Pediatric

Leukemias
Resident
Education
Lecture Series

Cancer of the bone marrow

Major types

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

Factoids

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

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
1955-65
1965-75
1975-85
1985-95
1995-2005

% cured

single agents
< 1
combination therapy
5
CNS prophylaxis
45
tumor biology
50
intensification therapy 75
molecular biology
80
pharmacology
genome polymorphisms

Improved Survival in Childhood ALL

by Study Era
Estimated Survival Percentage

100

1996-2000
(n=3421)
1989-1995
(n=5121)

80

1983-1988
(n=3711)
60

1978-1983
(n=2984)
1975-1977
(n=1313)

40

1972-1975
(n=936)
1970-1972
(n=499)

20

1968-1970
(n=402)

0
0

Years From Study Entry

10

12

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
Asparaginase
Methotrexate
Mercatopurine
Cyclophosphamide

60 %

20 %

Drugs good for inducing remission were less

effective for sustaining remission

Early Combination Chemotherapy

Induction

Post-induction

Prednisone + vincristine
PV + asparaginase
PVA + daunorubicin
Methotrexate
Methotrexate + mercaptopurine
MM + prednisone + vincristine

84 %
94-98 %
98-99 %
5 mos
12 mos
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
ST J
ST J
ST J

# PTS #
I-III
41
V: + CSXRT
35
6: + CXRT/it MTX
45
- CXRT
49

CNSRL
15
3
2
33

# CCR
7
18
23
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

STANDARD

I
CNS

MODERN
I

INTENSIVE
CNS

SUCCESSFUL INTENSIFICATION
FOR ALL:WHATS 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 Childrens Hospital

B-Precursor ALL: Genotype and Outcome:

Childrens Oncology Group
100

Probability

Trisomies 4,10,17 (n = 746)

TEL (n =176)

80

t(1;19) (n = 139)
60

t(4;11) (n = 44)

40

4 Yr EFS (%)
Tris 4,10,17
92.1
TEL
89.0
t(1;19)
68.9
t(4;11)
49.9
t(9;22)
27.5

20

0
0

t(9;22) (n=132)

SE (%)
1.1
3.1
4.1
11.2
4.4

10

Years Followed

11

12

13

14

15

16

10/2001

Residual Disease Monitoring

at End Induction: Flow Cytometry
Dx

POG ALinC17 to Date:

1016 samples received
95% compliance
MRD Sensitivity
1/1000 - 1/10,000
24 hr turn around

d29
Tumor
Tumor

28.6% positive
median .069%

PROGNOSTIC VALUE OF MRD

IN CHILDHOOD ALL

%
RFS

MONTHS
van DONGEN
L 352:1731, 1998

MINIMAL RESIDUAL DISEASE

and RELAPSE RISK
END INDUCTION

MRD-

WEEK 14

WEEK 32

RR 7%

RR 2/8

n=123
RR 10%
14

MRD +

n=42
RR 43%

18

4
RR 68%

RR 4/4

COUSTAN-SMITH
BLOOD 96:2691, 2000

GENETIC CONTEXT OF MRD

MAY BE IMPORTANT
MRD+ End Induction
Abnormality

>.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%

1972

13.0%

21.8%

Overall

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

Still an evil disease

AML

AML subtypes

M6

M1

M4 and M4eo

M3

M7

ACUTE MYELOCYTIC LEUKEMIA: AML

M0
M1

undifferentiated
AML without differentiation

M2
M3

AML with differentiation

promyelocytic leukemia

M4
M5

myelomonocytic leukemia
monocytic leukemia

M6
M7

erythroleukemia
megakaryocytic leukemia

Prognostic factors

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

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

Accelerated

Some systemic sxs;

peripheral and marrow blasts < 10% (NCI says 5%),
thrombo- and leukocytosis
Progressive sxs including splenomegaly;
blasts 10 (5?) -30%, basos+eos > 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

Additional chemo required if disease has

progressed

Morphologic vs cytogenetic vs molecular remission

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 + pros (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

Thank you
Thank you
Thank you
Thank you
Thank you
Thank you