Transcript Pediatric Leukemias

Pediatric Leukemias
Resident Education
Lecture Series
Cancer of the bone marrow
Major types
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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
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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;
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linked to trisomy 21,
Fanconi, p53 mutations,
Bloom, AT, ionizing
radiation, and benzene
Definitions
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Marrow
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M1: < 5% blasts in
normocellular marrow
(remission marrow)
M2: 5-25% blasts
M3: > 25% blasts
(definition of
leukemia)
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CNS*
(varies by protocol & disease)
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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
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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
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
2
4
6
8
Years From Study Entry
10
12
ALL subtypes
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Formerly L1, L2, L3 (morphology); no longer
used (L3 morphology = mature B, aka Burkitt)
Now surface markers
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B-lineage:
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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
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Variable ability of drugs to induce remission:
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Prednisone
Vincristine
Asparaginase
Methotrexate
Mercatopurine
Cyclophosphamide
60 %
20 %
Drugs good for inducing remission were less
effective for sustaining remission
Early Combination Chemotherapy
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Induction
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Post-induction
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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
2004
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1967
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ASPARAGINASE
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CYCLOPHOSPHAMIDE
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MERCAPTOPURINE
METHOTREXATE
PREDNISONE
VINCRISTINE
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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
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Postulate: early intensive chemotherapy
with a combination of drugs will improve
cure by
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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?
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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
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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
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
1
2
3
4
t(9;22) (n=132)
SE (%)
1.1
3.1
4.1
11.2
4.4
5
6
7
8
9
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
100
80
%
RFS
60
LOW
INTERMED
HIGH
40
20
0
3
15
27
39
51
63
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%
8
18
4
RR 68%
RR 4/4
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%
1972
13.0%
21.8%
Overall
COG ALL Risk Groups 2004:
B-Precursor ALL
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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
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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
M2
M3
M4
M5
M6
M7
undifferentiated
AML without differentiation
AML with differentiation
promyelocytic leukemia
myelomonocytic leukemia
monocytic leukemia
erythroleukemia
megakaryocytic leukemia
Prognostic factors
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Bad
Good
M4eo (inv16)
 WBC > 100,000
 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
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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
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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
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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
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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
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Granulocytic sarcoma
Down syndrome
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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
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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
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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
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BCR-ABL fusion protein is generally P210,
whereas Ph+ALL is usually P190.
3 phases
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Chronic
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Accelerated
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Some systemic sxs;
peripheral and marrow blasts < 10% (NCI says 5%),
thrombo- and leukocytosis
Progressive sxs including splenomegaly;
blasts 10 (5?) -30%, baso’s+eo’s > 20%
Blast
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Extramedullary disease symptoms;
blasts > 30%, blasts that look like ALL or AML
CML treatment
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Gleevac: aka STI571, aka imatinib mesylate
tyrosine kinase inhibitor that blocks the
function of the BCR-ABL fusion protein
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Additional chemo required if disease has
progressed
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Morphologic vs cytogenetic vs molecular remission
IFN, Ara-C, hydroxyurea
Transplant still the Rx of choice for Peds
JMML
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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
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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
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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
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Meghen Browning MD
Bruce Camitta MD
Anne Warwick MD MPH