Diagnosis and Management Of
Acute Leukemia in Children and
Adolescents
Grand Rounds
September 20, 2010
St. Elizabeth Hospital, Lafayette, Indiana
Bassem. I. Razzouk, MD, FAAP
Medical Director, St. Vincent Children’s
Center For Cancer & Blood Diseases
Pediatric Cancer Incidence
USA
Year
Population Incidence New cases
< 20 yrs
per 105
per year
1998
72,935,000
16.7
12,183
1999
73,120,000
16.8
12,321
2000
73,306,000
17.0
12,448
Childhood Cancer
Hematopoiesis
PLURIPOTENT
MIXED
STEM CELL PROGENITOR
CELL
COMMITTED
PROGENITOR
CELL
RECOGNIZABLE
BONE MARROW
PRECURSOR CELL
BFU-E/CFU-E
CFU-Eos
red cell
neutrophil
monocyte
eosinophil
CFU-Baso
basophil
CFU-GM
myeloid
progenitor
cell
pluripotent
stem cell
lymphoid
progenitor
cell
pronormoblast
myeloblast
monoblast
MATURE
BLOOD
CELL
CFU-Meg
megakaryocyte
platelet
pre-T
lymphoblast
T-cell
pre-B
lymphoblast
B-cell
& plasma cell
Myeloid Maturation
myeloblast promyelocyte
myelocyte
metamyelocyte
band
neutrophil
MATURATION
Adapted and modified from U Va website
Principles of leukemogenesis
• A multistep process
• Neoplastic cell is a hematopoietic
pleuripotent cell or early myeloid cell
• Dysregulation of cell growth and
differentiation (associated with mutations)
• Proliferation of the leukemic clone with
differentiation blocked at an early stage
Classification of Leukemias
Acute
Chronic
Myeloid
origin
Acute Myeloid
Leukemia (AML)
Chronic Myeloid Leukemia
(CML)
Lymphoid
origin
Acute Lymphoblastic
Leukemia (ALL)
Chronic Lymphocytic Leukemia
(CLL)
Acute Leukemia
• Accumulation of blasts in the marrow
Epidemiology
• Childhood leukemia represents
12% of all leukemias; 60% of all
acute lymphoblastic leukemias
• Leukemia is the most common
cancer diagnosed in children at
4.3/100.000
Epidemiology
• ALL/AML = 5
• Peak incidence
–ALL: 2 to 5 years
–AML: 1 year, increases with age
• Boys > girls
–T-cell 4 times greater incidence
–Infant leukemia > in girls
Significance of Acute Leukemia
• A hematologic urgency/emergency
• Usually fatal within weeks to months without
chemotherapy
• With treatment, moderate to high morbidity
( acute and long term) due to disease or
treatment-related complications
• Notify Peds H/O promptly if acute leukemia is
suspected
Causes of Acute Leukemias
•
•
•
•
•
•
Idiopathic (most)
underlying hematologic disorders
chemicals, drugs
ionizing radiation
viruses (HTLV I)
hereditary/genetic conditions
Predisposing Factors
• Genetic Syndromes
– Down syndrome: 10-20 times increased
incidence (600 times in megakaryoblastic type)
– Bloom syndrome
– Neurofibromatosis
– Schwachman syndrome
– Ataxia Telangiectasia
– Klinefelter syndrome
Ataxia-Telangactasia
Predisposing Factors
• Familial aggregation
– Concordance in Twins
•
•
•
•
•
High birth weight
Ionizing radiation
Non-ionizing radiation (?EMF)
Alcohol consumption/cigarette smoking
Breast feeding has protective effect
Clinical Manifestations
• Symptoms due to:
– marrow failure
– tissue infiltration
– leukostasis
– constitutional symptoms: Fever, weight
loss, night sweats, anorexia
– other (DIC)
• Usually short duration ( 4-8 weeks)
Clinical Presentation
Very heterogenous
–Pallor
–Petechiae
–Hepatosplenomegaly
–Adenopathy
–Fever
–Bony pain
Clinical Presentation
Sign/Symptom
Fever
Bleeding
Adenopathy
Bony pain
ALL AML
34% 61%
18% 48%
50% 14%
50% 5%
Infiltration of tissues/organs
• Enlargement of liver, spleen, lymph
nodes
• Gum hypertrophy
• bone pain
• other organs: CNS, skin, testis, any
organ
Gum Hypertrophy
Chloromas
• Granulocytic Sarcoma (myeloblastoma)
– Localized mass of primitive myeloid
cells that infiltrate extramedullary
sites
– Involvement of every organ system
has been reported
Leukostasis
• Accumulation of blasts in microcirculation
with impaired perfusion
• lungs: hypoxemia, pulmonary infiltrates
