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‫לויקמיה ולימפומה‬
‫בילדים‬
‫ יצחק יניב‬.‫דר‬
‫מנהל המחלקה להמטולוגיה ואונקולוגיה‬
‫ילדים‬
‫מרכז שניידר לרפואת ילדים בישראל‬
Pediatric Hematology Oncology,
Schneider Children’s Medical Center of Israel, Petal-Tikva,
Sackler School of Medicine, Tel Aviv University, Israel.
Childhood malignancy
Cancer Cell, 2002
Childhood leukemia
 97% Acute leukemia
75% Acute lymphoblastic leukemia
20% Acute myeloblastic leukemia
Acute mixed lineage leukemia
Acute undifferentiated leukemia
 3% Chronic leukemia
Chronic myelocytic leukemia
Juvenile myelomonocytic leukemia
Risk Factors for Childhood Acute Leukemia
Genetic
Down
NF1
Bloom
Schwachman
Ataxia Telangiectasia
Fanconi Anemia
Kostmann Granulocytopenia
Environmental
Ionizing Radiation
In Utero X-ray
Benzene
Pesticide
Alkylating /Topo-II Inhib.
In Utero Topo II Inhib.
DNA damaging
Higher incidence among identical twins
ALL, AML
ALL, AML, JMML
ALL, AML
ALL, AML
ALL
AML
AML
ALL, AML
ALL
AML
AML
AML
Infant Und L.
ALL- Epidemiology
 The most common malignancy in
childhood
 Incidence 3-4 cases per 100000 children
 Peak incidence between 2-5 y
 Boys > Girls
 White >Black
Genetic predisposition <5%
Age distribution
Clinical Features at Diagnosis in Children with
Acute Lymphoblastic Leukemia
Clinical features/ Symptoms
Fever
Bleeding (petechiae or purpura)
Bone pain
Lymphadenopathy
Splenomegaly
Hepatosplenomegaly
% of patients
61
48
23
50
63
68
Laboratory Features at Diagnosis in Children with
Acute Lymphoblastic Leukemia
Laboratory features
Leukocyte count (mm3)
<10,000
10,000-49,000
>50,000
Hemoglobin (g/dl)
<7.0
7.0-11.0
>11.0
Platelet count (mm3)
<20,000
20,000-99,000
>100,000
% of patients
53
30
17
43
45
12
28
47
25
ALL testicular involvement
CNS leukemia
Differential Diagnosis in Childhood
Acute Lymphoblastic Leukemia
Nonmalignant conditions
Juvenile rheumatoid arthritis
Infectious mononucleosis
Idiopathic thrombocytopenic purpura
Pertussis; parapertussis
Aplastic anemia
Acute infectious lymphocytosis
Malignancies
Neuroblastoma
Retinoblastoma
Rhabdomyosarcoma
Unusual presentations
Hypereosinophilic syndrome
Diagnosis
 Blood count and smear
 Bone marrow: Morphology
Cytochemical stains
Immunophenotype
Cytogenetics
Haemopoiesis
FAB L1
FAB L2
FAB L3
Cytochemical stains
Lymphoid differentiation
T phenotype ALL
 Incidence 15%
(Israel – 20 %)
 Median age : 12y
 Male > Female
 High blood count
 Mediastinal mass
 Organomegaly
 CR < 90 %
 High relapse rate, CNS, Extra medullary
‫•‬
‫•‬
‫•‬
‫•‬
‫אחד מתוך ‪ 2000‬ילדים מפתח ‪ ALL‬לפני גיל ‪15‬‬
‫ברובם הארוע הראשון קורה ברחם‬
‫‪ 1/100‬נןשא טרנסלוקציה ‪ 12;21‬אך רק אחוז אחד מהם‬
‫יפתח לויקמיה‬
‫דרוש ארוע נוסף כדי שהלויקמיה תופיע וזה יכול להיות קשור‬
‫בזיהום או בתגובה לזיהום וגם במבנה הגנטי הקיים לגבי‬
‫מטבוליזם של תרופות ותיקון נזקי ‪DNA‬‬
Genetic (somatic) Abnormalities in Childhood Cancer
Numerical Chromosomal changes
