial nerve
palsies → DD side effects of
methotrexate and vincristine.
3- hypothalamic involvement [rare] →wt.
gain and behavioral disturbance.
Minimal residual disease [
MRD]
Remission status in leukemia is usually determined
on the basis of morphologic findings alone [BM
blasts <5%]
However, patients in complete remission can still
have as many as 1010 malignant cells in BM, and
this is responsible for relapse in 10- 20%.
MRD is the lowest level of disease detectable in
patients in remission using sensitive methods as
1-flow cytometry: detect tumor- associated
aberrant immunophenotype 1: 104
2- PCR: detect leukemic cell DNA or RNA 1: 105
sensitive than morphology.
 Oncologic Emergencies

1- Metabolic and endocrine disturbances:

*hyperleukocytosis
*tumor lysis syndrome:
#hyperuricemia #hyperkalemia
#hyperphosphatemia #hypocalcemia
#hypercalcemia #renal failure
*SIAD
 Oncologic Emergencies
2- Space- occupying lesions that can press on or
obstruct vital organs and cause mechanical/
surgical emergencies.
[thoracic, abdominal, neurologic emergencies]

3- Pancytopenia secondary to BM replacement or

chemotherapy that can result in Hge, anemia,
and susceptibility to overwhelming infection.
 Treatment of ALL
Supportive:
Psychological, medical
Specific:
1- Induction of remission
2- Consolidation
3- CNS prophylaxis
4- Maintenance and
5- Reinforcement
BMT
Differential diagnosis of
ALL
1- Pancytopenia: BM failure d.t. aplastic
,anemia, myelofibrosis, hypersplenism.
2- Infections: EBV, CMV, Toxoplasma
3- Rheumatic fever, rheumatoid arthritis.
4- Lymphocytosis 2ry to pertussis.
5- Other malignancies infiltrating BM.
Presentation of Anemia, Neutropenia and Thrombocytopenia

Hemorrhagic lesion of the gums in a patient with aplastic anemia caused

by infection with Capnocytophaga ochraceus; such lesions are easily
confused with those of herpes simplex.
Aplastic bone marrow
Etiology
 Acquired:
– Drugs: Antimetabolites, antimitotic agents, gold,
chloramphenicol, phenylbutazone and sulfonamides
– Radiation
– Chemicals: benzenes, Solvents, insecticides
– Viruses : Hepatitis A,B,C, E, G, and Parvo B19, CMV
– PNH
– Misc: pregnancy, connective tissue disorders, Graft-vs-Host
disease

 Idiopathic:
– 50-65 % of cases

 Hereditary:
– Fanconi’s Anemia
– Dyskeratosis congenita
– Shwachman Syndrome
 Functions of the Spleen

Rigid RBC RBC inclusions

Antibody coated RBC

Excess membrane cholesterol

Complement coated RBC

Senescent RBC
 Hypersplenism
* CBC: depression of 1 or more bl. elements
* BM: Active formation

* Splenomegaly  sequestration, hormone

* Corrected by splenectomy
* 1ry: ITP,
* 2nd Splenomegaly: lymphoma, thalassemia,
leukemia, Schistosomiasis
 EBV in children and
young adult

fever

lymphadeno
pathy pharyngitis
Later findings
leukocytosis
References:
 http://web.ebscohost.com/ehost/ebookviewer/ebook/bmxlYmt
fXzM0NTA5NF9fQU41?sid=379d0e89-3c09-4dc8-8c99-
6634632aec40@sessionmgr110&vid=12&format=EB&ppid=pp
_1
 http://web.ebscohost.com/dynamed/detail?sid=546f1cb7-
bd08-4c35-b0c4-Anemia - differential diagnosis
 61ec86b265b4%40sessionmgr115&vid=3&expand=categoriza
tion&hid=108&bdata=JnNpdGU9ZHluYW1lZC1saXZlJnNjb3BlP
XNpdGU%3d#db=dme&AN=240897&anchor=categorization
 Linda S. Nield and Deepak Kamat
 Lymphadenopathy in Children: When and How to
Evaluate
 Clin Pediatr (Phila) 2004; 43; 25
 Nelson Textbook of Pediatrics, 2015
 Dworkin, Algranati; National Medical Series for Independent
Study. NMS Pediatrics, 5th ed., 2009.
Thank you!