• CNS: stroke
• Mostly seen with WBC >> 50 x 109/L in
AML and > 100 X109/L in ALL
Differential Diagnosis
• Juvenile Rheumatoid Arthritis- caution to use
steroids / oral methotrexate before completely
ruling out leukemia
• Mycobacterial infections ( TB & non-TB)
• Infectious mononucleosis
• Aplastic anemia
• Neuroblastoma
• Rhabdomyosarcoma
• Hypereosinophilic syndrome
Laboratory Data
•
•
•
•
White blood cell count: variable
Hemoglobin levels: low
Platelet count: low
Serum chemical values
– Uric Acid and LDH: elevated
– Calcium: elevated
• Chest X-ray: Mediastinal Mass; Preferable to do
CXR with initial diagnosis of asthma, especially
if you plan to use steroids
• Coagulation screening: abnormal
WBC
< 10.000
10,000-49,000
> 50,000
53%
30%
17%
Newly Diagnosed Patients with
Leukemia- Work-up
• Establish a diagnosis
Peripheral blood and bone marrow studies
Morphology
Immunopathology (cell markers)
Cytogenetics
Molecular Genetics
• Risk assessment
• Protocol enrollment- patients enrolled on clinical
trials have better outcome
• Consent Process
Bone Marrow Aspirate/Biopsy
• Necessary for diagnosis: Aspirate for
ALL; Aspirate/biopsy for AML
• Useful for determining type
• Useful for prognosis
• Acute leukemias are defined by the
presence of > 20% blasts (AML) or 25 %
blasts (ALL) in bone marrow (% of
nucleated marrow cells)
Diagnosis
Morphology, cytochemistry and
immunophenotype
Leukemia
• Acute vs. Chronic
• Lymphoid vs. Myeloid
ALL
AML
Auer rods in AML
Cytochemistry
Lymph
Myelo
Mono
Megak
MPO
+
-
ANB
+
-
ANA
+, diffuse
+, granular
Morphology/
Cytochemistry
Key Points In ALL And AML
• The childhood acute leukemias are
a very heterogeneous group of
diseases
• Accurate diagnosis is important
• Selection of optimal therapy is
pivotal
Blood Cells
Immunophenotype
Immunologic Classification
CD3, CD7, CD10, CD19, CD79
Lymphoid
Myeloid M6/M7
CD41a, CD61, and CD42b
FVIII
Lymphoid Vs. M0-M7
Hemoglobin
Classification - ALL
Immunophenotype Frequency (%)
Early pre-B
57
Pre-B
25
Transitional
1
B-cell
2
T-cell
15
Classification - AML
Morphology
M0
M1
M2
M3
M4
(%) Morphology (%)
2
M4
19
13
M5
21
28
M6
1
6
M7
10
19
Genetics of Childhood ALL
• B-lineage ALL
Translocation
t(12;21)
t(1;19)
t(4;11)
t(9;22)
Fusion
Incidence Cure
rates
TEL-AML1
25%
90%
E2A-PBX1
5-6%
75%
MLL-AF4
2-5%
35%
BCR-ABL
3-5%
<30%
(70 % ) with TKI’s
AML-associated chromosomal
abnormalities
Abnormality
t(8;21)
inv (16)
t(15;17)
t(9;11)
t(11;19)
t(1;22)
Fusion
AML1-ETO
CBFβ-MYH11
PML-RAR
MLL-AF9
MLL-ELL
Unknown
FAB
Incidence
M2
M4Eo
M3
M4,M5
M4, M5
M7
15%
8-12%
8- 10%
7%
1%
1%
PROGNOSTIC FACTORS
DISEASE
Heterogeneity
Tx
Intensity
Specificity
Prognostic Factors - ALL
•
•
•
•
•
Initial white blood cell count
Age at diagnosis
Immunophenotype
Genetic Features
Extramedullary involvement ( CNS,
testis)
Response to therapy
ALL- Risk Groups
St. Jude
Estimated
Low
Standard
High
40%
50%
10%
COG
Standard
High
Very High
Prognostic Factors- AML
• Favorable
– Age < 1 year of age
– Genetics: t(15;17), inv16, t(8;21) and t(1;22)
– Down syndrome
• Intermediate
– Genetics: normal karyotype, other 11q23
– Residual disease after induction
• High-risk
– Cytogenetics: -7, -5, t(6;9), complex karyotype
– AML arising from MDS
– Persistent disease after induction
Risk Assignment
• Provisional risk assignment at
diagnosis
• Definitive assignment at end of
induction therapy after evaluation of
response to early therapy is available
• The objective of rigorous risk
assignment is to avoid over- or undertreatment
Principles of Treatment
• combination chemotherapy
– first goal is complete remission
– further Rx to prevent relapse
• supportive medical care
– transfusions, antibiotics, nutrition,
metabolic /electrolyte abnormalities
• psychosocial support