Structural Chromosomal changes
Translocation
Inversion
Deletion
Addition / duplication
Amplification
Childhood ALL
Hyperdiploid
G-banding
FISH
cep4/cep10
Cep4: centromere 4
Cep10: centromere 10
Ca-Cytogenet. -SCMCI
Genetic (somatic) Abnormalities in Childhood Cancer
Numerical Chromosomal changes
Structural Chromosomal changes
Translocation
Inversion
Deletion
Addition / duplication
Amplification
Genetic Abnormalities in Childhood Cancer
Protooncogen Activation
Suppressor gene Inactivation
Altered function of:
Growth factors
Growth factor receptors
Kinase inhibitors
Signal transducers
Transcription factors
Altered down stream Genes Expression
G-banding
Childhood ALL
Philadelphia chromosome
FISH
bcr/abl
bcr: 22q11
abl: 9q34
46,XY,t(9;22)(q34;q11)
Ca-Cytogenet. -SCMCI
ALL-B lineage Chromosomal rearrangement
Activation of transcriptional control Genes
ALL
Translocation
Genes
Frequency
Early B
Pre. B
Pro. B
t(12;21)(p12;q22)
t(1;19) (q23;p13)
t(17;19)(q22;p13)
t(4;11) (q21;q23)
TEL-AML1
E2A-PBX1
E2A-HLF
MLL-AF4
25%
5%
<1%
4%
B cell/Burkitt
t(8;14) (q24;q32)
t(2;8) (p12;q24)
t(8;22) (q24;q11)
t(3;11) (q27;q23)
MYC (IgH)
MYC (IgL)
MYC (IgL)
BCL6
5%
<1%
<1%
1%
B cell
Childhood ALL – t(12;21) (TEL/AML1),del(12p)
G-band
FISH
SKY
46,XY,t(12;21)(p13;q22),der(12)t(1;12p)
Ca-Cytogenet. -SCMCI
H.M.
Expression profiles of diagnostic bone marrow ALL blasts
Yeon, Cancer Cel 2002
Molecular subtypes of ALL
Cancer Cell, 2002
Childhood ALL, Event Free Survival by Genetic Features
St Jude
Pui, NEJM, 1998
Prognostic Risk Factors in ALL
Age:
WBC:
Phenotype.:
1-6, 1-10y
20.000, 50.000
T, “B”, CALLA neg.
Ploidy:
Cytogenetic:
<2n, 3n
t(9;22),t(4;11)
t(12;21)
Gene Expression Profile ?
Early response to treatment !!!!!!
PB D8, BM D15, D33
Morphology, MRD
Sex, Race, CNS, Testicular involvement
Early response to therapy
 D-8 ( PB ; BM )
 D- 14 ( BM )
 D- 33 ( BM )
 MRD Slop by
BM aberrant phenotype
BM clonal Ig/TCR rearrangement
MRD
Minimal Residual Disease
 Precise definition of remission
 Prognostic significance (blast <0.01% )
Treatment modification
Immunogobuline gene
rearrangement
van Dongen ASH 2002
. therapy antileukemic Patterns of early cellular responses to
Pui, 2000
International BFM Study Group
Risk
MRD
TP1 TP2
Low
Intermediate
High
<10-4 <10-4
>10-3 10-3
5 year Relapse
Rate - %
2
24
84
Combined Information of MRD from Time Points 1+2
1.0
Low risk group (n=55)
neg at tp 1
0.8
Intermediate risk group (n=55)
< 10e-3 at tp 2
0.6
0.4
High risk group (n=19)
≥ 10e-3 at tp 2
0.2
0.0
0
1
2
3
4
5
6
years from time point 2
Low risk group
pRFS = 0.98 ± 0.02
Intermediate risk group pRFS = 0.76 ± 0.06
High risk group
pRFS = 0.16 ± 0.08
7
8
p<0.001
9
Principles of treatment
Risk group
Combination chemotherapy:
Remission induction
CNS prevention•
Consolidation
Maintenance
Irradiation
BMT
Late effect consideration
Leukemic cell kinetics
Event- Free Survival of ALL children- St. Jude
