Cancer in Down Syndrome :
Focus on
Disorders of Infancy
James A. Whitlock, M.D.
Division Head, Hematology/Oncology
Women’s Auxiliary Millennium Chair in Haematology/Oncology
The Hospital for Sick Children
Professor of Paediatrics, University of Toronto
Disclosures
• No Relevant Potential Conflicts of
Interest
• Non-relevant Disclosures:
– Current consultant:
• EUSA Pharmaceuticals
• Hanna Biosciences
– Research funding:
• Glaxo-Smith-Kline
• I will discuss many off-label uses of
drugs
Objectives of my Presentation
• Be familiar with:
– hematologic aspects of DS in neonatal period
– Differential diagnosis of cancers in DS in infancy
– This talk has been truncated for the purposes of
focusing on a neonatal specific topic by Dr Phillip
Gordon (with the author’s permission)
Summary of my Presentation:
Individuals with DS…
• are 10-20 times more likely to develop leukemia
than those without DS, and less likely to develop
solid tumors
• have a 1 in 10 risk of transient myeloproliferative
disorder (TMD), a form of self-limited leukemia,
during infancy
• have better outcomes for childhood AML than
non-DS children, despite less intensive treatment
• have similar outcomes for childhood ALL as nonDS children, despite more severe toxicities, after
accounting for differing biologic features
Down Syndrome is caused
by Trisomy 21
1866: Langdon Down
describes the clinical
features of Down syndrome
1959: Jerome Lejeune
describes trisomy 21 in
association with DS
Leukemias are more
common in Down Syndrome
1845: Rudolph Virchow,
the “Father of Pathology,”
describes leukemia
(“white blood”)
1957: Krivit & Good recognize
association of DS & leukemia
Leukemias are more
common in Down Syndrome
 Incidence of leukemia in DS is 1 in 200-300
 10-20 fold higher incidence than in non-DS subjects
 Myeloid leukemias are overrepresented in DS:
 Ratio of ALL : AML
 non-DS:
4:1
 DS:
1:1
 46-fold excess incidence of myeloid diseases in DS
 This increased risk does not extend into adulthood
Robison, J Peds 105:235, 1984; Gurbuxani, Blood 103:399,2004
Solid tumors are less
common in Down Syndrome
 Incidence of solid tumors
in DS is 50% lower than
expected vs. non-DS
population
 Lower incidence of solid
tumors (except for
testicular cancers) occurs
in both children and adults
with DS
Hasle, Lancet 355:165, 2000; Yang, Lancet 359:1019, 2002
Why are solid tumors
less common in DS?
 Tumors establish a blood supply by
secreting pro- angiogenic factors (VEGF, etc)
 Endostatin is an endogenously occurring
inhibitor of angiogenesis whose gene maps
to chromosome 21
 Increased endostatin levels may protect
against cancer (-> therapeutic applications?)
 DS subjects have significantly higher serum
levels of endostatin than controls (39 vs 20
ng/mL; p<0.0001)
 Thus, increased serum endostatin levels may
protect against development of solid tumors
in DS subjects
Zorick, Eur J Hum Genet 9:811, 2001
Why are solid tumors
less common in DS?
 Ts65Dn mice, trisomic for ~100 Hsa21
gene orthologues, recapitulate DS.
 Mice carrying the ApcMin mutation
recapitulate familial adenomatous
polyposis (FAP), predisposing them to
intestinal tumors.
 Crossing of these 2 strains leads to a
significant reduction in size and incidence
of intestinal tumors.
Sussan et al , Nature 451:73, 2008
Multiple Types of Leukemia
Are Increased in DS
1. Acute lymphoblastic leukemia (ALL)
2. Acute myeloid leukemia (AML)
3. Transient myeloproliferative disorder
(TMD) (also transient leukemia or TL)
Gurbuxani et al, Blood 103:399, 2004
Multiple Types of Leukemia
Are Increased in DS
1. Acute lymphoblastic leukemia (ALL)
2. Acute myeloid leukemia (AML)
3. Transient myeloproliferative disorder
(TMD) (also transient leukemia or TL)
Gurbuxani et al, Blood 103:399, 2004
Case Presentation #1
 Hx: 32 week EGA female infant born by C-S
 Known DS due to elevated maternal AFP
 Day 2: WBC 30,000 (1% blasts)
 Day 3: WBC 50,000 (8% blasts)
 Peripheral blood flow cytometry: AML
 Management: aggressive observation
 Day 15: WBC 20,000 (2% blasts)
 Day 55: normal CBC
Transient Myeloproliferative
Disorder is Unique to DS
 What is TMD?
 accumulation of immature blasts in
peripheral blood, liver and BM of
DS infants
 usually presents by 3 weeks of age
 typically spontaneously regresses
by 2-3 months
 at least 10% of DS infants have
TMD; many mildly affected patients
likely go undetected
Lange, BJH 110:512, 2000; Gurbuxani, Blood 103:399, 2004
Hematologic Abnormalities
are Common in DS Neonates
 In 157 DS infants < 1 wk old with CBCs:
 neutrophilia
80%
 thrombocytopenia < 50K
 polycythemia
 peripheral blasts
6%
33%
6%
 anemia, thrombocytosis, or neutropenia
<1% each
Henry et al, Am J Med Genet 143A:42, 2007
Is TMD really leukemia?
