Pediatr Blood Cancer 2011;57:1–3

HIGHLIGHTby Jeffrey W. Taub, MD

1,2,3* and Yaddanapudi Ravindranath, MBBS1,2,3

What’s Up With Down Syndrome and Leukemia-A Lot!(Commentary on Taga et al., page 36)

J ust over 50 years ago, Lejeune et al. [1] identified that the

underlying genetic abnormality in Down syndrome (DS) was

the presence of three copies of chromosome 21 (trisomy 21). Since

than, many of the landmark studies that have identified various

clinical and biological features of DS relate to the patterns of

malignancies in individuals with DS. Children with DS represent

approximately 3% and 15% of pediatric acute lymphoblastic

leukemia (ALL) and acute myeloid leukemia (AML) cases,

respectively [2,3]. In contrast, there is a paradoxical lower

incidence of solid tumors in DS individuals [4,5], leading to the

identification of several chromosome 21-localized genes which

appear to play a protective role in preventing the development of

tumors including genes linked to angiogenesis [e.g., ADAMTS1;

ERG; Down syndrome candidate region 1 (DSCR1)] and

transcription factors [e.g., ETS2] [6–8].

Beginning in the late 1980’s, Dr. Alvin Zipursky highlighted

several of the unique features of myeloid malignancies in children

with DS, including: (i) the remarkably high predisposition to

develop acute megakaryocytic leukemia (AMkL), which is

estimated to be 500-fold greater compared to children without DS

and (ii) an estimation that up to 10% of neonates with DS are born

with the transient myeloproliferative disorder (TMD), a precursor to

AMkL, which can resolve spontaneously in a high proportion of

cases with supportive care [9–11]. Children with DS and TMD have

an approximate 30% risk of developing myeloid malignancies

characterized by either myelodysplasia or AMkL, which are

frequently referred collectively as myeloid leukemias of DS.

In 1992, the Pediatric Oncology Group (POG) reported an

unexpected and remarkable finding that 12 children with DS and

AML had event-free survival (EFS) rates of 100% compared to 28%

for a group of children without DS treated in a similar fashion on the

POG 8498 clinical trial [12]. Since this initial report, multiple

clinical trials reported by POG, the Children’s Cancer Group

(CCG), Children’s Oncology Group (COG), Berlin-Frankfort-

Munster (BFM)-AML, Nordic Society of Pediatric Hematology/

Oncology (NOPHO), Medical Research Council (MRC), Hospital

for Sick Children (Toronto), France, and Japanese Childhood AML

cooperative groups have confirmed that children with DS and

myeloid leukemias typically have EFS rates of approximately 80%

associated with low relapse/induction failure rates [3,13–20].

In this issue of Pediatric Blood & Cancer, the results of the

Japanese Children’s Cancer and Leukemia Study Group AML 9805

study which enrolled 24 patients with DS were reported. Although

the number of patients enrolled on the trial was less than other

reported studies, it still serves to highlight several important issues

for clinicians treating children with DS. All of the patients were

younger than 4 years of age (95% of DS AML cases occur before

the age of 4 years [3]), 7 (29%) patients had a past history of TMD

and all of the patients were classified as having AMkL. Twenty-one

patients achieved complete remission, while three patients died

of infectious complications during induction. Post-induction

therapy, there were no deaths from toxicity and only one patient

suffered an off therapy extramedullary relapse. All four patients

with monosomy 7 remained in remission. The 5-year overall and

EFS were 87.5%� 6.8% and 83.1%� 7.7%, respectively.

One of the challenges faced in treating children with DS and

leukemia is balancing curative therapy against potential toxicities,

which are typically infectious complications secondary to myelo-

suppression and potential cardiac toxicity against a background of

individuals who have a high incidence of congenital heart defects. In

the POG 8498 study, the cumulative cytarabine dose used was

40,700 mg/m2; in the current COG AAML0431 clinical trial AAML

0431 ‘‘The Treatment of Down Syndrome Children with Acute

Myeloid Leukemia and Myelodysplastic Syndrome Under the Age

of 4 Years,’’ the cumulative cytarabine dose is 27,800 mg/m2 and in

this Japanese study, 12,600 mg/m2. What is the minimum effective

cytarabine dose schedule in DS AMkL cases? A recent study from

France reported that the results with the ultra low dose schedule as

originally proposed by Zipursky et al. was less effective than a

combination of standard 100–200 mg/m2/dose� 7 days course

during induction and high dose cytarabine (�500 mg/m2/dose� 4–

12) in consolidation [10,20]. The current study from Japan suggests

that cytarabine doses of 1 g/m2/dose� 10 doses for consolidation

may be as effective as regimens using higher cytarabine dose

schedules and may be associated with less toxicity. Biological

studies, including minimal residual disease detection, may identify

subsets of patients with DS and AML who could be treated with low

dose cytarabine regimens.

