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Pediatric Leukemias
Resident Education
Lecture Series

Cancer of the bone marrow
 Leukemia incidence:
4.1 cases/100,000
children < 15 years
 ALL most common;
2000 cases/year
(we see 30-40
cases/year)
 AML @ 500 cases/year
(we see ~6)
 CML < 100 cases/year,
and CLL not seen
 JMML even less common
 Typically presents
with s/s of anemia,
fever, bone pain,
bleeding/bruising,
HSM/LAD (less in
AML; large spleen in
CML)
 Probable genetic
component based on
twin studies;
 linked to trisomy 21,
Fanconi, p53 mutations,
Bloom, AT, ionizing
radiation, and benzene
Major types Factoids

Definitions
 Marrow
 M1: < 5% blasts in
normocellular marrow
(remission marrow)
 M2: 5-25% blasts
 M3: > 25% blasts
(definition of
leukemia)
 CNS*
(varies by protocol & disease)
 CNS 1: cytospin (-),
independent of cell count
 CNS 2: cytospin (+),
<5 WBC on count
 CNS 3: cytospin (+),
>5 WBC; or CNS sxs
 Traumatic: this is worse
than CNS 2!

ALL: TREATMENT ERAS
 1945-55 single agents < 1
 1955-65 combination therapy 5
 1965-75 CNS “prophylaxis” 45
 1975-85 tumor biology 50
 1985-95 intensification therapy 75
 1995-2005 molecular biology 80
pharmacology
genome polymorphisms
% cured

Years From Study Entry
Improved Survival in Childhood ALL
by Study Era
0
20
40
60
80
100
0 2 4 6 8 10 12
1996-2000
(n=3421)
1989-1995
(n=5121)
1983-1988
(n=3711)
1978-1983
(n=2984)
1975-1977
(n=1313)
1972-1975
(n=936)
1970-1972
(n=499)
1968-1970
(n=402)

ALL subtypes
 Formerly L1, L2, L3 (morphology); no longer
used (L3 morphology = mature B, aka Burkitt)
 Now surface markers
 B-lineage: 85%
 Early pre-B 57%; pre-B 25%
 T-ALL: 13%
 B (mature): 1-2% (surface Ig)
 True biphenotypic is bad; a few T or AML marks
in o/w classic ALL is fine
 And molecular subsets

ALL: EARLY CHEMOTHERAPY
 Variable ability of drugs to induce remission:
 Prednisone
 Vincristine 60 %
 Asparaginase
 Methotrexate
 Mercatopurine 20 %
 Cyclophosphamide
 Drugs good for inducing remission were less
effective for sustaining remission

Early Combination Chemotherapy
 Induction
 Prednisone + vincristine 84 %
 PV + asparaginase 94-98 %
 PVA + daunorubicin 98-99 %
 Post-induction
 Methotrexate 5 mos
 Methotrexate + mercaptopurine 12 mos
 MM + prednisone + vincristine 12-18 mos
 95 % of patients still relapsed, frequently
only in the csf

CHEMOTHERAPY for ALL
1967
 ASPARAGINASE
 CYCLOPHOSPHAMIDE
 MERCAPTOPURINE
 METHOTREXATE
 PREDNISONE
 VINCRISTINE
2004
 ASPARAGINASE
 CYCLOPHOSPHAMIDE
 CYTOSINE ARABINOSIDE
 DEXAMETHASONE
 DOXORUBICIN
 ETOPOSIDE
 METHOTREXATE
 MERCAPTOPURINE
 PREDNISONE
 THIOGUANINE
 VINCRISTINE

CNS “PROPHYLAXIS”
STUDY # PTS # CNSRL # CCR
 ST J I-III 41 15 7
 ST J V: + CSXRT 35 3 18
 ST J 6: + CXRT/it MTX 45 2 23
- CXRT 49 33 7
C = cranial; CS = craniospinal; XRT = radiation; it = intrathecal
CNSRL = CNS relapse; CCR = continuous complete remission
Subsequent studies have shown similar results with
intrathecal treatment alone.
XRT now reserved for patients with CNS leukemia
and patients with higher risk T-ALL.

