Clincal Aspect

ACUTE LEUKEMIAS IN
CHILDREN

BAMBANG SUDARMANTO
Department of child health Medical faculty Diponegoro University/
Kariadi General Hospital Semarang Indonesia

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 Key Points :
• Acute leukemia constitute 30-35% of all childhood
malignancy, ALL is the commonest.
• The ages and total WBC count at diagnosis remain the
most important prognostic indicators in childhood ALL
• Diagnosis must be confirmed by BONE MARROW
(morphologic ), immunophenotypic, genetic (if it possible)
• The four main components of therapy of ALL include
remission induction, CNS prophylaxis, consolidation and
maintenance therapy
• Clinically it is usually difficult to differentiate ALL from AML
• AML still remains a disease that is difficult to treat

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Distribution of Childhood Cancer

NBL Hodgkin's
8% 5% NHL CNS
3% 18%
Soft Tissue
Sarcoma Liver
7% 1%
Wilm's
Tumor Leukemia
6% Retina 33%
Bone Other Germ Cell 3%
5% 3%
8%

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 Type Of Leukemia

19% 5%

77%

ALL AML CML

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 Three type of leukemia are seen in
children

• Acute Lymphoblastic Leukemia (ALL- 75%- 83% of all

leukemia)
• Acute Myeloid Leukemia (AML- about 17% - 20% of
leukemia)
• Chronic Myeloid Leukemia (CML – 5% of all leukemias)
chronic Lymphocytic leukemia is not seen in children.

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 Acute Lymphoblastic Leukemia
ALL

Clinical Feature :
– Anemia (fatigue, irritability, pallor)
– Thrombocytopenia (petechiae, ecchymosis, purpura,
bleeding in 48%)
– Neutropenia (fever in 60%) or extramedullary diseases in
the form of lymphadenopaty (50%)
– Hepatosplenomegali (68%) bone and joint pain (leukemic
infiltrate of joint, 28%).

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 Mediastinal Lymphnodes-ALL

Organomegaly

ALL:Cervical Lymphadenopathy

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 Acute Lymphoblastic Leukemia

Thrombocytopenia Neutropenia(fever) Lymphadenopaty

Hepatosplenomegali Leukemic

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 Differential Diagnosis
Non-Malignant conditions
– Juvenile rheumatoid arthritis
– Infectious mononucleosis
– Idiopathic thrombocytopenic purpura
– Pertusis / parapertusis
– Aplastic anemia
– Acute infectious lymphocytosis
Malignant conditions (with bone marrow involvement)
– Neuroblastoma
– Retinoblastoma
– Rhabdomyosarcoma
Unusual presentation
– Hypereosinophilic syndrome

Pizzo and Poplack.Ped.Onc.,2006

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 Diagnosis

ALL-L1

Bone marrow aspirate

French-American-British Co-operative group (FAB)
proposed criteria for classifying ALL into three
subtypes L1, L2, and L3 :

­ ALL-L1 is the most frequent subtype in childhood ALL-L2

ALL
­ ALL-L2 morphology is more common in adults
­ ALL-L3 morphology is usually associated with B-
cell leukemia with t(8; 14) requiring a specific
therapeutic approach

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ALL-L3
 Hence surface antigen merkers were
used to characterize ALL in terms of
cell of origin and stage of differentiation
:

pre-B ALL B cell leukemia

pre-B ALL and transitional pre-B ALL
B-cell ALL
T-cell ALL

T cell leukemia

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 PROGNOSTIC FACTORS
• WBC count at diagnosis
• Age at diagnosis
• Rapidity of leukemic cytoreduction during the
early period of treatment.
• Cytogenetics [t(8; 14), t(9; 22), t(4; 11), t(1;
19), unfavourable; t(12; 21) favourable]
• Ploidy (DNA index > 1.16, favourable)
• Mediastinal mass (unfavourable)
• CNS disease at presentation (unfavourable)

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 HIGH RISK
• Age : < 1 year and > 10 year
• WBC > 50.000/mm3
• Mediastinal mass : +
• Meningeal leukemia : +
• After one week treatment in induction :
lymphoblast>1.000/mm3

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 When to suspect
A high index of suspicion in certain classical clinical situations
is likely to help in early diagnosis.
These include :
– Recurrent fever with bone pains
– Pallor and fatigue with or without neck nodes
– Hepatosplenomegaly with petechiae
– Pancytopenia
– Leucocytosis

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 Treatment
• Spesific Therapy :
- The risk category : standard risk , high risk
- These include remission induction, CNS prophylaxis,
consolidation
and maintenance therapy

• Induction : Vincristine, L-asparaginase with or without

Daunorubicin. This is the most critical period of treatment as
the patient has very low counts and is susceptible to
complications.
A bone marrow is done at the end of induction to establish
remission status (CR=less than 5% blasts in marrow)

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 Treatment (con’t)
• CNS Prophylaxis in the form of intrathecal methotrexate
(some also use cytarabine) starts during induction after
achieving CR, radiation to be brain is also given to
children > 2 years

• Consolidation is an intensification of treatment and many

protocols use same drugs as in induction and call it re-
induction treatment

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Treatment of relaps ALL
• Side of relapse: medullar , testes, CNS
• Chemotherapy
• Role of stem cell transplantation
• Minimal residual disease
• Recent developments and future plans

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 Monitoring of Patient During
Maintenance
• ANC (usually 1000 to 1500)
• It is important to always monitor for clinical signs of
relapse like persistent unexplained fever,
hepatosplenomegaly, lymphadenopathy, testicular
enlargement or new CNS deficits as well as suspicious
peripheral blood values

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 When to refer
• Immediately after suspecting acute leukemia either
clinically or by laboratory parameters

• Early referral by the pediatrician can avoid many disease

related potentially life threatening conditions like severe
infection, bleeding and metabolic problems

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 Essential Laboratory Work-up
• Hb, total and differential WBC count
• Bone marrow aspirate
• Chest X-ray (mediastinal mass)
• Uric acid and electrolytes : Na, K, Ca, PO4
• LDH/KFT/LFT
• Diagnostic spinal tap

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 Acute Myelogenous Leukemia
AML

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Introduction and incidence
• Acute Myelogenous Leukemia (AML) accounts for 15-20% of
all childhood leukemia.
• Ratio AML : ALL = 1 : 4.