Pui, 1998 NEJM
CHILDHOOD-ALL
ISRAEL NATIONAL STUDIES. EFS
1.0
.9
.8
.7
INS-98
.6
.5
.4
INS-89
.3
.2
INS-84
.1
0.0
0
Years
2
4
6
8
10
12
Aug 2002
14
16
18
CHILDHOOD ALL-INS 89
EFS by RISK-GROUPS
1.0
.9
.8
.7
Non-HRG: 79%
.6
(N=259)
.5
Cum Survival
.4
.3
.2
HRG:
.1
(N=43)
.0
0
Years
2
4
6
8
10
12
14
Aug 2002
16
33%
Host Pharmacogenetics Affects Treatment Response
excessive toxicity
nonresponders
responders
Determinants of Treatment Response in Leukemia
Leukemia
Host
Tumor burden
Growth potential
Drug resistance
Age
Pharmacogenomics
Treatment
response
Therapy
Drug dosage
Drug interactions
Impact of Pharmacogenomics on Treatment Response
+ Benefit
+ Toxicity
Optimize
treatment
with
individualized
dose
Same treatment
to all patients
+ Benefit
+ No Toxicity
No Benefit
+ Toxicity
No Benefit
No Toxicity
Treat with alternative drug
BMT – (BFM-95)
 t ( 9 ; 22 ) or BCR /ABL recombination
 t ( 4 ; 11 ) or MLL / AF4 recombination
 No CR D – 33
 PPR + T immunophenotype
pre B immunology
WBC > 100000
‫סיבוכים מאוחרים של קרינה למ‪.‬ע‪.‬מ‪ .‬וכמותרפיה אינטנסיבית‬
‫קרינה‬
‫גדולי מח משניים ‪-‬‬
‫אפיפודופילוטוקסינים‪ .‬תרופות מאלקלות‬
‫לאוקמיה משנית ‪-‬‬
‫אנטרהציקלינים‬
‫אנטרהציקלינים‬
‫קרדיומיופתיה ‪-‬‬
‫קרינה‪ ,‬מטוטרקסאת‪ ,‬גלוקוקורטיקואידים‬
‫אנצפלופתיה ‪-‬‬
‫קרינה‪ ,‬גלוקוקורטיקואידים‬
‫קומה נמוכה ‪-‬‬
‫קרינה‬
‫השמנה ‪-‬‬
‫קרינה‪ ,‬גלוקוקורטיקואיד‪ ,‬אנטימטבוליטים‬
‫אוסטאופורוזיס ‪-‬‬
‫נמק אווסקולרי לעצמות ‪ -‬גלוקוקורטיקואיד‬
‫!!‪Relapse remains the major problem of childhood leukemia‬‬
Cancer Cell, 2002
Science, 1997
AML-M2,
t(8;21)
NEJM, 1999
AML
G-banding
FISH
Eto: 8q22
AML1: 21q22
Ca-Cytogenet. -SCMCI
AM-M3, Hypergranular, t(15;17)
Bennet, leukemia 2000
AML-MRC-10. Overall Survival by Cytogenetic abnormalities
Grimwade, Blood, 1998
AML-MRC-10. Overall Survival by Cytogenetic abnormalities
Grimwade, Blood, 1998
Cancer Cell, 2002
Lymphomas
Classification along three axes
Classification by cell of origin (B vs. T vs. NK)
Classification by grade – Low grade, intermediate
grade, high-grade
Hodgkin disease (HD) vs. Non-Hodgkin Lymphoma
(NHL)
Lymphoma
• Malignancies of the lymphoid system
• Classification by cell of origin (B vs. T)
• Classification by grade – Low/intermediate/high
In children – only high-grade lymphomas
• Hodgkin disease (HD) vs. Non-Hodgkin Lymphoma (NHL)
Pediatric lymphomas
Non-Hodgkin Lymphoma in Children
• B-Cell – Burkitt’s lymphoma (40%)
Diffuse large B-cell (DLBCL) (20%)
B-cell lymphoblastic lymphoma (5%)
• T-Cell – Lymphoblastic Lymphoma (25%)
• Anaplastic Large Cell Lymphoma (ALCL) (10%)
Burkitt’s lymphoma
Burkitt’s lymphoma - Pathogenesis
• The B-Lymphocyte is produced in the bone marrow
• It differentiates into an antibody producing cell
(Immunoglobulin-Ig)
• It can be found in all lymph nodes and extra-nodal organs
• Burkitt’s lymphoma and DLBCL are thought to arise in
germinal centers of lymph nodes during B-cell
development