Intensive Chemotherapy
 Postulate: early intensive chemotherapy
with a combination of drugs will improve
cure by
 more rapid elimination of sensitive cells
 prevention of the development of resistance
 treatment of resistant cells

TREATMENT STRATEGIES FOR ALL
I
I INTENSIVE
CNS
CNS
STANDARD
MODERN

SUCCESSFUL INTENSIFICATION
FOR ALL:WHAT’S INSIDE THE BOX?
 Weekly asparaginase (DFCC)
 Intermediate-high dose methotrexate
(MCCC; POG/CCG)
 Delayed reinduction-intensification
(BFM/CCG)
 Multiple rotating pairs of drugs (MCCC; POG)
All of these improved cure rates to 70-80%

Favorable Prognostic Factors in ALL
 AGE 1-9
 WBC lower
 Gender female
 Chromosomes t(12;21), hyperdiploid
 Treatment response rapid
 Residual disease (MRD) less

Genetic Heterogeneity in Childhood
ALL:
St. Jude Children’s Hospital
> 50
TEL:AML t (12;21)
RANDOM
BCR-ABL t(9;22)
t 11q23
< 45
TCR B 7q35
TCR AD 14q11
MYC
E2A-PBX t(1;19)

B-Precursor ALL: Genotype and Outcome:
Children’s Oncology Group
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
0
20
40
60
80
100
Probability
10/2001
TEL (n =176)
4 Yr EFS (%) SE (%)
Tris 4,10,17 92.1 1.1
TEL 89.0 3.1
t(1;19) 68.9 4.1
t(4;11) 49.9 11.2
t(9;22) 27.5 4.4
Years Followed
t(4;11) (n = 44)
t(9;22) (n=132)
t(1;19) (n = 139)
Trisomies 4,10,17 (n = 746)

Tumor
Tumor
Dx
d29
POG ALinC17 to Date:
1016 samples received
95% compliance
MRD Sensitivity
1/1000 - 1/10,000
24 hr turn around
28.6% positive
median .069%
Residual Disease Monitoring
at End Induction: Flow Cytometry

PROGNOSTIC VALUE OF MRD
IN CHILDHOOD ALL
0
20
40
60
80
100
3 15 27 39 51 63
LOW
INTERMED
HIGH
%
RFS
MONTHS
van DONGEN
L 352:1731, 1998

MINIMAL RESIDUAL DISEASE
and RELAPSE RISK
n=123
RR 10%
n=42
RR 43%
14
18 4
8
RR 7%
RR 68%
RR 2/8
RR 4/4
COUSTAN-SMITH
BLOOD 96:2691, 2000
END INDUCTION WEEK 14 WEEK 32
MRD-
MRD +

GENETIC CONTEXT OF MRD
MAY BE IMPORTANT
Abnormality n >.1% >.01%
BCR-ABL 41 63% 73%
E2A-PBX1 87 6.9% 12.6%
TEL-AML1 431 2.6% 7.9 %
Trisomy 4&10 431 9.3% 19.3%
MRD+ End Induction
Overall 13.0% 21.8%
1972

COG ALL Risk Groups 2004:
B-Precursor ALL
• NCI Risk Groups
• Trisomies 4, 10, & 17
• TEL/AML 1
• CNS Disease
• MLL
• Slow Early Response
• End of Induction MRD
• BCR-ABL
• Chromosomes <45
• Induction Failure
Low Risk
Standard Risk
High Risk
Very High Risk

Principles of Cure
 Cure depends upon a complex interaction of
patient, disease and treatment-related
factors
 Treatment of all patients with similar
regimens risks both overtreatment and
undertreatment of individuals
 Understanding differences in tumor and
host genetics (polymorphisms) will be crucial
to individualization of therapy

AML subtypes
M1
M3
M7
M4 and M4eo
M6

ACUTE MYELOCYTIC LEUKEMIA: AML
M0 undifferentiated
M1 AML without differentiation
M2 AML with differentiation
M3 promyelocytic leukemia
M4 myelomonocytic leukemia
M5 monocytic leukemia
M6 erythroleukemia
M7 megakaryocytic leukemia

Prognostic factors
 WBC > 100,000
 Secondary
 Monosomy 7 (7q-)
 ? Very young
 ? Splenomegaly
 ? M4 and M5
 ? M1 w/o Auer rods
 M4eo (inv16)
 M6
 M# = t(15;17)
 Matched sibling
transplant up-front
 Down Syndrome
 ? t(8;21)
(latest paper says no)
 ? Rapid CR
EFS ranges 45-80%
Good Bad
Ugly

AML: INDUCTION THERAPY
 Two cycles of cytosine arabinoside +
daunorubicin +/-thioguanine and other
agents gives remissions in 70-90%
 Timed sequential therapy (giving the second
cycle at a specified time) does not the
increase remission rate but does increase
long-term cures when compared to waiting
for marrow recovery (or failure) before
giving the second cycle (Blood 87:4979,
1996)