YES
NO
1. TMD blasts are
1. TMD blasts often
morphologically
spontaneously regress
indistinguishable
without treatment
from acute megakaryocytic
leukemia (AMKL)
2. TMD blasts are clonal
3. TMD blasts can have
acquired cytogenetic
alterations
Lange, BJH 110:512, 2000; Gurbuxani, Blood 103:399, 2004
Complications of TMD
 Hepatic dysfunction due to infiltration by blasts
 Hepatic fibrosis
 Hyperleukocytosis (markedly high WBC count)
 Respiratory insufficiency due to hyperleukocytosis or
hepatic enlargement
 Renal failure due to infiltration of blasts
 Hydrops fetalis
Lange, BJH 110:512, 2000
Management of TMD
 Goals of management of TMD:
 address complications
 minimize therapy-related toxicities
 Management strategies:
 hyperleukocytosis: exchange transfusion or leukopheresis
 hepatic dysfunction: low-dose chemotherapy (Ara-C)
Lange, BJH 110:512, 2000
Natural History of TMD in DS:
POG 9481
 Eligibility criteria:
 trisomy 21 < 3 mo age with blasts in PB, BM or liver
 Results (n = 48):
 average age at diagnosis: 7 days
 74% had trisomy 21 as sole cytogenetic abnormality
 89% spontaneously cleared blasts
 74% normalized blood counts
 17% suffered early death:
 risk factors: high WBC, hepatic dysfunction
 19% subsequently developed AMKL @ mean age 20 mo.
 risk factor: additional cytogenetic abnormalities
Massey et al, Blood 107:4606, 2006
Genetic Etiology of Myeloid
Diseases in Down Syndrome
 GATA1: a transcription factor which regulates control of
normal hematopoesis
 mutations in GATA1 found exclusively in TMD, DS-AMKL
www.einstein.yu.edu/GRAFLAB/graffactors.html; Wechsler et al, Nat Genet 32:148, 2002
Genetic Etiology of AML in
Down Syndrome
 GATA1 mutations found in 2 / 21 (10%) neonatal blood
spots from randomly selected healthy DS newborns
 Proposed model for GATA1 in DS leukemogenesis:
2nd mutation
2nd mutation
+ 2nd mutation
Vyas, Hemtol J, 4:210a, 2003; Vyas, Early Child Devel, 82:767,2006
Acute Myeloid Leukemia in
Down Syndrome
 ~30% of TMD patients develop
AML within 3 yrs; most of these
are AMKL
 ~50% of AML in DS is AMKL
(vs. <5% in non-DS)
 most AML in DS children < 4 years
is AMKL
 most AML in DS children > 4 years
is not AMKL
Crispino, Ped Blood Cancer 44:40, 2005; Hasle et al, Leukemia 22:1428, 2008
Age Influences Prognosis in
DS-AML: CCG-2891
Gamis et al , JCO 21:3415, 2003
Children with DS-AML have
Favorable Outcomes with Standard
Therapy: POG 8498
 4-yr EFS: 100% vs 28%
Ravindranath et al, Blood 80:2210, 1992
Children with DS-AML Maintain
Excellent Outcomes with Reduced
Intensity Therapy: COG A5971
 3-yr EFS: 79% (A5971) vs. 77% (2891)
1
A2971 (n=129)
Event-free survival
0.75
2891 (n=161)
0.5
0.25
p=0.688
0
0
5
10
15
Years from study entry
Courtesy of Alan Gamis, MD
Summary:
Myeloid Disease in DS
• Children with DS have a ~50-fold increase in
myeloid diseases compared to non-DS children
• Transient Myeloproliferative Disorder (TMD):
–
–
–
–
–
occurs in 10% of children with DS
most cases spontaneously resolve
high WBC or hepatic dysfunction predict a poor outcome
predisposes to later development of AMKL (30%)
is due to an acquired mutation in GATA1
• Acute Megakaryocytic Leukemia:
– is the most common AML subtype in DS
– occurs primarily in patients < 4 years of age
– has an excellent outcome with reduced therapy in DS
• DS-AML in pts > 4 yrs behaves more like NDS-AML