The normal lymph node
Malignancies of B-lymphocytes
Burkitt’s lymphoma - Pathogenesis
• Cell of origin – B-cell centroblast (relatively mature Bcell)
• t(8;14) – C-MYC
• Role of EBV
• African (Endemic) vs. Sporadic form
Burkitt’s lymphoma - Pathogenesis
• Cytogenetics t(8;14), t(2;8), t(22;8)
• Common theme – Chr. 8 – C-MYC - a cellular oncogene
• Partners – Immunoglobulin regulatory regions
Burkitt’s lymphoma - Pathogenesis
Regulator
Chromosome 8
¥
▅_▅_▅____▅__▅__
Regulator
Chromosome 14
C-MYC
Ig
¥
▅_▅_▅____▅__▅__
Burkitt’s lymphoma - Pathogenesis
C-MYC Regulator
Ig
Chromosome 8;14
▅_▅_▅____▅__▅__
Ig Regulator
C-MYC
Chromosome 14;8
▅_▅_▅____▅__▅__
Burkitt’s lymphoma - Pathogenesis
• The regulatory region of the Ig gene, which is usually very
active in B-Cells, now drives the expression of C-MYC
• C-MYC is an oncogene – the cell enters the cell cycle and
divides
• The result – the B-cell is driven to proliferate
Burkitt’s lymphoma - Pathogenesis
Burkitt’s Lymphoma is the tumor with the greatest
proliferative capacity with a doubling time of 24-48 hours.
The role of EBV in Burkitt’s lymphoma
• EBV – a DNA herpesvirus
• The cause of infectious mononucleosis – a self limiting
infection of B-cells
• The genome of EBV can be found in Burkitt’s lymphoma
cells: 100% of cases of African Burkitt’s, ~50% of cases in
Latin America, and only in 20% of cases in the west.
• Its exact role in lymphomagenesis is unclear
The role of EBV in Burkitt’s lymphoma
• In normal hosts - EBV causes a transient
lymphoproliferation that is controlled by the immune
system
• In the immunocompromised host – EBV can cause a
lymphoproliferative state than can be polycolonal or
monoclonal (PTLD)
• Immunodeficiency or chronic infection (malaria) allows
continuous proliferation of EBV-infected B-cells that may
be the reservoir of cells vulnerable to malignant
transformation
Burkitt’s Lymphoma – Clinical Features
• Commonest location – abdomen – Localized (ileocecal intussusception)
- Disseminated mesenteric, peritoneal
- Renal involvement
• Head and neck – pharynx, Waldeyer ring, paranasal sinuses, tonsils, gums
• Epidural, ovary, bone
• African form – Jaw tumors
• Spread to extra lymphatic organs – CNS, BM (20%)
• Rapid growth – metabolic derangements
Burkitt’s - Diagnostic Evaluation
• Diagnostic biopsy
-
lymph node
abdominal mass
bone marrow (stage 4 - B-cell leukemia)
intestinal resection (intussusception)
Burkitt’s lymphoma - Pathology
• Rapidly proliferating B-Cells (MIB1)
• Starry sky appearance (macrophages)
• Subtypes – Burkitt’s, Burkitt-like, (DLBCL)
Burkitt’s lymphoma Pathology
Burkitt’s- Diagnostic Evaluation
• Clinical extent
• Lab- CBC, Uric acid, LDH, P, Ca, K,
renal function
• Imaging – CT
• Radionucleide scan – Gallium, PET
• Bone marrow, CNS involvement
• Pre-treatment - Echo,Fertility preservation
Burkitt’s Lymphoma - Staging
St. Jude/NCI system