AML: Post-induction Therapy
 Chemotherapy alone has given 30-50 %
cure rates.
 Cure is higher after timed-sequential
induction therapy (42% vs. 27%).
 Short (4-12 months) of post-induction
therapy is adequate
 CNS leukemia is less common than in ALL;
‘prophylaxis’ may be accomplished with
high dose Ara-C +/- intrathecal Ara-C

AML: Bone Marrow Transplantation
 Bone marrow transplantation from a
matched sibling donor during first
remission gives better cure rates than
chemotherapy (50-60 % vs. 30-50 %)
 Autologous BMT during first remission
gives results similar to chemotherapy
 BMT from a matched sibling in second
remission gives 30-40 % cure rate but is
limited by the difficulty in achieving
second remission.

AML Treatment Issues
 50% incidence of serious bacterial infection:
therefore use of G-CSF accepted
 New protocol is European-based and returns
to the old high-dose Ara-C, with the addition
of myelotarg (anti-CD33, aka gemtuzumab)

Special circumstances
 Granulocytic sarcoma
 Down syndrome
 Increased incidence of all leukemias; ALL still > AML
total, but RELATIVE increase of AML
 Do not use intensive timing (increased toxicity with
therapy), but OK to use anthracyclines even with CHD
 M7 AML most often
 Transient Myeloproliferative Disease occurs in
newborn period
 M3 (the 15;17 translocation)

Promyelocytic Leukemia: M3
 Characterized by a translocation [t(15;17)]
that fuses the retinoic acid receptor and
PML genes
 The t(15;17) transcript blocks differentiation
that depends upon the normal receptor
 High dose all-trans retinoic acid overcomes
this blockade
 Arsenic trioxide may cause apoptosis or may
induce differentiation in PML cells

Promyelocytic Leukemia: M3
 Induction: all-trans retinoic acid +/- an
anthracycline
 Intensification: anthracycline +/- Ara-C
 Continuation: intermittent all-trans
retinoic acid +/- chemotherapy
RESULTS: 90-95 % remission
: 70-85 % event-free survival
: high salvage rate of relapses with
retinoic acid, arsenic or BMT
Blood 105:3019, 2005 JClinOncol 22:1404, 2004

CML
On which we are going to
spend very little time

CML overview
 BCR-ABL fusion protein is generally P210,
whereas Ph+ALL is usually P190.
 3 phases
 Chronic
 Some systemic sxs;
peripheral and marrow blasts < 10% (NCI says 5%),
thrombo- and leukocytosis
 Accelerated
 Progressive sxs including splenomegaly;
blasts 10 (5?) -30%, baso’s+eo’s > 20%
 Blast
 Extramedullary disease symptoms;
blasts > 30%, blasts that look like ALL or AML

CML treatment
 Gleevac: aka STI571, aka imatinib mesylate
tyrosine kinase inhibitor that blocks the
function of the BCR-ABL fusion protein
 Morphologic vs cytogenetic vs molecular remission
 Additional chemo required if disease has
progressed
 IFN, Ara-C, hydroxyurea
 Transplant still the Rx of choice for Peds

JMML
 Juvenile myelomonocytic leukemia
 Sometimes called JCML
 Think of it as stem cell leukemia, but it acts like an
MDS more than a leukemia
 Associated with NF1 (10+%)
 Young kids (nearly all < 4; most < 2)
 Lab findings include high HgbF, hypersensitivity to
GM-CSF (in vitro), monosomy 7, NO BCR-ABL, < 20%
blasts + pro’s (marrow or peripheral), and monocytosis
(can have a very high total WBC)
 Usually treated with SCT, although very often fatal

From ABP
Certifying Exam Content Outline
 Pancytopenia 1. General aspects
 Recognize that a bone marrow aspirate is necessary in
the evaluation of a child with multiple pancytopenias

From ABP
Certifying Exam Content Outline, continued
 WBC disorders b. Acquired (leukemia)
 Understand that aplastic anemia and childhood leukemia may
both present with purpura, pallor, and fever
 Know that the absence of blasts in the peripheral blood of a
patient with pancytopenia does not rule out the diagnosis of
leukemia
 Recognize bone pain as a symptom of leukemia
 Understand that most patients with acute lymphoblastic
leukemia will be cured of their disease using current treatment
strategies
 Identify the central nervous system and testicles as important
sites of relapse of acute lymphoblastic leukemia
 Identify Down syndrome as a disease with an increased risk of
leukemia

Credits
 Meghen Browning MD
Bruce Camitta MD
Anne Warwick MD MPH

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08_pediatric_leukemias.ppt

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