– patient and family
Therapeutic Concepts in ALL
• Induce a complete remission and restore
normal hematopoiesis avoiding excessive
toxicity
• Reduce inapparent leukemia with short-term,
high-dosage cytocidal therapy early in
remission when the child is well and drug
sensitivity is greatest
• Prevent CNS leukemia (concept of sanctuary)
• Use prolonged combination chemotherapy to
eradicate residual disease when there is no
evidence of leukemia
Basic Therapy in Childhood ALL
•
•
•
•
•
•
Induction Treatment
4-8 wk
Consolidation treatment (intensification)
2-10 wk
Continuation treatment (maintenance)
2-3 y
Reinduction therapy (delayed intensification) 2-7 wk
CNS-directed therapy
1-2 y
Cessation of therapy
2.5 y for girls, 3.5 y for boys
Facts about Childhood ALL
• Long-term Event Free Survival ( EFS) greater than
80%
• Accomplished by
– Multiagent Chemotherapy
– CNS-Directed Therapy
– Improved Supportive Care
– Trageted therapy with tyrosine kinase inhibitors (
Gleevec and others) for Philadelphia positive
ALL
– Treatment of adolescents and young adults ( up
to 30 years) on “Pediatric Inspired protocols”
Survival of ALL According to Treatment Era
at St. Jude
1
XV (2000–Present) n=254
0.9
XIII–XIV (1991–99) n=465
XI–XII (1984–91) n=546
0.8
0.7
X (1979–83) n=428
0.6
0.5
V–IX (1967–79) n=828
0.4
0.3
0.2
I–IV (1961–66) n=90
0.1
0
0
5
10
15
20
25
Years from Diagnosis
30
35
40
Pediatric AML Treatment
• Standard Induction Therapy
• 80%-90% achieve hematologic CR
• Differentiation therapy : All trans retinoic acid ( ATRA) for
specific variant ; acute promyelocytic leukemia ( APL);
which needs emergency treatment since patients present
with bleeding
• Post-remission Therapy
• Historical controls suggest High dose Ara-C consolidation
improves outcome
• Recent data suggest 60-70% of children with matched
family donors achieved cure with Allo transplant, but data
is conflicting
• Maintenance Therapy
• No data demonstrates efficacy
Results of St. Jude AML Trials
1.0
0.9
0.8
0.7
0.6
0.5
AML97 (n=40)
0.4
AML91 (n=63)
AML87 (n=41)
0.3
AML80 (n=65)
0.2
AML83 (n=45)
0.1
0
0
5
10
15
Time (years)
20
25
Supportive Care
• Patient stabilization
– Metabolic : hydration, alkalinization, allopurinol ,
and occasionally Rasbruicase ( recombinant
urate oxidase) for tumor lysis syndrome
– Hemorrhage (DIC)- FFP, platelets
– Infection- Braod spectrum antibiotics (Cefipeme)
– Leukostasis- leukapheresis in AML /early
therapy
• Central Venous Catheter
• Blood Products ( irradiated, leukoreduced, CMV
negative until CMV status is known)
Hematopoietic Stem Cell
transplantation
• Permits “rescue” from otherwise excessively
toxic treatment especially in relapsed/refractory
cases
• Additional advantage of graft-vs-leukemia effect
in allogeneic transplants
• Less used for Philadelphia positive ALL, CML,
and AML with tyrosine kinase inhibitors and
better outcome with chemotherapy
• Trade-off for allogeneic transplantation: greater
anti-leukemic effect but more toxicity
Side Effects of Therapy-Acute
•
•
•
•
Nausea/vomiting/mucositis/hair loss
Neutropenia/Anemia/Thrombocutopenia
Infections/fever
Extravsation of vesicants ( Vincristine,
Anthracyclines)- Central line
• Weight loss/anorexia- Nutritional Support
• SIADH- VCR/Cyclophosphamide
• Hemorraghic cystistis- Cyclophosphamide;
Hydration/MESNA
Long term Side effects
• Neuro-Cognitive abnormalities: High-dose and
intrathechal Methotrexate, Cranial irradiation
• Second cancers : Cyclo/Etoposide, radiation
• Cardiomyopathy: Anthracyclines ( dose
dependent)
• Sterility: cyclophosphamise, Stem cell
transplantation, Radiation
• Endocrine abnormalities: radiation
• Employment problems/Insurance
• Psycho-social support: parents /siblings
• Obesity: ? Females, ? Cranial radiation