• Congenital leukemia’s have higher frequency of AML

• Age incidence is similar between 0 – 10 years

• AML is equally distributed among the sexes

• Treatment related mortality and death in aplasia remain

significant and survival rates are between 35% and 40% at
different centre and with different subtypes of AML

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 Etiologic Factors
– Acquired
– Genetic predisposing factors :
Down syndrome, Fanconi anemia, Bloom syndrome,
Kostmann syndrome, Diamond Blackfan anemia,
paroxysmal nocturnal haemoglobinuria, Li-Fraumeni
syndrome, neurofibromatosis etc. Well established inciting
agents include exposure to benzene, alkylating agents
(AML M1, M2) nitrosoureas, epipodophyllotoxins (M4, M5)
and ionizing radiation.

– A link between infectious agents and AML has not been

established

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 Clinical presentation
• These children may present either with very few
symptoms or with severe sepsis and or bleeding.

• The clinical feature usually reflect marrow failure and

involvement of extramedulllary organ.

• Characteristic presentations of AML are gingival

hyperplasia (M4/M5);DIC (M3),soft tissue chloromas,
leukemia cutis (blue berry muffin)

• CNS involvement is very rare.

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 Diagnosis
• A high index suspicion is needed in cases with fever,
bruise, pallor and or bone pains.

• History and physical examination followed by a complete

hemogram and peripherals smear examination should
help confirm suspicion.

AML-M5 - Gum Hypertrophy

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 FAB classification and childhood AML
FAB Class Histochemistry* Cell surface marker Associated
cytogenetic findings

AML M0 MP– CD33+, CD13+, CD14+, HLA DR-

NSE–
AML M1 MP+ CD33+, CD13+, CD11+, HLA DR+ +8, -5, -7
AML M2 MP+ CD33+, CD13+, CD11+ t(8;21)
AML M3 MP+ CD33+, CD13+, CD11+ t(15;17)
AML M4 MP+ CD33+, CD13+, CD11+, HLA DR+ inv 16
NSE+
AML M5 NSE+ CD33+, CD13+, CD11+, HLA DR+ t(1;11)
t(9;11)
AML M6 Pas+ Glycophorine+
MP+ Spectrin+, HLA DR+
AML M7 PPO+ Clycoprotein inv 3 or
IIb/IIIa (CD 41) t(3;3), t(1;23)
or IIIa (CD61)+

Abbreviations :
*MP, Myeloperoxidase; NSE, Non-Specific Esterase; PPO, Platelet Peroxidase
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 Diagnosis

ACUTE MYELOID LEUKEMIA

AML-M0

ACUTE MYELOID LEUKEMIA

AML-M1

ACUTE MYELOID LEUKEMIA

AML-M2
AML-M6 :
Erythroleukemia

AML-M5b : AML-M4 : Myelomonocytic ACUTE MYELOID LEUKEMIA

AML-M3
 Immunophenotyping
• Normal haematopoetic cell undergo maturation they
also undergo chjanges in expression of cell surface
markers.

• Monoclonal antibodies have been developed that

react with lineage specific and stage specific myeloid
antigen.

• Most AML cases express CD13; CD33,

CD15,CD14,CD11b,or CD36.

• Most of the FAB subtypes have their own

characteristic CD markers.

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 Cytogenetics
• Clonal chromosomal abnormalities are detected in
cases of AML.

• AML M3 t(15;17)(q22;q21)

• The 11q23 translocation involving the MLLgene

occurs in ceratin secondary AMLs as well as other
AML subtypes signifying poor prognosis.

• Philadelphia chromosome translocation t(9;22)

(q34;q11)accounts for <1%.

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 Treatment
• Supportive care: antibiotic; transfusion; nutrition and
metabolic complication

• Specific therapy:
Antracyclin: Daunorubicin;doxorubicin
Survival with chemotherapy alone is 35-40%.
In most studies 5 year actuarial leukemia free survival
averages about 60%.
• Bone marrow transplant (allogenic)
• The post transplant relapse rate in these studies is less than
20%.

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 Prognosis

• High WBC count

• Secondary AML/MDS
• Monosomy 7-or 7q
 Poor risk factors

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 Practical Points For The Pediatrician
• High index of suspicion will aid early
diagnosis
• Early referral may minimize life threatening
complications
• Treatment should be in an experienced set
up
• Bone marrow to be done at treating centre
• Disseminate information on treatment
options and survival

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 Problems in treatment
• Children come in more advanced stage
• Malnourished children tolerate
chemotherapy poorly
• Cost of drugs
• Organization of care
• Treatment leukemia in poor countries is
much more difficult

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 Toxic Effects of Chemotherapy

ANTHRACYCLIN Cardiomyopathy & heart failure

ASPARGINASE Hypertensitivity reaction

Coagulopathies
CYTARABINE Acute cerebelar syndrome

METHOTREXATE Nephrotoxic & hepatotoxic (high dose)

CYCLOPHOSPHAMIDE Cystitis hemorrhagica

VINCRISTIN Peripheral sensory & motor neuropathy

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 Thank you

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Aula Lab RSDK, 25 Nov 2010