Increased cardiac toxicity has been reported in prior studies

including a 17.5% incidence and three deaths from heart failure in

patients with DS treated on the POG 9421 AML trial, which used

daunorubicin and mitoxantrone with a combined cumulative

anthracycline dose of 535 mg/m2 (based on a conversion factor of

5:1 for mitoxantrone) [14]. In the current Japanese study, nine

patients had congenital heart defects and no severe cardiac toxicity

� 2011 Wiley-Liss, Inc.DOI 10.1002/pbc.23033Published online 7 April 2011 in Wiley Online Library(wileyonlinelibrary.com).

——————1Division of Pediatric Hematology/Oncology, Children’s Hospital of

Michigan, Michigan; 2Developmental Therapeutics Program, Barbara

Ann Karmanos Cancer Institute, Michigan; 3Departments of

Pediatrics, Wayne State University School of Medicine, Detroit,

Michigan

*Correspondence to: Jeffrey W Taub, Division of Hematology/

Oncology, Children’s Hospital of Michigan, Department of

Pediatrics, Wayne State University School of Medicine, 3901

Beaubien Blvd., Detroit, Michigan 48201, USA.

E-mail: jtaub@med.wayne.edu

Received 20 December 2010; Accepted 20 December 2010

was reported with the use of a lower cumulative anthracycline dose,

highlighting the importance of limiting anthracycline dosing.

Identifying factors associated with DS leukemogenesis accel-

erated significantly following the identification in 2002 by Wechsler

et al. [21] that somatic mutations in the chromosome X-linked

hematopoietic factor, GATA1, were present in DS AMkL cases.

Subsequent studies identified that GATA1 mutations are specific and

have been detected almost uniformly in all DS AMkL and TMD

cases and not detected in remission DS marrows, non-DS AML

cases nor DS ALL cases [22–24]. The mutations include deletions,

missense, non-sense, and splice site mutations at the exon 2/intron

boundary with the net effect of introducing early stop codons and the

synthesis of a shorter 40-kDa GATA1 protein, designated GATA1s,

that is translated from a downstream initiation site and distinguish-

able from the full-length 50-kDa GATA1 protein. The GATA1s

protein has altered transactivation activity, likely contributing to the

uncontrolled proliferation of megakaryocytes. The acquisition of

GATA1 mutations are likely early steps in a multistep process of

leukemogenesis and arise prenatally based on several studies

including their detection in fetal tissues, and retrospective detection

in Guthrie newborn screening cards from infants with DS who later

developed AMkL [25,26]. Trisomy 21 likely contributes to the

development of GATA1 mutations in DS potentially due to a gene

dosage effect of several chromosome 21-localized genes including

cystathionine-b-synthase (CBS), and zinc-copper superoxide dis-

mutase (SOD1) which are linked to abnormal intracellular folate

metabolism, uracil accumulation and increased oxidative stress

leading to DNA damage [27]. Although GATA1 analysis was not

performed in the current study, the mutations are specific for the DS

AMkL phenotype and would likely have been detected.

The basis for the high EFS rates in patients with DS and AML,

and in particular, individuals with AMkL, is likely due to increased

sensitivity of blasts to several drugs including cytarabine,

daunorubicin, and etoposide [28–30]. Overexpression of CBS has

been correlated with in vitro generation of ara-CTP, the active

intracellular cytarabine metabolite, and subsequent increased

cytarabine sensitivity in DS AMkL blast cells [29,31]. The presence

of GATA1 mutations and the generation of GATA1s, interacts and

modulates the expression of different genes, such as the cytidine

deaminase gene which would also enhance the activity of cytarabine

in DS blast cells [32,33]. Differential expression of additional genes

including GATA1 target genes between DS and non-DS blast cells,

also likely contributes to the high EFS rates of DS cases [34,35]. DS

AMkL blast cells exhibit high expression of CD36, a megakar-

yocyte maturation marker [36]. Interestingly, non-DS AMkL blasts

with high expression of CD 36 demonstrated a similar pattern of

in vitro drug sensitivity as DS cases which may identify a select

subset of non-DS AMkL cases with a better prognosis compared to

the typical poor overall outcome for AMkL in children without

DS [37].

Until recently, studies examining the biology of DS ALL have

lagged behind the progress in understanding the biology of DS

myeloid leukemias. DS ALL cases are now recognized to be

distinctly different compared to ALL in children without DS

including: (i) a lower frequency of ETV6/RUNX1 translocations

and hyperdiploidy with trisomies of chromosomes 4 and 10 [2],

(ii) acquired gain-of-function mutations in the Janus kinase 2

(JAK2; localized to chromosome 9p24) are present in approximately

20% of DS ALL cases [38–40], and (iii) increased expression of the

cytokine receptor-like factor 2 CRLF2 gene in approximately 50%

of cases via interstitial deletions creating the chimeric P2RY8-

CRLF2 transcript [38,41].

Although much progress has been made in understanding the

unique clinical and biological features of acute leukemias in

children with DS, considerable challenges lay ahead in ultimately

identifying the specific relationship of chromosome 21 and

leukemogenesis, explaining the relationship between TMD and

progression in a subset of patients to myeloid malignancies,

reducing the toxicity of treatments and learning whether lessons

from DS can be applied to improve our understanding of leukemia

biology in children without DS.

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