• Stage I – One nodal group- resected
• Stage II – Localized disease (AR) (Intussusception)
• Stage III – Extensive abdominal or mediastinal
disease, epidural
• Stage IV – Extra nodal disease – CNS, Bone marrow
(BM - Burkitt’s (B-cell) leukemia)
Most patients present with advanced disease (Stages III,
IV)
Burkitt’s Lymphoma - Staging
LMB (FAB – International) System
• Group 1 – One nodal group- resected
• Group 2 – Extensive localized disease - abdominal or
mediastinal, epidural, high LDH
• Group 3 – Extra nodal disease – CNS, Bone marrow
(BM - Burkitt’s (B-cell) leukemia)
Burkitt’s lymphoma - Treatment
 Metabolic stabilization – Tumor lysis syndrome (TLS)






Stage (Group) dependent
Chemotherapy
Intensive, short duration therapy
Minimal (if any) role for radiation therapy
Surgery – localized abdominal disease (intussusception)
High cure rate in newly diagnosed patients
 Relapse is rarely curable
Tumor Lysis Syndrome
• Rapid proliferation and death of cells
• Tumor cells outstrip their own blood supply and die
• Breakdown of nucleic acids – DNA – uric acid, phosphate
• Spontaneous cell death → Severe TLS can occur before
treatment
Tumor Lysis Syndrome
Diseases with rapid cellular turnover
• Lymphomas – Burkitt’s, lymphoblastic
• Leukemias – ALL, AML
• Solid tumors – less common – NB, RMS
Burkitt’s lymphoma - Chemotherapy
• Begin after metabolic stabilization
• Active agents– Cyclophosphamide, HD MTX, HD ARAC, vincristine, doxorubicin, steroids, ifosfamide, VP-16,
• CNS directed therapy – intrathecal (XRT unnecessary)
• Greatest dose-intensity possible (minimal interval between
cycles)
Burkitt’s Lymphoma – Treatment
The LMB approach
Reduction
phase
Vincristine
Cyclophosphamide –– Total 5.5 grams/M2
Doxorubicin –– Total 180 mg/M2
MTX -– Total 15 gram/M2
Prednisone
ARA-C
VP-16
Burkitt’s lymphoma - Outcome
• Modern therapy is highly effective.
Most patients are cured: 95% group B, 80% Group C.
Period of risk for relapse is short – 9-12 months
• Acute toxicity is substantial – Infections, mucositis, acute
mortality ~ 1-3%.
• Long term toxicity– mainly gonadal (cardiac)
Reduction in therapy?
Results of LMB-89 trial for Pediatric B-cell NHL
Patte C et al Blood 2001:97, 3370-9
B-NHL - Outcome by group
B-NHL - Outcome by stage
Outcome in group C – Importance of CNS disease
Gonadal Toxicity
• Mainly caused by alkylating agents
Cyclophosphamide, ifosfamide, busulfan, procarbazine
• Damage to gonads is related to cumulative dose
• Cyclophosphamide >6 grams is toxic
Burkitt’s lymphoma – Challenges
• Preserve cure rates while reducing acute and long term
toxicity
• Treatment of relapse
Relapsed Burkitt’s Lymphoma
• Relapse Burkitt’s lymphoma is currently incurable in the
overwhelming majority of patients
• Targeted therapy -
• Allo-BMT
Anti CD - 20 (rituximab)
Ibritumomab-tiuxetan Y90
Anti CD22 – Epratuzumab
hLL2-DOTA- Y90
Anti CD52 – Campath-1H,
Alemtuzumab