Pediatric Leukemias

Resident Education
Lecture Series
 Cancer of the bone marrow
Major types Factoids
 Leukemia incidence:  Typically presents
4.1 cases/100,000 with s/s of anemia,
children < 15 years fever, bone pain,
 ALL most common; bleeding/bruising,
2000 cases/year HSM/LAD (less in
(we see 30-40 AML; large spleen in
cases/year) CML)
 AML @ 500 cases/year  Probable genetic
(we see ~6) component based on
 CML < 100 cases/year, twin studies;
linked to trisomy 21,
and CLL not seen 
Fanconi, p53 mutations,
 JMML even less common Bloom, AT, ionizing
radiation, and benzene
 Definitions
 Marrow  CNS*
(varies by protocol & disease)
 M1: < 5% blasts in
 CNS 1: cytospin (-),
normocellular marrow independent of cell count
(remission marrow)  CNS 2: cytospin (+),
 M2: 5-25% blasts <5 WBC on count
 M3: > 25% blasts  CNS 3: cytospin (+),
>5 WBC; or CNS sxs
(definition of
leukemia)  Traumatic: this is worse
than CNS 2!
 ALL: TREATMENT ERAS
% cured
 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
 Improved Survival in Childhood ALL
by Study Era

100 1996-2000
(n=3421)
1989-1995
80 (n=5121)
1983-1988
(n=3711)
60 1978-1983
(n=2984)
1975-1977
40 (n=1313)
1972-1975
(n=936)
20 1970-1972
(n=499)
1968-1970
0 (n=402)
0 2 4 6 8 10 12

Years From Study Entry

 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
2004
 ASPARAGINASE
1967  CYCLOPHOSPHAMIDE
 ASPARAGINASE  CYTOSINE ARABINOSIDE
 CYCLOPHOSPHAMIDE  DEXAMETHASONE
 MERCAPTOPURINE  DOXORUBICIN
 METHOTREXATE  ETOPOSIDE
 METHOTREXATE
 PREDNISONE
 MERCAPTOPURINE
 VINCRISTINE
 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

STANDARD

I
CNS
MODERN

I INTENSIVE

CNS
 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

100

80 TEL (n =176) Trisomies 4,10,17 (n = 746)

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

60
t(4;11) (n = 44)

40

4 Yr EFS (%) SE (%) t(9;22) (n=132)

20 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
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Years Followed 10/2001
 Residual Disease Monitoring
at End Induction: Flow Cytometry

Dx POG ALinC17 to Date:

1016 samples received
95% compliance

MRD Sensitivity
d29 1/1000 - 1/10,000
Tumor 24 hr turn around
Tumor
28.6% positive
median .069%
 PROGNOSTIC VALUE OF MRD
IN CHILDHOOD ALL
100

80

60 LOW
%
INTERMED
RFS 40 HIGH

20

0
3 15 27 39 51 63

MONTHS
van DONGEN
L 352:1731, 1998
 MINIMAL RESIDUAL DISEASE
and RELAPSE RISK

END INDUCTION WEEK 14 WEEK 32

n=123
MRD- RR 7%
RR 10% RR 2/8

14 8

n=42 18 4
MRD + RR 68% RR 4/4
RR 43%

COUSTAN-SMITH
BLOOD 96:2691, 2000
 GENETIC CONTEXT OF MRD
MAY BE IMPORTANT
MRD+ End Induction
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%

Overall 1972 13.0% 21.8%

 COG ALL Risk Groups 2004:
B-Precursor ALL
• NCI Risk Groups
• Trisomies 4, 10, & 17
• TEL/AML 1
Low Risk
• CNS Disease
• MLL Standard Risk
• Slow Early Response
• End of Induction MRD High Risk
• BCR-ABL
Very High Risk
• Chromosomes <45
• Induction Failure
 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 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
Good Bad
 M4eo (inv16)  WBC > 100,000

 M6  Secondary

 M# = t(15;17)  Monosomy 7 (7q-)

 Matched sibling  ? Very young

transplant up-front  ? Splenomegaly

 Down Syndrome  ? M4 and M5

 ? t(8;21)  ? M1 w/o Auer rods

(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
 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